2024-03-28T18:58:23Zhttps://thescholarship.ecu.edu/oai/requestoai:TheScholarship.intra.ecu.edu:10342/123922023-03-03T08:16:29Zcom_10342_74com_10342_73col_10342_527
Garrigues, Ryan J.
Thomas, Sheila
Garcia, Brandon L.
Leong, John M.
2023-03-02T18:38:14Z
2023-03-02T18:38:14Z
2022-09-29
0021-9258
http://hdl.handle.net/10342/12392
10.1016/j.jbc.2022.102557
en_US
Lyme disease
molecular switch
protease C1s
Outer Surface Lipoproteins from the Lyme Sisease Spirochete Exploit the Molecular Switch Mechanism of the Complement Protease C1s
Article
Journal of Biological Chemistry
298
11
oai:TheScholarship.intra.ecu.edu:10342/32642021-03-03T20:55:28Zcom_10342_74com_10342_73col_10342_527
Dyson, Ossie F.
Oxendine, Telisha L.
Hamden, Khalief E.
Ford, Patrick W.
Akula, Shaw M.
2011-02-28T21:12:36Z
2011-05-17T01:40:10Z
2011-02-28T21:12:36Z
2011-05-17T01:40:10Z
2008-07
Cellular Microbiology; 10:7 p. 1546-1558
http://hdl.handle.net/10342/3264
PMC2614929
10.1111/j.1462-5822.2008.01149.x
Kaposi’s sarcoma-associated herpesvirus (KSHV) has two modes replication: latent and lytic replication. Reactivation from latency is dictated, in part, by the cell cycle. Herein, we have attempted to delineate the importance of cell cycle in KSHV pathogenesis by exploring the expression pattern of cell surface receptors during different phases of the cell cycle. αV integrin expression is augmented
during S phase in fibroblasts, epithelial, and KSHV infected cells. Using a Matrigel system, we pioneer the concept that KSHV infected primary effusion lymphoma (PEL) cells can attach to extracellular matrix proteins. This attachment is mediated primarily via αV integrins or virally encoded gB, and occurs preferentially in cells from S phase or cells from S phase actively supporting a lytic infection, respectively. Such an ability of infected B cells to attach to endothelial cells may
also aid in the dissemination of infection. The keystone of this work is that for the first time, we describe the ability of KSHV infected B cells to preferentially use cellular (αV) or viral (gB) receptors to specifically bind cells, depending upon the stage of the cell cycle and infection. Originally published Cellular Microbiology, Vol. 10, No. 7, July 2008
en_US
East Carolina University
http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2008.01149.x/abstract
Author notified of opt-out rights by Cammie Jennings.
KSHV
HHV-8
Cellular attachment
GB
Alpha-V
Integrins
Matrigel
Reactivation
Differential regulation of the attachment of KSHV infected human B cells to ECM by KSHV encoded gB and cellular alpha-V integrins
Article
Cellular Microbiology
10
7
1546-1558
oai:TheScholarship.intra.ecu.edu:10342/117342022-11-12T08:16:11Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
Martelli, Alberto M.
Paganelli, Francesca
Evangelisti, Camilla
Chiarini, Francesca
2022-11-11T13:28:40Z
2022-11-11T13:28:40Z
2022-05-31
2073-4409
http://hdl.handle.net/10342/11734
10.3390/cells11111812
en_US
chronic hematological malignancies
GSK-3
targeted therapy
Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies
Article
Cells
11
11
oai:TheScholarship.intra.ecu.edu:10342/95902022-02-01T08:15:46Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:21:32Z
2022-01-31T19:21:32Z
2019-07
0021-9541
http://hdl.handle.net/10342/9590
10.1002/jcp.27768
en_US
AKT2�mediated motility
cancer prostate cells
Clusterin (CLU)
Clusterin Enhances AKT2-mediated Motility of Normal and Cancer Prostate Cells Through a PTEN and PHLPP1 Circuit
Article
Journal of Cellular Physiology
234
7
11188-11199
oai:TheScholarship.intra.ecu.edu:10342/95862022-02-01T08:15:47Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:20:54Z
2022-01-31T19:20:54Z
2020-11
0892-6638
http://hdl.handle.net/10342/9586
10.1096/fj.202000933RR
en_US
deferasirox
inositides
reactive oxygen species
Phospholipase C Beta1 (PI-PLCbeta1)/Cyclin D3/protein Kinase C (PKC) Alpha Signaling Modulation During Iron-Induced Oxidative Stress in Myelodysplastic Syndromes (MDS)
Article
FASEB Journal
34
11
15400-15416
oai:TheScholarship.intra.ecu.edu:10342/55762021-03-03T21:07:03Zcom_10342_74com_10342_73col_10342_527
Candido, Saverio
Rapisarda, Venerando
Marconi, Andrea
Malaponte, Graziella
Bevelacqua, Valentina
Gangemi, Pietro
Scalisi, Aurora
McCubrey, James A.
Maestro, Roberta
Spandidos, Demetrios A.
Fenga, Concettina
Libra, Massimo
2016-06-14T13:42:09Z
2016-06-14T13:42:09Z
2014-03
Oncology Reports; 31:3 p. 1079-1082
1021-335X
http://hdl.handle.net/10342/5576
pmc3926654
10.3892/or.2014.2977
Sun-exposure is one of the risk factors associated with the development of a cutaneous neoplasm. In melanoma, the Ras-Raf-MEK-ERK (MAPK) signaling pathway is constitutively activated through multiple mechanisms, including B-RAF mutation. It has been hypothesized that B-RAF mutations in melanocytic lesions arise from DNA damage induced by ultraviolet (UV) radiation. However, it is still discussed if B-RAF mutations are associated with melanoma patients exposed to the sun. Therefore, in the present study, the known B-RAFV600E mutation was analysed in melanoma samples from 30 indoor and 38 outdoor workers. B-RAFV600E mutation was detected in 52 and 73% of outdoor workers and indoor workers, respectively. Of note, this mutation was identified in 12 of 14 (85%) melanoma of the trunk diagnosed in indoor workers and in 9 of 19 (47%) samples from outdoor workers (p=0.03). By analyzing melanomas of other body sites, no statistical difference in the frequency of B-RAFV600E mutation was identified between the groups of workers. It appears that the mutation detected among indoor workers may be associated with a recreational or intermittent exposure to the sun, as usually the trunk is a sun-protected body site. Overall, these data indicate that the B-RAFV600E mutation detected in melanoma is not associated with a chronic exposure to the sun. Mutations detected in other genes may also contribute to melanoma development in the subset of patients exposed to UV radiation.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926654/
occupational sun exposure
melanoma
B-RAFV600E mutations
Analysis of the mutation in cutaneous melanoma patients with occupational sun exposure
Article
Oncology Reports
31
3
1079-1082
oai:TheScholarship.intra.ecu.edu:10342/34332021-03-03T20:53:49Zcom_10342_74com_10342_73col_10342_527
Young, Kelly R.
Teal, Benjamin E.
Brooks, Yvonne
Green, Thomas D.
Bower, Joseph F.
Ross, Ted M.
2011-04-28T19:26:56Z
2011-05-17T01:40:09Z
2011-04-28T19:26:56Z
2011-05-17T01:40:09Z
2004-11
AIDS Research and Human Retroviruses; 20:11 p. 1259-1268
http://hdl.handle.net/10342/3433
PMC1550980
DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies. In this
study, DNA vaccines were constructed to express the gp120 subunit of Env from the isolate HIV-1R2 using both wild-type and codon- ptimized gene sequences. Three copies of the murine C3d were added to the carboxyl terminus to enhance the immunogenicity of the expressed fusion protein. Mice (BALB/c) vaccinated with DNA plasmid expressing the gp120R2 using codon-optimized Env sequences elicited high-titer anti-Env antibodies regardless of conjugation to C3d. In contrast, only
mice vaccinated with DNA using wild-type gp120R2 sequences fused to mC3d3, had detectable anti- Env antibodies. Interestingly, mice vaccinated with DNA expressing gp120R2 from codon-optimized
sequences elicited antibodies that neutralized both homologous and heterologous HIV-1 isolates. To determine if the unique sequence found in the crown of the V3 loop of the EnvR2 was responsible
for the elicitation of the cross-clade neutralizing antibodies, the codons encoding for the Pro-Met (amino acids 313–314) were introduced into the sequences encoding the gp120ADA (R5) or gp12089.6 (R5X4). Mice vaccinated with gp120ADA–mC3d3–DNA with the Pro–Met mutation had antibodies that neutralized HIV-1 infection, but not the gp12089.6–mC3d3–DNA. Therefore, the use of the unique sequences in the EnvR2 introduced into an R5 tropic envelope, in conjunction with C3d fusion, was effective at broadening the number of viruses that could be neutralized. However, the introduction of this same sequence into an R5X4-tropic envelope was ineffective in eliciting improved cross-clade neutralizing antibodies. Originally published AIDS Research and Human Retroviruses, Vol. 20, No. 11, Nov 2004
en_US
East Carolina University
http://www.liebertonline.com/doi/abs/10.1089/aid.2004.20.1259
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
HIV (Viruses)
Neutralizing antibodies
V3 loop sequence
Unique V3 Loop Sequence Derived from the R2 Strain of HIV-Type 1 Elicits Broad Neutralizing Antibodies
Article
oai:TheScholarship.intra.ecu.edu:10342/32762021-03-03T20:54:19Zcom_10342_74com_10342_73col_10342_527
Fooksman, David Robert
Shaikh, Saame Raza
Boyle, Sarah
Edidin, Michael
2011-03-02T15:32:51Z
2011-05-17T01:40:06Z
2011-03-02T15:32:51Z
2011-05-17T01:40:06Z
2009-05-01
Journal of Immunology; 182:9 p. 5179-5182
http://hdl.handle.net/10342/3276
PMC2799928
Little is known about the signaling that occurs in an antigen presenting cell (APC) during contact with a T cell. Here we report the concentration of the signaling lipid, PI(4,5)P2, at the APC side of the immunological synapse. In both human and mouse cells, a PI(4,5)P2-specific fluorescent reporter, PH-GFP, detected an antigen-dependent enrichment of PI(4,5)P2 at the synapse between antigen- specific T cells and APC. When PIP(4,5)P2 was sequestered by a high concentration of PH-GFP reporter, cells were less susceptible to CTL-mediated lysis than control cells. These findings suggest a new regulatory target for modulating immune function that may be exploited for immune escape by pathogens and tumors. Originally published Journal of Immunology, Vol. 182, No. 9, May 2009
en_US
East Carolina University
http://www.jimmunol.org/content/182/9/5179.long
Author notified of opt-out rights by Cammie Jennings.
Cytotoxicity
T cells cytotoxic
MHC
Antigen Presentation
PI(4,5)P2 concentration at the APC side of the Immunological Synapse is Required for Effector T cell Function
Article
oai:TheScholarship.intra.ecu.edu:10342/29782021-03-03T20:53:27Zcom_10342_74com_10342_73col_10342_527
Gee, Jason M.
Valderas, Michelle
Kovach, Michael E.
Grippe, Vanessa
Robertson, Gregory
Ng, Wai-Leung
Richardson, John
Winkler, Malcolm
Roop, Martin II
2010-11-08T16:38:59Z
2011-05-17T01:39:57Z
2010-11-08T16:38:59Z
2011-05-17T01:39:57Z
2005-05
Infection and Immunity; 73:5 p. 2873-2880
http://hdl.handle.net/10342/2978
PMC1087332
10.1128/IAI.73.5.2873-2880.2005
Two-dimensional gel electrophoretic analysis of cell lysates from Brucella abortus 2308 and the isogenic hfq mutant Hfq3 revealed that the RNA binding protein Hfq (also known as host factor I or HF-I) is required for the optimal stationary phase production of the periplasmic Cu,Zn superoxide dismutase SodC. An isogenic sodC mutant, designated MEK2, was constructed from B. abortus 2308 by gene replacement, and the sodC mutant exhibited much greater susceptibility to killing by O2 generated by pyrogallol and the xanthine oxidase reaction than the parental 2308 strain supporting a role for SodC in protecting this bacterium from O2 of exogenous origin. The B. abortus sodC mutant was also found to be much more sensitive to killing by cultured resident peritoneal macrophages from C57BL6J mice than 2308, and the attenuation displayed by MEK2 in cultured murine macrophages was enhanced when these phagocytes were treated with gamma interferon (IFN- ). The attenuation displayed by the B. abortus sodC mutant in both resting and IFN- - activated macrophages was alleviated, however, when these host cells were treated with the NADPH oxidase inhibitor apocynin. Consistent with its increased susceptibility to killing by cultured murine macrophages, the B. abortus sodC mutant also displayed significant attenuation in experimentally infected C57BL6J mice compared to the parental strain. These experimental findings indicate that SodC protects B. abortus 2308 from the respiratory burst of host macrophages. They also suggest that reduced SodC levels may contribute to the attenuation displayed by the B. abortus hfq mutant Hfq3 in the mouse model. Originally published in Infection and Immunity Vol. 73, No. 5.
en_US
East Carolina University
http://iai.asm.org/content/vol73/issue5/index.dtl
Author notified of opt-out rights by Kent Nixon Myers prior to upload of this article.
Brucella abortus
RNA binding protein
Isogenic mutants
The Brucella abortus Cu,Zn Superoxide Dismutase Is Required for Optimal Resistance to Oxidative Killing by Murine Macrophages and Wild-Type Virulence in Experimentally Infected Mice
Article
Infection and Immunity
73
5
2873-2880
oai:TheScholarship.intra.ecu.edu:10342/56572021-03-03T21:06:26Zcom_10342_74com_10342_73col_10342_527
Ding, Yong
Ndamukong, Ivan
Xu, Zaoshi
Lapko, Hanna
Fromm, Michael
Avramova, Zoya
2016-06-16T17:20:12Z
2016-06-16T17:20:12Z
2012-12
PLoS Genetics; 8:12 p. 1-12
1553-7390
http://hdl.handle.net/10342/5657
pmc3527332
10.1371/journal.pgen.1003111
Tri-methylated H3 lysine 4 (H3K4me3) is associated with transcriptionally active genes, but its function in the transcription process is still unclear. Point mutations in the catalytic domain of ATX1 (ARABIDOPSIS TRITHORAX1), a H3K4 methyltransferase, and RNAi knockdowns of subunits of the AtCOMPASS–like (Arabidopsis Complex Proteins Associated with Set) were used to address this question. We demonstrate that both ATX1 and AtCOMPASS–like are required for high level accumulation of TBP (TATA-binding protein) and Pol II at promoters and that this requirement is independent of the catalytic histone modifying activity. However, the catalytic function is critically required for transcription as H3K4me3 levels determine the efficiency of transcription elongation. The roles of H3K4me3, ATX1, and AtCOMPASS–like may be of a general relevance for transcription of Trithorax-activated eukaryotic genes.
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003111
ATX1-Generated H3K4me3 Is Required for Efficient Elongation of Transcription, Not Initiation, at ATX1-Regulated Genes
Article
PLoS Genetics
8
12
1-12
oai:TheScholarship.intra.ecu.edu:10342/30952021-03-03T20:54:02Zcom_10342_74com_10342_73col_10342_527
Smith, C. Jeffrey
Parker, Anita C.
2011-01-21T22:02:48Z
2011-05-17T01:40:01Z
2011-01-21T22:02:48Z
2011-05-17T01:40:01Z
1993-05
Journal of Bacteriology; 175:9 p. 2682-2691
http://hdl.handle.net/10342/3095
PMC204571
Transmissible cefoxitin (FX) resistance in Bacteroides vulgatus CLA341 was associated with the 12.5-kb,
mobilizable transposon, Tn4555, which encoded the 13-lactamase gene cfxA. Transfer occurred by a
conjugation-like mechanism, was stimulated by growth of donor cells with tetracycline (TC), and required the
presence of a Bacteroides chromosomal Tcr element. Transconijugants resistant to either FX, TC, or both drugs
were obtained, but only Fx Tcr isolates could act as donors of Fxr in subsequent matings. Transfer of Fxr could
be restored in FxF Tc' strains by the introduction of a conjugal Tcr element from Bacteroidesfragilis V479-1.
A covalently closed circular DNA form of Tn4555 was observed in donor cells by Southern hybridization, and
the levels of this circular transposon increased significantly in cells grown with TC. Both the cfxA gene and the
Tn4555 mobilization region hybridized to the circular DNA, suggesting that this was a structurally intact
transposon unit. Circular transposon DNA purified by CsCI-ethidium bromide density gradient centrifugation
was used to transform Tcs B. fragilis 638, and FXr transformants were obtained. Both the circular form and
the integrated Tn4555 were observed in transformants, but the circular form was present at less than one copy
per chromosomal equivalent. Examination of genomic DNA from Fxr transformants and transconjugants
revealed that Tn4555 could insert at a wide variety of chromosomal sites. Multiple transposon insertions were
present in many of the transconjugants, indicating that there was no specific barrier to the introduction of a second transposon copy. Originally published Journal of Bacteriology, Vol. 175, No. 9, May 1993
en_US
East Carolina University
http://jb.asm.org/archive/1993.dtl
Tn4555
Mobilizable transposon
Circular DNA
Identification of a circular intermediate in the transfer and transposition of Tn4555, a mobilizable transposon from Bacteroides spp.
Article
Journal of Bacteriology
175
9
2682-2691
oai:TheScholarship.intra.ecu.edu:10342/34322021-03-03T20:54:15Zcom_10342_74com_10342_73col_10342_527
Wagstaff, Patricia
Kang, Ho Young
Mylott, Dawn
Robbins, Penni J.
White, Martyn K.
2011-04-28T19:25:54Z
2011-05-17T01:40:11Z
2011-04-28T19:25:54Z
2011-05-17T01:40:11Z
1995-11
Molecular Biology of the Cell; 6:11 p. 1575-1589
http://hdl.handle.net/10342/3432
PMC301312
10.1091/mbc.6.11.1575
Vertebrate cells that are transformed by oncogenes such as v-src or are stimulated by mitogens have increased rates of glucose uptake. In rodent cels, the mechanisms whereby glucose transport is up-regulated are well understood. Stimulation of glucose transport involves an elevation in mRNA encoding the GLUT1 glucose transporter that is controlled at the levels of both transcription and mRNA stability. Cloning and sequencing of chicken GLUT1 cDNA showed that it shares 95% amino acid sequence similarity to mammalian GLUTls. Nevertheless, unlike mammalian GLUT1 mRNA, it was not induced by v-src, serum addition, or treatment with the tumor promoter 12-0-tetradecanoylphorbol 13-acetate in chicken embryo fibroblasts. Rather, the induction of glucose transport in chicken embryo fibroblasts by v-src, serum, and 12-0- tetradecanoylphorbol13-acetate was associated with induction of GLUT3 mRNA level and GLUT3 transcription. Rat fibroblasts were also found to express both GLUT1 and GLUT3 isoforms, but v-src induced GLUT1 and not GLUT3. This suggests that animal cels require both a basal and an upregulatable glucose transporter and that these functions have been subsumed by different GLUT isoforms in avian and mammalian cels. Originally published Molecular Biology of the Cell, Vol. 6, No. 11, Nov 1995
en_US
East Carolina University
http://www.molbiolcell.org/
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Glucose transporter
Chicken fibroblasts
Differential regulation
Characterization of the avian GLUT1 glucose transporter: differential regulation of GLUT1 and GLUT3 in chicken embryo fibroblasts.
Article
Molecular Biology of the Cell
6
11
1575-1589
oai:TheScholarship.intra.ecu.edu:10342/33162021-03-03T20:54:13Zcom_10342_74com_10342_73col_10342_527
Khan, Sharik R.
Gaines, Jennifer M.
Roop, R. Martin II
Farrand, Stephen K.
2011-04-13T20:54:59Z
2011-05-17T01:40:08Z
2011-04-13T20:54:59Z
2011-05-17T01:40:08Z
2008-08
Applied and Environmental Microbiology; 74:16 p. 5053-5062
http://hdl.handle.net/10342/3316
PMC2519271
10.1128/AEM.01098-08
Experiments requiring strong repression and precise control of cloned genes can be difficult to conduct because of the relatively high basal level of expression of currently employed promoters. We report the construction of a family of vectors that contain a reengineered lacIq-lac promoter-operator complex in which cloned genes are strongly repressed in the absence of inducer. The vectors, all based on the broad-host-range plasmid pBBR1, are mobilizable and stably replicate at moderate copy number in representatives of the alphaand gammaproteobacteria. Each vector contains a versatile multiple cloning site that includes an NdeI site allowing fusion of the cloned gene to the initiation codon of lacZ . In each tested bacterium, a uidA reporter fused to the promoter was not expressed at a detectable level in the absence of induction but was inducible by 10- to 100-fold, depending on the bacterium. The degree of induction was controllable by varying the concentration of inducer. When the vector was tested in Agrobacterium tumefaciens, a cloned copy of the traR gene, the product of which is needed at only a few copies per cell, did not confer activity under noninducing conditions. We used this attribute of very tight and variably regulatable control to assess the relative amounts of TraR required to activate the Ti plasmid conjugative transfer system. We identified levels of induction that gave wild-type transfer frequencies, as well as levels that induced correspondingly lower frequencies of transfer. We also used this system to show that the antiactivator TraM sets the level of intracellular TraR required for tra gene activation. Originally published Applied and Environmental Microbiology, Vol. 74, No. 16, Aug 2008
en_US
East Carolina University
http://aem.asm.org/cgi/content/abstract/74/16/5053
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Cloned genes
Controlled induction
Expression vectors
Broad-Host-Range Expression Vectors with Tightly Regulated Promoters and Their Use To Examine the Influence of TraR and TraM Expression on Ti Plasmid Quorum Sensing
Article
Applied and Environmental Microbiology
74
16
5053-5062
oai:TheScholarship.intra.ecu.edu:10342/33932021-03-03T20:53:47Zcom_10342_74com_10342_73col_10342_527
Sandstrom, Paul A.
Buttke, Thomas M.
2011-04-28T17:29:56Z
2011-05-17T01:40:05Z
2011-04-28T17:29:56Z
2011-05-17T01:40:05Z
1993-05-15
Proceedings of the National Academy of Sciences; 90:10 p. 4708-4712
http://hdl.handle.net/10342/3393
PMC46582
10.1073/pnas.90.10.4708
CCRF-CEM is a human T-cell line originally isolated from a child with acute lymphoblastic leukemia. At cell densities > 2 x 10 cells per ml, CEM cells grow in serum-free medium, but at lower cell densities the cultures rapidly undergo apoptosis, or programmed cell death. The viability of lowdensity CEM cells could be preserved by supplementing the serum-free medium with "conditioned" medium from highdensity CEM cultures, but a variety of known growth factors and lymphokines were ineffective. Fractionation ofconditioned medium by sequential chromatography on DEAE-cellulose, propyl agarose, chromatofocusing, and hydrophobic-interaction HPLC resulted in the isolation of a 60-kDa protein capable of sustaining CEM growth in the absence ofserum. The active protein was identified as human catalase based on its amino acid sequence and composition and was subsequently shown to exhibit catalase activity and to be replaceable by human erythrocyte catalase or bovine liver catalase. Comparison of the level of intracellular catalase activity with the amount released into the culture medium demonstrated that the latter accounted for <3% of the total catalase activity present in the cell culture. These findings show that, despite its low amount, the catalase released by CEM cells, and perhaps by T cells in general, provides a critical rust Ilne of defense against hydrogen peroxide (11202) present in the extracellular milieu. Originally published Proceedings of the National Academy of Sciences, Vol. 90, No. 10, May 1993
en_US
East Carolina University
http://www.pnas.org/content/by/year/1993
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
CEM
Apoptosis
Autocrine production
Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium.
Article
Proceedings of the National Academy of Sciences
90
10
4708-4712
oai:TheScholarship.intra.ecu.edu:10342/32032021-03-03T20:58:10Zcom_10342_74com_10342_73col_10342_527
Bellaire, Bryan H.
Elzer, Philip H.
Hagius, Sue
Walker, Joel
Baldwin, Cynthia L.
Roop, R. Martin II
2011-02-04T19:57:18Z
2011-05-17T01:40:00Z
2011-02-04T19:57:18Z
2011-05-17T01:40:00Z
2003-04
Infection and Immunity; 71:4 p. 1794-1803
http://hdl.handle.net/10342/3203
PMC152065
10.1128/IAI.71.4.1794-1803.2003
Brucella abortus reportedly produces the monocatechol siderophore 2,3-dihydroxybenzoic acid (2,3-DHBA) in response to iron limitation. Nucleotide sequence analysis of the cloned DHBA biosynthesis locus from virulent B. abortus 2308 and genetic complementation of defined Escherichia coli mutants were used to identify the B. abortus genes (designated dhbC, -B, and -A) responsible for synthesis of this siderophore. Reverse transcriptase PCR analysis of total RNA with dhb-specific primers demonstrated that dhbC, -B, and -A are transcribed as components of an operon, together with dhbE, a functional homolog of the Escherichia coli entE gene. Homologs of the E. coli entD and Vibrio cholerae vibH genes were also detected in the flanking regions immediately adjacent to the B. abortus dhbCEBA operon, suggesting that B. abortus has the genetic capacity to produce a more complex 2,3-DHBA-based siderophore. Slot blot hybridization experiments and primer extension analysis showed that transcription of the B. abortus dhbCEBA operon originates from two iron-regulated promoters located upstream of dhbC. Consistent with their iron-dependent regulation, both of the dhbCEBA promoter sequences contain typical consensus Fur-binding motifs. Although previously published studies have shown that 2,3-DHBA production is not required for the establishment and maintenance of chronic spleen infection by B. abortus in mice, experimental infection of pregnant cattle with the B. abortus dhbC mutant BHB1 clearly showed that production of this siderophore is essential for wild-type virulence in the natural ruminant host. Originally published Infection and Immunity, Vol. 71, No. 4, Apr 2003
en_US
East Carolina University
http://iai.asm.org/cgi/content/abstract/71/4/1794
Author notified of opt-out rights by Cammie Jennings
2,3-dihydroxybenzoic acid
Brucella abortus
Iron limitation
Genetic Organization and Iron-Responsive Regulation of the Brucella abortus 2,3-Dihydroxybenzoic Acid Biosynthesis Operon, a Cluster of Genes Required for Wild-Type Virulence in Pregnant Cattle
Article
Infection and Immunity
71
4
1794-1803
oai:TheScholarship.intra.ecu.edu:10342/124362023-03-24T19:24:17Zcom_10342_74com_10342_73col_10342_527
Akula, Shaw M.
Bolin, Paul
Cook, Paul P.
2023-03-24T19:24:17Z
2023-03-24T19:24:17Z
2022
1547-6286
http://hdl.handle.net/10342/12436
10.1080/15476286.2021.2010959
en_US
COVID-19
circulating biomarkers
plasma
Cellular miR-150-5p May Have a Crucial Role to Play in the Biology of SARS-CoV-2 Infection by Regulating nsp10 Gene
Article
RNA Biology
19
1
1-11
oai:TheScholarship.intra.ecu.edu:10342/96172022-02-01T08:15:35Zcom_10342_74com_10342_73col_10342_527
McCubrey, James
2022-01-31T19:26:07Z
2022-01-31T19:26:07Z
2017
http://hdl.handle.net/10342/9617
en_US
hematopoietic cells
apoptotic pathways
chemosensitivity
Targeting Signaling and Apoptotic Pathways Involved in Chemotherapeutic Drug-Resistance of Hematopoietic Cells
Article
Oncotarget
8
44
76525-76557
oai:TheScholarship.intra.ecu.edu:10342/34402021-03-03T20:55:46Zcom_10342_74com_10342_73col_10342_527
Sakalakis, Sotirios
Menke, Jay
Stripp, Barry
Stone, Henry
2011-04-29T13:05:38Z
2011-05-17T01:40:04Z
2011-04-29T13:05:38Z
2011-05-17T01:40:04Z
1992-02
Nucleic Acids Research; 20:3 p. 616
http://hdl.handle.net/10342/3440
PMC310439
en_US
East Carolina University
http://nar.oxfordjournals.org/content/by/year/1992
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Phosphoprotein
Newcastle disease
Nucleotide sequence of the phosphoprotein (P) gene of Newcastle disease virus (strain Beaudette C).
Article
oai:TheScholarship.intra.ecu.edu:10342/32742021-03-03T20:54:23Zcom_10342_74com_10342_73col_10342_527
Fala, Federica
Blalock, William L.
Tazzari, Pier Luigi
Cappellini, Alessandra
Chiarini, Francesca
Martinelli, Giovanni
Tafuri, Agostino
McCubrey, James A.
Cocco, Lucio
Martelli, Alberto M.
2011-03-02T15:28:30Z
2011-05-17T01:40:03Z
2011-03-02T15:28:30Z
2011-05-17T01:40:03Z
2008-09
Molecular Pharmacology; 74:3 p. 884-895
http://hdl.handle.net/10342/3274
PMC2659779
Constitutively activated AKT kinase is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that the novel AKT inhibitor (2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2Hindazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) leads to rapid cell death of T-ALL lines and patient samples. Treatment of CEM, Jurkat, and MOLT-4 cells with nanomolar doses of the inhibitor led to AKT phosphorylation accompanied by dephosphorylation and activation of the downstream target, glycogen synthase kinase-3â. Effects were time- and dose-dependent, resulting in apoptotic cell death. Treatment of Jurkat cells with A443654 resulted in activation of caspase-2, -3, -6, -8, and -9. Apoptotic cell death was mostly dependent on caspase-2 activation, as demonstrated by preincubation with a selective pharmacological inhibitor. It is remarkable that A443654 was highly effective against the drug-resistant cell line CEMVBL100, which expresses 170-kDa P-glycoprotein. Moreover, A443654 synergized with the DNA-damaging agent etoposide in both drug-sensitive and drug-resistant cell lines when coadministered [combination index (CI) = 0.39] or when pretreated with etoposide followed by A443654 (CI = 0.689). The efficacy of A443654 was confirmed using blasts from six patients with T-ALL, all of whom displayed low levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and constitutive phosphorylation of Akt on Ser473. At 1 ìM, the inhibitor was able to induce apoptotic cell death of T-ALL blast cells, as indicated by flow cytometric analysis of samples immunostained for active (cleaved) caspase-3. Because activated AKT is seen in a large percentage of patients with T-ALL, A443654, either alone or in combination with existing drugs, may be a useful therapy for primary and drug-resistant T-ALL. Originally published Molecular Pharmacology, Vol. 74, No. 3, Sep 2008
en_US
East Carolina University
http://molpharm.aspetjournals.org/content/74/3/884.long
Author notified of opt-out rights by Cammie Jennings.
T-cell acute lymphoblastic leukemia
Akt
A443654
Proapoptotic Activity and Chemosensitizing Effect of the Novel Akt Inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-Cell Acute Lymphoblastic Leukemia
Article
oai:TheScholarship.intra.ecu.edu:10342/96162022-02-01T08:15:36Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:26:00Z
2022-01-31T19:26:00Z
2020-01-27
1945-4589
http://hdl.handle.net/10342/9616
10.18632/aging.102776
en_US
Pancreatic ductal adenocarcinoma (PDAC)
TP53 gene
SERPINE1
TP53/miR-34a-Associated Signaling Targets SERPINE1 Expression in Human Pancreatic Cancer
Article
Aging
12
3
2777-2797
oai:TheScholarship.intra.ecu.edu:10342/96432022-02-05T08:16:22Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:48:46Z
2022-02-04T13:48:46Z
2017-02-21
2045-2322
http://hdl.handle.net/10342/9643
10.1038/srep43013
en_US
PTEN
MEK and mTOR inhibition
cancer
PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
Article
Scientific Reports
7
43013
oai:TheScholarship.intra.ecu.edu:10342/112832022-09-22T07:15:56Zcom_10342_74com_10342_73col_10342_527
Ratlif, Michelle L.
Bhowmick, Debajit
van Diepen, Frank
Pfauth, Anita
Tissier, Renaud
2022-09-21T12:23:16Z
2022-09-21T12:23:16Z
2021
2045-2322
http://hdl.handle.net/10342/11283
10.1038/s41598-021-99831-7
en_US
flow cytometry
fluorescence spillover
Spillover Spreading Matrix (SSM)
A Gain and Dynamic Range Independent Index to Quantify Spillover Spread to Aid Panel Design in Flow Cytometry
Article
Scientific Reports
11
1
oai:TheScholarship.intra.ecu.edu:10342/121842023-02-08T08:16:36Zcom_10342_74com_10342_73col_10342_527
Palethorpe, Samantha
Farrow III, John M.
Wells, Greg
Pesci, Everett
Milton, Morgan E.
Cavanagh, John
Actis, Luis
2023-02-07T16:53:14Z
2023-02-07T16:53:14Z
2022-02-15
0021-9193
http://hdl.handle.net/10342/12184
10.1128/jb.00494-21
en_US
Acinetobacter baumannii
two-component system
stress response
Acinetobacter baumannii Regulates Its Stress Responses via the BfmRS Two-Component Regulatory System
Article
Journal of Bacteriology
204
2
oai:TheScholarship.intra.ecu.edu:10342/56912021-03-03T21:06:58Zcom_10342_74com_10342_73col_10342_527
Wright, Diana Grace
Wurm, Torsten
Polakowski, Nicholas
Mesnard, Jean-Michel
Lemasson, Isabelle
2016-06-22T20:05:50Z
2016-06-22T20:05:50Z
2011-
Retrovirology; 8:Suppl 1 p. A150-A150
1742-4690
http://hdl.handle.net/10342/5691
pmc3112621
10.1186/1742-4690-8-S1-A150
HBZ inhibits the HAT activity of the cellular coactivators p300 and CBP
Article
Retrovirology
8
Suppl 1
A150-A150
oai:TheScholarship.intra.ecu.edu:10342/33882021-03-03T20:54:14Zcom_10342_74com_10342_73col_10342_527
Robertson, Kirstin P.
Smith, C. Jeffrey
Gough, Andrea M.
Rocha, Edson R.
2011-04-28T15:35:38Z
2011-05-17T01:40:11Z
2011-04-28T15:35:38Z
2011-05-17T01:40:11Z
2006-04
Infection and Immunity; 74:4 p. 2304-2316
http://hdl.handle.net/10342/3388
PMC1418898
10.1128/IAI.74.4.2304-2316.2006
This study describes the presence of 10 hemolysin orthologs in the genome of the opportunistic human anaerobic pathogen Bacteroides fragilis, which is currently classified as a nonhemolytic bacterium. The hemolysins were designated HlyA through HlyI plus HlyIII. All cloned hemolysin genes were able to confer hemolytic activity to a nonhemolytic Escherichia coli strain on blood agar plates. Interestingly, HlyH was found to be present in the genome of the B. fragilis NCTC9343 strain but absent in strains 638R, YCH46, and Bacteroides thetaiotaomicron VPI-5482. The hemolysins HlyA, HlyB, and HlyIII were selected for further characterization. HlyA, HlyB, and HlyIII were cytolytic to erythrocytes on liquid hemolytic assay. When hlyA and hlyB were expressed together in a nonhemolytic E. coli strain, the strain showed enhanced hemolytic activity on blood agar plates. Further analysis revealed that HlyA and HlyB have synergistic hemolytic activity as detected by the liquid hemolytic assay. In addition, the two-component hemolysins HlyA and HlyB form a protein-protein complex in vivo as determined by bacterial two-hybrid system assay. The hlyB and hlyA genes are organized in an operon that is coordinately regulated by iron and oxygen. Northern blot hybridization analysis revealed that hlyBA were expressed as a bicistronic mRNA induced approximately 2.5-fold under low-iron conditions and repressed in iron-rich medium. The normal ironregulated expression of hlyBA mRNA was lost in the furA mutant strain. In contrast, the hlyA gene was also expressed as a single mRNA in iron-rich medium, but its expression was reduced approximately threefold under low-iron conditions in a Fur-independent manner. This suggests that hlyA alone is regulated by an unidentified iron-dependent regulator. Moreover, the expression levels of hlyBA and hlyA were reduced about threefold following oxygen exposure and treatment with hydrogen peroxide. Taken together, these results suggest that iron and oxidative stress have an effect on the control of hlyBA and hlyA transcriptional levels. A hlyBA mutant was constructed, and its hemolytic activity was greatly diminished compared to those of the hlyIII mutant and parent strains. In addition, the hlyBA mutant had a significant modification in colony morphology and growth deficiency compared to the parent strain. The implications of these findings for the pathophysiology of B. fragilis in extraintestinal infections and competition in ecological systems for this organism are discussed. Originally published Infection and Immunity, Vol. 74, No. 4, Apr 2006
en_US
East Carolina University
http://iai.asm.org/cgi/content/abstract/74/4/2304
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Bacteroides fragilis
Hemolysins
Synergistic activity
Characterization of Bacteroides fragilis Hemolysins and Regulation and Synergistic Interactions of HlyA and HlyB
Article
Infection and Immunity
74
4
2304-2316
oai:TheScholarship.intra.ecu.edu:10342/110502022-09-09T07:16:21Zcom_10342_74com_10342_73col_10342_527
Xu, Hui
Motaleb, Md A.
Chang, Yunjie
Liu, Jun
2022-09-08T14:46:46Z
2022-09-08T14:46:46Z
2021-11-23
2150-7511
http://hdl.handle.net/10342/11050
10.1128/mbio.02494-21
en_US
molecular machine
motility
periplasmic flagella
Characterization of the Flagellar Collar Reveals Structural Plasticity Essential for Spirochete Motility
Article
mBio
12
6
oai:TheScholarship.intra.ecu.edu:10342/33722021-03-03T20:54:15Zcom_10342_74com_10342_73col_10342_527
Rogers, Marc B.
Parker, Anita C.
Smith, C. Jeffrey
2011-04-28T14:28:12Z
2011-05-17T01:40:09Z
2011-04-28T14:28:12Z
2011-05-17T01:40:09Z
1993-11
Antimicrobial Agents and Chemotherapy; 37:11 p. 2391-2400
http://hdl.handle.net/10342/3372
PMC192397
10.1128/AAC.37.11.2391
Bacteroides frgiglis CS30 is a clinical isolate resistant to high concentrations of benzylpenicillin and cephaloridine but not to cephamycin or penem antibiotics. beta-Lactam resistance is mediated by a chromosomally encoded cephalosporinase produced at a high level. The gene encoding this beta-lactamase was cloned from genomic libraries constructed in Escherichia coli and then mated with B. fragilis 638 for identification of ampicillin-resistant (Apr) strains. Apr transconjugants contained a nitrocefin-reactive protein with the physical and enzymatic properties of the original CS30 isolate. The beta-lactamase gene (cepA) was localized by deletion analysis and subcloned, and its nucleotide sequence was determined. The 903-bp cepA open reading frame encoded a 300-amino-acid precursor protein (predicted molecular mass, 34,070 Da). A 13-lactamase-deficient mutant strain of B. fiugilis 638 was constructed by insertional inactivation with the cepA gene of CS30, demonstrating strict functional homology between these chromosomal beta-lactamase genes. An extensive comparison of the CepA protein sequence by alignment with other beta-lactamases revealed the strict conservation of at least four elements common to Ambler class A. A further comparison of the CepA protein sequence with protein sequences of beta-lactamases from two other Bacteroides species indicated that they constitute their own distinct subgroup of class A beta-lactamases. Originally published Antimicrobial Agents and Chemotherapy, Vol. 37, No. 11, Nov 1993
en_US
East Carolina University
http://aac.asm.org/archive/1993.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Bacteroides fragilis
Beta-lactamase
Cephalosporinase
Cloning and characterization of the endogenous cephalosporinase gene, cepA, from Bacteroides fragilis reveals a new subgroup of Ambler class A beta-lactamases.
Article
Antimicrobial Agents and Chemotherapy
37
11
2391-2400
oai:TheScholarship.intra.ecu.edu:10342/96332022-02-05T08:16:01Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:46:29Z
2022-02-04T13:46:29Z
2015-07-10
1949-2553
http://hdl.handle.net/10342/9633
10.18632/oncotarget.3940
en_US
Hepatocellular carcinoma (HCC)
NVP-BGT226
PI3K/Akt signaling
The Novel Dual PI3K/mTOR Inhibitor NVP-BGT226 Displays Cytotoxic Activity in Both Normoxic and Hypoxic Hepatocarcinoma Cells
Article
Oncotarget
6
19
17147–17160
oai:TheScholarship.intra.ecu.edu:10342/34372021-03-03T20:54:38Zcom_10342_74com_10342_73col_10342_527
Armstrong, Sandra K.
Clements, Mark O.
2011-04-28T19:30:45Z
2011-05-17T01:40:11Z
2011-04-28T19:30:45Z
2011-05-17T01:40:11Z
1993-02
Journal of Bacteriology; 175:4 p. 1144-1152
http://hdl.handle.net/10342/3437
PMC193031
Iron acquisition by the gram-negative pathogens Bordetella bronchiseptica and Bordetella pertussis is thought to occur by hydroxamate siderophore-mediated transport as well as an apparently siderophore-independent process by which host transferrins bind to bacterial surface receptors. We constructed B. bronchiseptica mutants deficient in siderophore activity by insertional mutagenesis with miniTn5/LacZl. The mutants could be placed into four distinct complementation groups, as determined from cross-feeding assays which demonstrated restored siderophore synthesis. Mutants deficient in siderophore activity were BRM1, BRM6, and BRM9, exhibiting approximately 36 to 41% of wild-type siderophore levels, and BRM3 and BRM8, which appeared to produce very little or no detectable siderophore. Mutant BRM4 was found to be a leucine auxotroph, while mutants BRM2 and BRM7 could synthesize siderophore only in low-iron medium which was supplemented with various amino acids. Evaluation of all transcriptional fusions revealed an apparent lack of iron-regulated lacZ expression. Genomic regions flanking the transposable element in the siderophore mutants were homologous with B. pertussis chromosomal DNA, while bioassays suggested siderophore cross-feeding between B. pertussis and B. bronchiseptica. These results indicate probable similarity between the siderophore biosynthetic and transport systems of the two species. Originally published Journal of Bacteriology, Vol. 175, No. 4, Feb 1993
en_US
East Carolina University
http://jb.asm.org/archive/1993.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Bordetella bronchiseptica
Siderophore activity
Iron acquisition
Isolation and characterization of Bordetella bronchiseptica mutants deficient in siderophore activity.
Article
oai:TheScholarship.intra.ecu.edu:10342/34152021-03-03T20:54:36Zcom_10342_74com_10342_73col_10342_527
Ruvolo, Vivian R.
Kurinna, Svitlana M.
Karanjeet, Kul B.
Schuster, Todd F.
Martelli, Alberto M.
McCubrey, James A.
Ruvolo, Peter P.
2011-04-28T18:17:32Z
2011-05-17T01:40:04Z
2011-04-28T18:17:32Z
2011-05-17T01:40:04Z
2009-12-19
Journal of Biological Chemistry; 283:51 p. 35474-35485
http://hdl.handle.net/10342/3415
PMC2602900
Protein phosphatase 2A (PP2A) is a heterotrimer comprising catalytic, scaffold, and regulatory (B) subunits. There are at least 21 B subunit family members. Thus PP2A is actually a family of enzymes defined by which B subunit is used. The B56 family member B56 is a phosphoprotein that regulates dephosphorylation of BCL2. The stress kinase PKR has been shown to phosphorylate B56 at serine 28 in vitro, but it has been unclear how PKRmight regulate the BCL2 phosphatase. In the present study, PKR regulation of B56 in REH cells was examined, because these cells exhibit robust BCL2 phosphatase activity. PKR was found to be basally active in REH cells as would be predicted if the kinase supports B56 -mediated dephosphorylation of BCL2. Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56 phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity. PKR supports stress signaling in REH cells, as suppression of PKR promoted chemoresistance to etoposide. Suppression of PKR promoted B56 proteolysis, which could be blocked by a proteasome inhibitor. However, the mechanism by which PKR supports B56 protein does not involve PKR-mediated phosphorylation of the B subunit at serine 28 but may involve eIF2 activation of AKT. Phosphorylation of serine 28 by PKR promotes mitochondrial localization of B56 , because wild-type but not mutant S28A B56 promoted mitochondrial PP2A activity. Cells expressing wildtype B56 but not S28A B56 were sensitized to etoposide. These results suggest that PKR regulates B56 -mediated PP2A signaling in REH cells. Originally published Journal of Biological Chemistry, Vol. 283, No. 51, Dec 2008
en_US
East Carolina University
http://www.jbc.org/content/283/51/35474.full.pdf+html
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Protein phosphatase 2A
B56 alpha
Dephosphorylation
PKR Regulates B56 alpha-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells
Article
oai:TheScholarship.intra.ecu.edu:10342/33912021-03-03T20:54:20Zcom_10342_74com_10342_73col_10342_527
Roux, Christelle M.
Booth, Natha J.
Bellaire, Bryan H.
Gee, Jason M.
Roop, R. Martin II
Kovach, Michael E.
Tsolis, Renee M.
Elzer, Philip H.
Ennis, Don G.
2011-04-28T15:44:10Z
2011-05-17T01:40:08Z
2011-04-28T15:44:10Z
2011-05-17T01:40:08Z
2006-07
Journal of Bacteriology; 188:14 p. 5187-5195
http://hdl.handle.net/10342/3391
PMC1539968
Very little is known about the role of DNA repair networks in Brucella abortus and its role in pathogenesis. We investigated the roles of RecA protein, DNA repair, and SOS regulation in B. abortus. While recA mutants in most bacterial species are hypersensitive to UV damage, surprisingly a B. abortus recA null mutant conferred only modest sensitivity. We considered the presence of a second RecA protein to account for this modest UV sensitivity. Analyses of the Brucella spp. genomes and our molecular studies documented the presence of only one recA gene, suggesting a RecA-independent repair process. Searches of the available Brucella genomes revealed some homology between RecA and RadA, a protein implicated in E. coli DNA repair. We considered the possibility that B. abortus RadA might be compensating for the loss of RecA by promoting similar repair activities. We present functional analyses that demonstrated that B. abortus RadA complements a radA defect in E. coli but could not act in place of the B. abortus RecA. We show that RecA but not RadA was required for survival in macrophages. We also discovered that recA was expressed at high constitutive levels, due to constitutive LexA cleavage by RecA, with little induction following DNA damage. Higher basal levels of RecA and its SOS-regulated gene products might protect against DNA damage experienced following the oxidative burst within macrophages. Originally published Journal of Bacteriology, Vol. 188, No. 14, July 2006
en_US
East Carolina University
http://jb.asm.org/archive/2006.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Brucella abortus
RecA
RadA
DNA repair
RecA and RadA Proteins of Brucella abortus Do Not Perform Overlapping Protective DNA Repair Functions following Oxidative Burst
Article
oai:TheScholarship.intra.ecu.edu:10342/117322022-11-12T08:16:10Zcom_10342_74com_10342_73col_10342_527
Abrams, Stephen L.
Akula, Shaw M.
Steelman, Linda S.
McCubrey, James A.
2022-11-11T13:17:53Z
2022-11-11T13:17:53Z
2022-02-24
2073-4409
http://hdl.handle.net/10342/11732
10.3390/cells11050794
en_US
mutant TP53 reactivators
nutlin-3a
targeted therapy
Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53
Article
Cells
11
5
oai:TheScholarship.intra.ecu.edu:10342/46592021-03-03T21:01:53Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Roop, Roy
Martinson, David A.
Microbiology and Immunology
2015-02-02T19:25:36Z
2016-05-11T21:42:06Z
2014
http://hdl.handle.net/10342/4659
Members of the genus Brucella are small, Gram-negative intracellular bacterial pathogens that are capable of infecting a wide range of mammalian hosts including humans. Brucella primarily reside inside of host macrophages. As an intracellular pathogen, Brucella must overcome iron sequestration in the host cell by utilizing highly efficient iron transport systems. These systems must be tightly regulated, however, as excess intracellular iron is toxic to the bacterial cells. Most of the alpha-proteobacteria rely on a transcriptional regulator called the iron response regulator (Irr) to control the expression of their iron metabolism genes. The work presented in this dissertation provides evidence to support the proposition that the Irr protein is the main iron-responsive transcriptional regulator in Brucella. Irr serves as an activator of genes coding for products that are involved in iron acquisition and a repressor of genes for products that require high levels of iron for their function, or serve as iron export and storage proteins when cellular iron levels are low. Irr is a conditionally stable protein that is present when cellular iron levels are low, and is degraded when cellular iron levels are high. Irr activity is controlled by inactivation and degradation through its interaction with heme, which is synthesized when cellular iron levels rise. Brucella has another iron-responsive regulator that is also found in some members of the alpha-proteobacteria called the rhizobial iron regulator (RirA). RirA is active when cellular iron levels are high, and its regulon partially overlaps with that of Irr in Brucella. The activity of Irr when cellular iron levels are low, and the activity of RirA when cellular iron levels are high, ensures that cellular iron levels are maintained at physiological levels, protecting against iron starvation, and against iron related toxicity in Brucella. Â
Ph.D.
242 p.
dissertations, academic
East Carolina University
Microbiology
Brucella
Fur
Iron
Irr
RirA
The iron response regulator Irr controls iron homoeostasis in Brucella
Doctoral Dissertation
oai:TheScholarship.intra.ecu.edu:10342/44452021-03-03T20:55:37Zcom_10342_74com_10342_73col_10342_527
Barna, Barbara P.
Judson, Marc A.
Thomassen, Mary Jane
2014-08-04T18:28:58Z
2014-08-04T18:28:58Z
2014-06-23
Nanomaterials; 4:2 p. 508-521
http://hdl.handle.net/10342/4445
10.3390/nano4020508
Use of nanomaterials in manufactured consumer products is a rapidly expanding industry and potential toxicities are just beginning to be explored. Combustion-generated multiwall carbon nanotubes (MWCNT) or nanoparticles are ubiquitous in non-manufacturing environments and detectable in vapors from diesel fuel, methane, propane, and natural gas. In experimental animal models, carbon nanotubes have been shown to induce granulomas or other inflammatory changes. Evidence suggesting potential involvement of carbon nanomaterials in human granulomatous disease, has been gathered from analyses of dusts generated in the World Trade Center disaster combined with epidemiological data showing a subsequent increase in granulomatous disease of first responders. In this review we will discuss evidence for similarities in the pathophysiology of carbon nanotube-induced pulmonary disease in experimental animals with that of the human granulomatous disease, sarcoidosis.
en_US
http://www.mdpi.com/2079-4991/4/2/508
Carbon nanotubes
Sarcoidosis
Alveolar macrophages
Review: Carbon Nanotubes and Chronic Granulomatous Disease
Article
oai:TheScholarship.intra.ecu.edu:10342/30712021-03-03T20:54:00Zcom_10342_74com_10342_73col_10342_527
Pesci, Everett C.
Milbank, Jared B. J.
Pearson, James P.
McKnight, Susan L.
Kende, Andrew S.
Greenberg, E. Peter
Iglewski, Barbara H.
2011-01-21T20:52:01Z
2011-05-17T01:39:59Z
2011-01-21T20:52:01Z
2011-05-17T01:39:59Z
1999-09-28
Proceedings of the National Academy of Sciences; 96:20 p. 11229-11234
http://hdl.handle.net/10342/3071
PMC18016
Numerous species of bacteria use an elegant
regulatory mechanism known as quorum sensing to control
the expression of specific genes in a cell-density dependent
manner. In Gram-negative bacteria, quorum sensing systems
function through a cell-to-cell signal molecule (autoinducer)
that consists of a homoserine lactone with a fatty acid side
chain. Such is the case in the opportunistic human pathogen
Pseudomonas aeruginosa, which contains two quorum sensing
systems (las and rhl) that operate via the autoinducers,
N-(3-oxododecanoyl)-L-homoserine lactone and N-butyryl-Lhomoserine
lactone. The study of these signal molecules has
shown that they bind to and activate transcriptional activator
proteins that specifically induce numerous P. aeruginosa
virulence genes. We report here that P. aeruginosa produces
another signal molecule, 2-heptyl-3-hydroxy-4-quinolone,
which has been designated as the Pseudomonas quinolone
signal. It was found that this unique cell-to-cell signal controlled
the expression of lasB, which encodes for the major
virulence factor, LasB elastase. We also show that the synthesis
and bioactivity of Pseudomonas quinolone signal were
mediated by the P. aeruginosa las and rhl quorum sensing
systems, respectively. The demonstration that 2-heptyl-3-
hydroxy-4-quinolone can function as an intercellular signal
sheds light on the role of secondary metabolites and shows
that P. aeruginosa cell-to-cell signaling is not restricted to
acyl-homoserine lactones. Originally published Proc. Natl. Acad. Sci, Vol. 96, No. 20, Sep. 1999
en_US
East Carolina University
http://www.pnas.org/content/by/year/1999
Quorum sensing
Homoserine lactone
Bacteria regulation mechanism
Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa
Article
oai:TheScholarship.intra.ecu.edu:10342/55562021-03-03T21:07:31Zcom_10342_74com_10342_73col_10342_527
Berman, Albert E.
Leontieva, Olga V.
Natarajan, Venkatesh
McCubrey, James A.
Demidenko, Zoya N.
Nikiforov, Mikhail A.
2016-06-10T19:24:25Z
2016-06-10T19:24:25Z
2012-12
Oncotarget; 3:12 p. 1522-1532
1949-2553
http://hdl.handle.net/10342/5556
pmc3681491
It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the “hyperfunction theory�, which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the “hyperfunction model�, many (or actually all) of them also play roles in cancer. So these “participants� in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal such as Oncotarget is the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681491/
senescence
quasi-programmed aging
diseases
cancer
Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes
Article
Oncotarget
3
12
1522-1532
oai:TheScholarship.intra.ecu.edu:10342/110332022-09-07T07:16:08Zcom_10342_74com_10342_73col_10342_527
Farrow, John M. ,III
Pesci, Everett C.
Slade, Daniel
2022-09-06T19:01:49Z
2022-09-06T19:01:49Z
2021-03-11
2576-098X
http://hdl.handle.net/10342/11033
10.1128/mra.00017-21
en_US
Genome Sequences
Acinetobacter baumannii
Unicycler Hybrid Assembly
Genome Sequences for Two Acinetobacter baumannii Strains Obtained Using the Unicycler Hybrid Assembly Pipeline
Article
Microbiology Resource Announcements
10
10
oai:TheScholarship.intra.ecu.edu:10342/96352022-02-05T08:16:18Zcom_10342_74com_10342_73col_10342_527
2022-02-04T13:46:52Z
2022-02-04T13:46:52Z
2016-11-08
1949-2553
http://hdl.handle.net/10342/9635
10.18632/oncotarget.11805
en_US
microRNAs
bladder cancer
Computational identification
Computational identification of microRNAs associated to both epithelial to mesenchymal transition and NGAL/MMP-9 pathways in bladder cancer
Article
Oncotarget
7
45
72758-72766
oai:TheScholarship.intra.ecu.edu:10342/96232022-02-05T08:16:05Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:41:40Z
2022-02-04T13:41:40Z
2017-02-20
1949-2553
http://hdl.handle.net/10342/9623
10.18632/oncotarget.15542
en_US
PI3K isoform inhibition
CT B-acute lymphoblastic leukemia (B-ALL)
B-cell progenitor
PI3K Isoform Inhibition Associated with Anti Bcr-Abl Drugs Shows in Vitro Increased Anti-leukemic Activity in Philadelphia Chromosome-positive B-acute Lymphoblastic Leukemia Cell Lines
Article
Oncotarget
8
14
23213-23227
oai:TheScholarship.intra.ecu.edu:10342/107802022-07-19T07:16:07Zcom_10342_74com_10342_73col_10342_527
Ratti, Stefano
Rusciano, Isabella
Mongiorgi, Sara
Neri, Irene
Alessandra Cappellini, Alessandra
Cortelli, Pietro
Suh, Pann-Ghill
McCubrey, James A.
Manzoli, Lucia
Cocco, Lucio
Ramazzotti, Giulia
2022-07-18T18:04:43Z
2022-07-18T18:04:43Z
2021-09-28
2073-4409
http://hdl.handle.net/10342/10780
10.3390/cells10102566
en_US
Lamin B1
reactive astrocyte
cell viability
Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
Article
Cells
10
10
2566
oai:TheScholarship.intra.ecu.edu:10342/95882022-02-01T08:15:37Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:21:11Z
2022-01-31T19:21:11Z
2016-01-12
1949-2553
http://hdl.handle.net/10342/9588
10.18632/oncotarget.6361
en_US
Synergistic Cytotoxic Effects of Bortezomib and CK2 Inhibitor CX-4945 in Acute LymphOblastic Leukemia: Turning Off the Prosurvival ER Chaperone BIP/Grp78 and Turning on the Pro-apoptotic NF-κB
Article
Oncotarget
7
2
1323-1340
oai:TheScholarship.intra.ecu.edu:10342/96152022-02-01T08:15:37Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:25:55Z
2022-01-31T19:25:55Z
2016
2679-4644
http://hdl.handle.net/10342/9615
10.1080/15384101.2016.1138183
en_US
Phosphatase and tensin homolog (PTEN)
Hepatocellular carcinoma (HCC)
tumor suppressor gene
A PTEN Inhibitor Displays Preclinical Activity Against Hepatocarcinoma Cells
Article
Cell Cycle
15
4
573-583
oai:TheScholarship.intra.ecu.edu:10342/109692022-12-14T17:28:56Zcom_10342_74com_10342_73col_10342_527
Garcia, Brandon L.
Coburn, Jenifer
Hu, Linden T.
Jewett, Mollie W.
Kraiczy, Peter
Norris, Steven J.
Skare, Jon
2022-08-01T15:00:31Z
2022-08-01T15:00:31Z
2021
1467-3037
http://hdl.handle.net/10342/10969
10.21775/cimb.042.473
en_US
Lyme Disease
Pathogenesis
tick transmitted
Lyme Disease Pathogenesis
Article
Current Issues in Molecular Biology
42
473-518
oai:TheScholarship.intra.ecu.edu:10342/56762021-03-03T21:08:13Zcom_10342_74com_10342_73col_10342_527
Demidenko, Zoya N.
McCubrey, James A.
2016-06-16T19:56:54Z
2016-06-16T19:56:54Z
2011-12
Aging (Albany NY); 3:12 p. 1154-1162
1945-4589
http://hdl.handle.net/10342/5676
pmc3273895
In recent years, numerous new targets have been identified and new experimental therapeutics have been developed. Importantly, existing non-cancer drugs found novel use in cancer therapy. And even more importantly, new original therapeutic strategies to increase potency, selectivity and decrease detrimental side effects have been evaluated. Here we review some recent advances in targeting cancer.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273895/
cancer
target
therapy
leukemia
anticancer drugs
Recent progress in targeting cancer
Article
Aging (Albany NY)
3
12
1154-1162
oai:TheScholarship.intra.ecu.edu:10342/118282022-12-08T08:17:01Zcom_10342_74com_10342_73col_10342_527
Parker, Anita C.
Seals, Nathaniel L.
Rocha, Edson R.
Baccanale, Cecile L.
2022-12-07T15:39:21Z
2022-12-07T15:39:21Z
2022-01-25
0019-9567
http://hdl.handle.net/10342/11828
10.1128/IAI.00469-21
en_US
B. fragilis
Bacteroides
TonB-dependent transporter
Analysis of Six tonB Gene Homologs in Bacteroides Fragilis Revealed That tonB3 is Essential for Survival in Experimental Intestinal Colonization and Intra-Abdominal Infection
Article
Infection and Immunity
90
1
oai:TheScholarship.intra.ecu.edu:10342/55742021-03-03T21:06:18Zcom_10342_74com_10342_73col_10342_527
Mannie, Mark D.
Blanchfield, J. Lori
Islam, S.M. Touhidul
Abbott, Derek J.
2016-06-14T13:38:02Z
2016-06-14T13:38:02Z
2012-08
Frontiers in Immunology; 3: p. 1-16
1664-3224
http://hdl.handle.net/10342/5574
pmc3422719
10.3389/fimmu.2012.00255
Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS). Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE) in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen) fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre-treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was as follows: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL-13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422719/
multiple sclerosis
experimental autoimmune encephalomyelitis
tolerogenic therapeutic vaccine
cytokine-neuroantigen fusion protein
immunological tolerance
interferon-beta
granulocyte-macrophage colony-stimulating factor
autoimmune demyelination
Cytokine-Neuroantigen Fusion Proteins as a New Class of Tolerogenic, Therapeutic Vaccines for Treatment of Inflammatory Demyelinating Disease in Rodent Models of Multiple Sclerosis
Article
Frontiers in Immunology
3
1-16
oai:TheScholarship.intra.ecu.edu:10342/56662021-03-03T21:06:50Zcom_10342_74com_10342_73col_10342_527
Wright, Diana Grace
Polakowski, Nicholas
Lemasson, Isabelle
2016-06-16T19:14:57Z
2016-06-16T19:14:57Z
2014
Retrovirology; 11:Suppl 1 p. P109-P109
1742-4690
http://hdl.handle.net/10342/5666
pmc4044427
10.1186/1742-4690-11-S1-P109
We previously reported that HTLV-1 basic leucine zipper factor (HBZ) interacts with the cellular coactivator p300 in cells derived from ATL patients. We further determined that HBZ directly binds to the histone acetyltransferase (HAT) domain of both p300 and its homologue CBP. HAT activity transfers an acetyl group to lysine residues on histone tails and transcription factors to generally upregulate transcription. We observed that the HBZ interaction with the HAT domain of p300/CBP inhibits acetylation of histones and of the tumor suppressor p53. In this study, we wanted to determine whether inhibition of HAT activity was limited to p300/CBP or extended to other HAT families. We focused on the GCN5/ p/CAF and MYST HAT families. We found that HBZ co-immunoprecipitates with both p/CAF and HBO1. These data support a recent finding that HBZ interacts with HBO1 in a yeast two-hybrid assay. Through in vitro HAT assays using recombinant proteins we found that HBZ inhibits acetylation of histone H3 and histone H4 by p/CAF and HBO1, respectively. Furthermore, HBZ reduces acetylation of p53 by p/CAF. Since both p300 and p/CAF acetylate p53 to increase its DNA-binding activity, we performed quantitative RT-PCR to evaluate expression of the p53 target genes, GADD45A and NOXA. We observed reduced mRNA levels of these genes when cells expressed HBZ. Overall these results suggest that HBZ inhibits the HAT activity of coactivators from different HAT families to contribute to transcriptional deregulation.
https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-11-S1-P109
Inhibition of histone acetyltransferase (HAT) activity by HBZ extends beyond the p300/CBP HAT family
Article
Retrovirology
11
Suppl 1
P109-P109
oai:TheScholarship.intra.ecu.edu:10342/57002021-03-03T21:07:44Zcom_10342_74com_10342_73col_10342_527
Taylor, Jackson R.
Lehmann, Brian D.
Chappell, William H.
Abrams, Stephen L.
Steelman, Linda S.
McCubrey, James A.
2016-06-23T14:50:00Z
2016-06-23T14:50:00Z
2011-08
Oncotarget; 2:8 p. 610-626
1949-2553
http://hdl.handle.net/10342/5700
pmc3248208
Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248208/
Akt
ERK
mTOR
Senescence
Drug Resistance
Tamoxifen
Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells
Article
Oncotarget
2
8
610-626
oai:TheScholarship.intra.ecu.edu:10342/34252021-03-03T20:54:13Zcom_10342_74com_10342_73col_10342_527
Smalley, Darren
Rocha, Edson R.
Smith, C. Jeffrey
2011-04-28T18:44:52Z
2011-05-17T01:40:11Z
2011-04-28T18:44:52Z
2011-05-17T01:40:11Z
2002-02
Journal of Bacteriology; 184:4 p. 895-903
http://hdl.handle.net/10342/3425
PMC134816
10.1128/jb.184.4.895-903.2002
Bacteroides fragilis, a component of the normal intestinal flora, is an obligate anaerobe capable of long-term survival in the presence of air. Survival is attributed to an elaborate oxidative stress response that controls the induction of more than 28 peptides, but there is limited knowledge concerning the identities of these peptides. In this report, RNA fingerprinting by arbitrarily primed PCR identified five new genes whose expression increased following exposure to O2. Nucleotide sequence analysis of the cloned genes indicated that they encoded an outer membrane protein, an aspartate decarboxylase, an efflux pump, heat shock protein HtpG, and an NrdA ortholog constituting the large subunit of a class Ia ribonucleotide reductase (RRase). Attention was focused on the nrdA gene since class I RRases are obligate aerobic enzymes catalyzing the reduction of ribonucleoside 5'-diphosphates by a mechanism that requires molecular oxygen for activity. Sequence analysis of the nrd locus showed that two genes, nrdA and nrdB, are located in the same orientation in a 4.5-kb region. Northern hybridization and primer extension experiments confirmed induction of the genes by O2 and suggested they are an operon. The B. fragilis nrdA and nrdB genes were overexpressed in Escherichia coli, and CDP reductase assays confirmed that they encoded an active enzyme. The enzyme activity was inhibited by hydroxyurea, and ATP was shown to be a positive effector of CDP reductase activity, while dATP was an inhibitor, indicating that the enzyme was a class Ia RRase. A nrdA mutant was viable under anaerobic conditions but had decreased survival following exposure to O2, and it could not rapidly resume growth after O2 treatment. The results presented indicate that during aerobic conditions B. fragilis NrdAB may have a role in maintaining deoxyribonucleotide pools for DNA repair and growth recovery. Originally published Journal of Bacteriology, Vol. 184, No. 4, Feb 2002
en_US
East Carolina University
http://jb.asm.org/archive/2002.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Bacteroides fragilis
Ribonucleotide Reductases
Aerobic environment
Aerobic-Type Ribonucleotide Reductase in the Anaerobe Bacteroides fragilis
Article
Journal of Bacteriology
184
4
895-903
oai:TheScholarship.intra.ecu.edu:10342/50882021-03-03T20:58:44Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Lemasson, Isabelle
Wright, Diana Grace
Microbiology and Immunology
2016-01-14T16:12:19Z
2018-01-23T17:31:55Z
1/13/16
http://hdl.handle.net/10342/5088
Of the 20 million individuals infected worldwide with the complex retrovirus, Human T-cell Leukemia Virus Type 1, 5% will develop an incurable and fatal form of leukemia known as adult T-cell leukemia (ATL). During the course of infection, the promoter responsible for genome replication and expression of most viral genes is often inactivated by DNA methylation, mutation and deletion. The only gene expressed in the malignant cells is the hbz gene, which contains the open reading frame for HTLV-1 basic leucine zipper (bZIP) factor (HBZ). HBZ is regulated by a unique promoter which is unaffected by modifications. The observation that HBZ is persistently expressed and the fact that transgenic mice expressing HBZ develop symptoms similar to ATL suggest that HBZ is involved in ATL development. HBZ interacts with the homologous cellular coactivators, p300 and CBP. These proteins contain a histone acetyl transferase (HAT) domain that mediates transfer of acetyl groups from acetyl-coenzyme A to lysine residue. p300/CBP acetylate specific lysines on histones to increase transcription. These coactivators also acetylate transcription factors to modulate, among other functions, their DNA binding capacity. We found that the bZIP domain of HBZ interacts directly with the HAT domain of p300/CBP. This interaction has for consequence to inhibit acetylation of histone H3 and of the NF-kB transcription factor, p65. Inhibition of p65 acetylation leads to a decrease of its transcriptional activity. Because the transcriptional activity of the tumor suppressor p53 is also dependent on acetylation, we analyzed the effect of HBZ on this protein. We found that inhibition of p300/CBP HAT activity by HBZ reduces the acetylation of p53, which is modified following DNA damage. We also observed that HBZ interacts with HBO1, which is a HAT protein in the MYST family that acts as a transcriptional coactivator for p53. The fact that HBZ inhibits both p300/CBP and HBO1 HAT activity is correlated with a reduction of CDKN1A/p21 activation by p53. Consequently, we observed a delay in the cell cycle arrest after DNA damage in cells expressing HBZ. We propose that HBZ, by interacting with cellular coactivators and disrupting their HAT activities, could promote ATL development.
Ph.D.
167 p.
dissertations, academic
East Carolina University
Molecular biology
Virology
Microbiology
Acetyltransferase
Adult T-cell leukemia
HBZ
P300/CBP
Transcription
Human T-lymphotropic virus 1
Basic-Leucine Zipper Transcription Factors
Acetyltransferases
Leucine Zippers
Human T-cell Leukemia Virus Type 1 Basic Leucine Zipper Factor (HBZ) Interacts and Inhibits the Acetyltransferase Activity of Multiple Cellular Coactivator Families to Deregulate Transcription
Doctoral Dissertation
oai:TheScholarship.intra.ecu.edu:10342/95972022-02-01T08:15:37Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:22:49Z
2022-01-31T19:22:49Z
2019-05-15
http://hdl.handle.net/10342/9597
en_US
HSP90
Sorafenib
Hepatocellular carcinoma (HCC)
Targeting HSP90 with the Small Molecule Inhibitor AUY922 (luminespib) as a Treatment Strategy Against Hepatocellular Carcinoma
Article
International Journal of Cancer
144
10
2613-2624
oai:TheScholarship.intra.ecu.edu:10342/95812022-02-01T08:15:48Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:20:22Z
2022-01-31T19:20:22Z
2017-08
1019-6439
http://hdl.handle.net/10342/9581
10.3892/ijo.2017.4049
hepatocellular carcinoma
reactive oxygen species
extra-virgin olive oil
Oleocanthal Exerts Antitumor Effects on Human Liver and Colon Cancer Cells Through ROS Generation
Article
International Journal of Oncology
51
2
533-544
oai:TheScholarship.intra.ecu.edu:10342/96342022-02-05T08:16:01Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:46:39Z
2022-02-04T13:46:39Z
2017
1097-4644
http://hdl.handle.net/10342/9634
10.1002/jcb.25894
en_US
Inositide
Phospholipase C
Signaling
Nuclear Inositide Signaling Via Phospholipase C
Article
Journal of Cellular Biochemistry
18
1969–1978
oai:TheScholarship.intra.ecu.edu:10342/75362022-12-05T17:25:35Zcom_10342_74com_10342_73col_10342_527
Bertrand, Fred E.
Whelan, Jarrett Thomas
2019-11-11T18:38:02Z
2019-11-11T18:38:02Z
2008-09-25
International Publication # WO2008115470A2
http://hdl.handle.net/10342/7536
This invention provides methods for treating or preventing the onset of a tumor in a subject, wherein the tumor is determined to overexpress a Hox gene, including administering to the subject a therapeutically or prophylactically effective amount of an insulin-like growth factor-1 receptor (IGF-1R) antagonist. The invention also provides methods for determining whether a tumor in a subject is amenable to treatment with an IGF-1R antagonist including determining whether the tumor overexpresses a Hox gene, wherein overexpression of the Hox gene indicates that the tumor is amenable to treatment with an IGF-1R inhibitor.
en_US
https://patents.google.com/patent/WO2008115470A2/en?oq=inassignee:%22East+Carolina%22
cancer
genetics
Hox-gene expression as a biomarker for igf-1r therapeutics
Patent
oai:TheScholarship.intra.ecu.edu:10342/95822022-02-01T08:15:50Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-01-31T19:20:29Z
2022-01-31T19:20:29Z
2020-06-03
1945-4589
http://hdl.handle.net/10342/9582
10.18632/aging.103377
en_US
TP53
rapamycin
collagen
Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines
Article
Aging
12
11
10194-10210
oai:TheScholarship.intra.ecu.edu:10342/56972021-03-03T21:07:12Zcom_10342_74com_10342_73col_10342_527
Walker, Lia R.
Hussein, Hosni Ahmed Mohamed
Akula, Shaw M.
2016-06-23T14:41:45Z
2016-06-23T14:41:45Z
2016-01
Cell & Bioscience; 6: p. 1-10
2045-3701
http://hdl.handle.net/10342/5697
pmc4714431
10.1186/s13578-015-0066-2
Background
Virus entry involves multiple steps and is a highly orchestrated process on which successful infection collectively depends. Entry processes are commonly analyzed by monitoring internalized virus particles via Western blotting, polymerase chain reaction, and imaging techniques that allow scientist to track the intracellular location of the pathogen. Such studies have provided abundant direct evidence on how viruses interact with receptor molecules on the cell surface, induce cell signaling at the point of initial contact with the cell to facilitate internalization, and exploit existing endocytic mechanisms of the cell for their ultimate infectious agenda. However, there is dearth of knowledge in regards to trafficking of a virus via endosomes. Herein, we describe an optimized laboratory procedure to isolate individual organelles during different stages of endocytosis by performing subcellular fractionation. This methodology is established using Kaposi’s sarcoma-associated herpesvirus (KSHV) infection of human foreskin fibroblast (HFF) cells as a model. With KSHV and other herpesviruses alike, envelope glycoproteins have been widely reported to physically engage target cell surface receptors, such as integrins, in interactions leading to entry and subsequent infection.
Results
Subcellular fractionation was used to isolate early and late endosomes (EEs and LEs) by performing a series of centrifugations steps. Specifically, a centrifugation step post-homogenization was utilized to obtain the post-nuclear supernatant containing intact intracellular organelles in suspension. Successive fractionation via sucrose density gradient centrifugation was performed to isolate specific organelles including EEs and LEs. Intracellular KSHV trafficking was directly traced in the isolated endosomal fractions. Additionally, the subcellular fractionation approach demonstrates a key role for integrins in the endosomal trafficking of KSHV. The results obtained from fractionation studies corroborated those obtained by traditional imaging studies.
Conclusions
This study is the first of its kind to employ a sucrose flotation gradient assay to map intracellular KSHV trafficking in HFF cells. We are confident that such an approach will serve as a powerful tool to directly study intracellular trafficking of a virus, signaling events occurring on endosomal membranes, and dynamics of molecular events within endosomes that are crucial for uncoating and virus escape into the cytosol.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714431/
Fractionation
Ultracentrifugation
Sucrose density gradient,
Endosomes
Virus entry
Endocytosis
Subcellular fractionation method to study endosomal trafficking of Kaposi’s sarcoma-associated herpesvirus
Article
Cell & Bioscience
6
1-10
oai:TheScholarship.intra.ecu.edu:10342/113942022-10-04T07:16:08Zcom_10342_74com_10342_73col_10342_527
Garrigues, Ryan J.
Garcia, Brandon L.
Pierce, Alexandra D. Powell
Hammel, Michal
Skare, Jon T.
2022-10-03T13:29:50Z
2022-10-03T13:29:50Z
2021-07-04
0022-1767
http://hdl.handle.net/10342/11394
10.4049/jimmunol.2100815
en_US
protease C1r
Lyme disease spirochetes
inhibition
A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes
Article
Journal of immunology
207
11
2856-2867
oai:TheScholarship.intra.ecu.edu:10342/52122021-03-03T20:59:13Zcom_10342_74com_10342_73col_10342_527
Mannie, Mark D.
2016-03-01T17:42:20Z
2016-03-01T17:42:20Z
2014-12-30
US 8,920,808 B2
http://hdl.handle.net/10342/5212
The present invention provides fusion proteins including an autoimmune antigen, an allergen antigen or an alloantigen, and an anti-inflammatory cytokine. Compositions and meth ods including the fusion proteins are also provided.
CYTOKINE-BASED FUSION PROTEINS FOR TREATMENT OF MULTIPLE SCLEROSIS
Patent
oai:TheScholarship.intra.ecu.edu:10342/30352021-03-03T20:54:16Zcom_10342_74com_10342_73col_10342_527
Koslowski, Kim M.
Shaver, Patti R.
Wang, Xiao-Yang
Tenney, Daniel J.
Pederson, Nels E.
2011-01-06T21:54:15Z
2011-05-17T01:40:00Z
2011-01-06T21:54:15Z
2011-05-17T01:40:00Z
1997-12
Journal of Virology; 71:12 p. 9118-9123
http://hdl.handle.net/10342/3035
PMC230212
Herpesvirus DNA is packaged into capsids in the nuclei of infected cells in a process requiring at least six
viral proteins. Of the proteins required for encapsidation of viral DNA, UL15 and UL28 are the most conserved
among herpes simplex virus type 1 (HSV), varicella-zoster virus, and equine herpesvirus 1. The subcellular
distribution of the pseudorabies virus (PRV) UL28 protein was examined by in situ immunofluorescence. UL28
was present in the nuclei of infected cells; however, UL28 was limited to the cytoplasm in the absence of other
viral proteins. When cells expressing variant forms of UL28 were infected with a PRV UL28-null mutant, UL28
entered the nucleus, provided the carboxyl-terminal 155 amino acids were present. Additionally, PRV UL28
entered the nucleus in cells infected with HSV. Two HSV packaging proteins were tested for the ability to affect
the subcellular distribution of UL28. Coexpression of HSV UL15 enabled PRV UL28 to enter the nucleus in a
manner that required the carboxyl-terminal 155 amino acids of UL28. Coexpression of HSV UL25 did not affect
the distribution of UL28. We propose that an interaction between UL15 and UL28 facilitates the transport of
a UL15-UL28 complex to the infected-cell nucleus. Originally published Journal of Virology 1997 Vol. 71, No. 12.
en_US
East Carolina University
http://jvi.asm.org/content/vol71/issue12/index.dtl
Herpes virus
Viral Proteins
Viral DNA
Pseudorabies virus
The pseudorabies virus UL28 protein enters the nucleus after coexpression with the herpes simplex virus UL15 protein
Article
oai:TheScholarship.intra.ecu.edu:10342/51232021-03-03T20:58:44Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Akula, Shaw M.
Walker, Lia R.
Interdisc Biological Sciences
2016-01-15T14:44:44Z
2015-12
2015-12-10
December 2015
2016-01-15T13:52:16Z
http://hdl.handle.net/10342/5123
KSHV, also referred to as human herpesvirus-8 (HHV-8), is the eighth and latest identified human herpesvirus. It is the causative agent for a variety of malignancies namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). The processes and mechanisms involved in virus entry are among the many intricacies not fully understood regarding KSHV and other viruses. As in other herpesviruses, KSHV target cell entry is a complex process consisting of multiple steps which include: initial attachment/binding to the cell, virus:cell surface receptor interactions, virus internalization/uptake, and subsequent trafficking of the virus for nuclear delivery. Viral envelope glycoproteins interact with target cell surface receptor molecules to facilitate entry into cells. For instance, virus envelope associated glycoprotein B (gB) of KSHV is known to interact with integrins via its RGD (Arg-Gly-Asp; 27-29aa) integrin binding domain. RGD of KSHV functionally interacts with integrins α3β1, αVβ3, and αVβ5 that have a role in initiating internalization. Cell surface receptors, like integrins, aid in a virus’ ability to establish a successful infection. In addition to RGD, KSHV gB also harbors the lesser studied integrin recognition motif, disintegrin-like domain (DLD; 66-85aa). As it pertains to virus entry in general, few studies have sought to establish a role for DLD, which is highly conserved among gB homologs. In the following studies, we employed phage display peptide library screening and recombinant viruses to determine that DLD of KSHV gB binds α9β1 integrin on the surface of target cells in an interaction critical for infection. We go on to specify a role for DLD-binding α9β1 in mediating KSHV entry by employing subcellular fractionation. The virus interactions with α9β1 are crucial for endosomal trafficking of KSHV, as integrin α9β1was observed to have a role in late endosomal escape of KSHV for cytosolic delivery. These studies provide new insights in regards to KSHV infectious entry into target cells. Advancing our knowledge of virus entry is critical for a thorough understanding of KSHV pathogenesis.
application/pdf
en
East Carolina University
Disintegrin-like domain
Disintegrins
Integrins
Herpesviruses
Viruses--Receptors
FUNCTION OF DISINTEGRIN-LIKE DOMAIN OF KSHV gB IN REGULATING VIRUS INFECTION
Doctoral Dissertation
text
Ph.D./Au.D.
Doctoral
PHD-Interdisc Biological Sci
East Carolina University
Interdisc Biological Sciences
Open Access
oai:TheScholarship.intra.ecu.edu:10342/96452022-02-05T08:16:24Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:49:13Z
2022-02-04T13:49:13Z
2016-03-25
1932-6203
http://hdl.handle.net/10342/9645
10.1371/journal.pone.0152104
en_US
PI3K/AKT
MAPK Signaling Pathways
Malignant melanoma
Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer
Article
PLoS ONE
11
3
oai:TheScholarship.intra.ecu.edu:10342/52012021-03-03T20:59:56Zcom_10342_107com_10342_73com_10342_74col_10342_5056col_10342_527
Walker, Lia R.
Hussein, Hosni Ahmed Mohamed
Akula, Shaw M.
2016-02-10T15:47:45Z
2016-02-10T15:47:45Z
2016-01-15
2016-02-10T11:09:43Z
Cell & Bioscience. 2016 Jan 15;6(1):1
http://dx.doi.org/10.1186/s13578-015-0066-2
http://hdl.handle.net/10342/5201
Background:
Virus entry involves multiple steps and is a highly orchestrated process on which successful infection collectively depends. Entry processes are commonly analyzed by monitoring internalized virus particles via Western blotting, polymerase chain reaction, and imaging techniques that allow scientist to track the intracellular location of the pathogen. Such studies have provided abundant direct evidence on how viruses interact with receptor molecules on the cell surface, induce cell signaling at the point of initial contact with the cell to facilitate internalization, and exploit existing endocytic mechanisms of the cell for their ultimate infectious agenda. However, there is dearth of knowledge in regards to trafficking of a virus via endosomes. Herein, we describe an optimized laboratory procedure to isolate individual organelles during different stages of endocytosis by performing subcellular fractionation. This methodology is established using Kaposi’s sarcoma-associated herpesvirus (KSHV) infection of human foreskin fibroblast (HFF) cells as a model. With KSHV and other herpesviruses alike, envelope glycoproteins have been widely reported to physically engage target cell surface receptors, such as integrins, in interactions leading to entry and subsequent infection.
Results:
Subcellular fractionation was used to isolate early and late endosomes (EEs and LEs) by performing a series of centrifugations steps. Specifically, a centrifugation step post-homogenization was utilized to obtain the post-nuclear supernatant containing intact intracellular organelles in suspension. Successive fractionation via sucrose density gradient centrifugation was performed to isolate specific organelles including EEs and LEs. Intracellular KSHV trafficking was directly traced in the isolated endosomal fractions. Additionally, the subcellular fractionation approach demonstrates a key role for integrins in the endosomal trafficking of KSHV. The results obtained from fractionation studies corroborated those obtained by traditional imaging studies.
Conclusions:
This study is the first of its kind to employ a sucrose flotation gradient assay to map intracellular KSHV trafficking in HFF cells. We are confident that such an approach will serve as a powerful tool to directly study intracellular trafficking of a virus, signaling events occurring on endosomal membranes, and dynamics of molecular events within endosomes that are crucial for uncoating and virus escape into the cytosol.
en_US
en
http://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-015-0066-2
Endocytosis
Endosomes
Virus entry
Sucrose density gradient
Ultracentrifugation
Fractionation
Subcellular fractionation method to study endosomal trafficking of Kaposi’s sarcoma-associated herpesvirus
Article
Walker et al.
Cell & Bioscience
6
1
1
oai:TheScholarship.intra.ecu.edu:10342/58672021-03-03T21:08:05Zcom_10342_74com_10342_73col_10342_527
Cervello, Melchiorre
McCubrey, James A.
Cusimano, Antonella
Lampiasi, Nadia
Azzolina, Antonina
Montalto, Giuseppe
2016-08-10T13:16:43Z
2016-08-10T13:16:43Z
2012-03
Oncotarget; 3:3 p. 236-260
1949-2553
http://hdl.handle.net/10342/5867
pmc3359882
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies.
Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed.
Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease.
In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359882/
HCC
targeted therapy
VEGF
Ras/Raf/MEK/ERK
PI3K/Akt/PTEN/mTOR
signal transduction inhibitors
Targeted therapy for hepatocellular carcinoma: novel agents on the horizon
Article
Oncotarget
3
3
236-260
oai:TheScholarship.intra.ecu.edu:10342/56792021-03-03T21:06:54Zcom_10342_74com_10342_73col_10342_527
Evangelisti, Cecilia
Evangelisti, Camilla
Teti, Gabriella
Chiarini, Francesca
Falconi, Mirella
Melchionda, Fraia
Pession, Andrea
Bertaina, Alice
Locatelli, Franco
McCubrey, James A.
Beak, Dong Jae
Bittman, Robert
Pyne, Susan
Pyne, Nigel J.
Martelli, Alberto M.
2016-06-22T16:17:04Z
2016-06-22T16:17:04Z
2014-09
Oncotarget; 5:17 p. 7886-7901
1949-2553
http://hdl.handle.net/10342/5679
pmc4202168
Sphingosine 1-phosphate (S1P) is a bioactive lipid that is formed by the phosphorylation of sphingosine and catalysed by sphingosine kinase 1 (SK1) or sphingosine kinase 2 (SK2). Sphingosine kinases play a fundamental role in many signaling pathways associated with cancer, suggesting that proteins belonging to this signaling network represent potential therapeutic targets. Over the last years, many improvements have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL); however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of SKi and ROMe, a sphingosine kinase 1 and 2 inhibitor and SK2-selective inhibitor, respectively. While SKi induced apoptosis, ROMe initiated an autophagic cell death in our in vitro cell models. SKi treatment induced an increase in SK1 protein levels in Molt-4 cells, whereas it activated the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathway in Jurkat and CEM-R cells as protective mechanisms in a sub-population of T-ALL cells. Interestingly, we observed a synergistic effect of SKi with the classical chemotherapeutic drug vincristine. In addition, we reported that SKi affected signaling cascades implicated in survival, proliferation and stress response of cells. These findings indicate that SK1 or SK2 represent potential targets for treating T-ALL.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202168/
T-cell acute lymphoblastis
leukemia
sphingosine kinase inhibitors
apoptosis
autophagy
unfolded protein response
Assessment of the effect of sphingosine kinase inhibitors on apoptosis,unfolded protein response and autophagy of T-cell acute lymphoblastic leukemia cells; indications for novel therapeutics
Article
Oncotarget
5
17
7886-7901
oai:TheScholarship.intra.ecu.edu:10342/56522021-03-03T21:06:27Zcom_10342_74com_10342_73col_10342_527
Novak, Elizabeth A.
Sultan, Syed Z.
Motaleb, Md. A.
2016-06-16T17:04:11Z
2016-06-16T17:04:11Z
2014-05
Frontiers in Cellular and Infection Microbiology; 4: p. 1-11
2235-2988
http://hdl.handle.net/10342/5652
pmc4013479
10.3389/fcimb.2014.00056
In nature, the Lyme disease spirochete Borrelia burgdorferi cycles between the unrelated environments of the Ixodes tick vector and mammalian host. In order to survive transmission between hosts, B. burgdorferi must be able to not only detect changes in its environment, but also rapidly and appropriately respond to these changes. One manner in which this obligate parasite regulates and adapts to its changing environment is through cyclic-di-GMP (c-di-GMP) signaling. c-di-GMP has been shown to be instrumental in orchestrating the adaptation of B. burgdorferi to the tick environment. B. burgdorferi possesses only one set of c-di-GMP-metabolizing genes (one diguanylate cyclase and two distinct phosphodiesterases) and one c-di-GMP-binding PilZ-domain protein designated as PlzA. While studies in the realm of c-di-GMP signaling in B. burgdorferi have exploded in the last few years, there are still many more questions than answers. Elucidation of the importance of c-di-GMP signaling to B. burgdorferi may lead to the identification of mechanisms that are critical for the survival of B. burgdorferi in the tick phase of the enzootic cycle as well as potentially delineate a role (if any) c-di-GMP may play in the transmission and virulence of B. burgdorferi during the enzootic cycle, thereby enabling the development of effective drugs for the prevention and/or treatment of Lyme disease.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013479/
c-di-GMP
Borrelia burgdorferi
Lyme disease
motility
chemotaxis
virulence
The cyclic-di-GMP signaling pathway in the Lyme disease spirochete,
Article
Frontiers in Cellular and Infection Microbiology
4
1-11
oai:TheScholarship.intra.ecu.edu:10342/33892021-03-03T20:54:26Zcom_10342_74com_10342_73col_10342_527
Ross, Ted M.
Xu, Yan
Green, Thomas D.
Montefiori, David C.
Robinson, Harriet L.
2011-04-28T15:36:39Z
2011-05-17T01:40:05Z
2011-04-28T15:36:39Z
2011-05-17T01:40:05Z
2001-06-10
AIDS Research and Human Retroviruses; 17:9 p. 829-835
http://hdl.handle.net/10342/3389
PMC1783761
10.1089/088922201750252025.
DNA vaccination can elicit both humoral and cellular immune responses and can confer protection against several pathogens. However, DNA vaccines expressing the envelope (Env) protein of human immunodeficiency virus (HIV) have been relatively ineffective at generating high titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, we report that fusion of Env and the complement component, C3d, in a DNA vaccine, enhances the titers of antibody to Env. Plasmids were generated that expressed a secreted form of Env (sgp120) from three isolates of HIV and these same forms fused to three tandem copies of the murine homologue of C3d (sgp120-3C3d). Analyses of titers and avidity maturation of the raised antibody indicated that immunizations with each of the sgp120-3C3d-expressing DNAs accelerated both the onset and the avidity maturation of antibody to Env. Originally published AIDS Research and Human Retroviruses, Vol. 17, No. 9, June 2001
en_US
East Carolina University
http://www.liebertonline.com/doi/abs/10.1089/088922201750252025
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
DNA vaccination
Titers
Avidity maturation
Enhanced Avidity Maturation of Antibody to Human Immunodeficiency Virus Envelope: DNA Vaccination with gp120-C3d Fusion Proteins
Article
AIDS Research and Human Retroviruses
17
9
829-835
oai:TheScholarship.intra.ecu.edu:10342/109852022-08-07T07:16:04Zcom_10342_74com_10342_73col_10342_527
Xu, Hui
Hu, Bo
Flesher, David A.
Liu, Jun
Motaleb, Md A.
2022-08-07T01:21:52Z
2022-08-07T01:21:52Z
2021-10-01
1664-302X
http://hdl.handle.net/10342/10985
10.3389/fmicb.2021.692707
en_US
Lyme disease
peptidoglycan hydrolases
cryo-elecron tomography
BB0259 Encompasses a Peptidoglycan Lytic Enzyme Function for Proper Assembly of Periplasmic Flagella in Borrelia burgdorferi
Article
Frontiers in Microbiology
12
oai:TheScholarship.intra.ecu.edu:10342/96282022-02-05T08:16:02Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:45:14Z
2022-02-04T13:45:14Z
2017-12-06
1949-2553
http://hdl.handle.net/10342/9628
10.18632/oncotarget.22956
en_US
drug transporters
MEK1
cancer stem cells
Drug-resistance in doxorubicin-resistant FL5.12 hematopoietic cells: elevated MDR1, drug efflux and side-population positive and decreased BCL2-Family Member Expression
Article
Oncotarget
8
68
113013-113033
oai:TheScholarship.intra.ecu.edu:10342/110452022-09-08T07:16:08Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Hopersberger, Dariel Anne
Microbiology and Immunology
2022-09-07T20:26:10Z
2022-07
2022-08-05
July 2022
2022-08-30T19:21:19Z
http://hdl.handle.net/10342/11045
Brucella abortus is an intracellular pathogen that causes spontaneous abortion in cattle and undulant fever in humans. As a member of the a-proteobacteria, B. abortus is closely related to the bacterial species Caulobacter crescentus and Agrobacterium tumefaciens, which have been shown to produce a holdfast and a unipolar polysaccharide (UPP), respectively, at one pole of the bacterial cell. Although little is currently known about exopolysaccharide production and function in Brucella species, recent evidence suggests that these bacteria are capable of producing exopolysaccharides, and with the exception of a flippase gene, B. abortus 2308 carries the genes for a complete UPP biosynthetic pathway.
In A. tumefaciens, UPP can be detected by crystal violet, Congo red, or lectin staining; however, UPP production was not detected in B. abortus 2308 using these assays. UPP production can also be increased in A. tumefaciens by overexpressing the diguanylate cyclase PleD, which regulates intracellular cyclic di-GMP levels, but we were unable to demonstrate that UPP is regulated by cyclic di-GMP in B. abortus 2308.
Nonetheless, upp homologs in B. abortus 2308 are able to restore biofilm production in A. tumefaciens. In A. tumefaciens, knockout mutants of the outer membrane transporter uppC
and the polyisoprenylphosphate hexose-1-phosphate transferase uppE result in strong biofilm phenotypes, wherein the ability of A. tumefaciens to produce a biofilm is nearly abrogated. B. abortus 2308 uppC and uppE homologs restore biofilm production in the respective Agrobacterium upp mutants, indicating that uppC and uppE from B. abortus 2308 produce functional proteins.
A uppCE mutant in B. abortus 2308 also exhibits significant attenuation in mice and an altered intracellular replication profile in cultured murine macrophages. Accordingly, uppCE appears to be required for virulence in B. abortus 2308, although by a currently unknown mechanism. Additional studies will be needed to determine whether B. abortus 2308 produces an authentic UPP as well as define the mechanisms by which the putative upp genes contribute to virulence.
application/pdf
en
East Carolina University
Brucella abortus, Unipolar Polysaccharide
A Wzx-Wzy-like Polysaccharide Biosynthetic Pathway Contributes to Virulence in Brucella abortus 2308 through an Unknown Mechanism
Doctoral Dissertation
text
2024-07-01
2024-07-01
Ph.D.
Doctoral
PHD-Microbiology & Immunology
East Carolina University
Microbiology and Immunology
Open Access
oai:TheScholarship.intra.ecu.edu:10342/32882021-03-03T20:54:25Zcom_10342_74com_10342_73col_10342_527
Gallagher, Larry A.
McKnight, Susan L.
Kuznetsova, Marina S.
Pesci, Everett C.
Manoil, Colin
2011-03-02T19:49:09Z
2011-05-17T01:40:10Z
2011-03-02T19:49:09Z
2011-05-17T01:40:10Z
2002-12
Journal of Bacteriology; 184:23 p. 6472-6480
http://hdl.handle.net/10342/3288
PMC135424
10.1128/JB.184.23.6472-6480.2002
A set of 30 mutants exhibiting reduced production of the phenazine poison pyocyanin were isolated following transposon mutagenesis of Pseudomonas aeruginosa PAO1. The mutants could be subdivided into those with defects in the primary phenazine biosynthetic pathway and those with more pleiotropic defects. The largest set of pleiotropic mutations blocked the production of the extracellular Pseudomonas quinolone signal (PQS), a molecule required for the synthesis of secondary metabolites and extracellular enzymes. Most of these pqs mutations affected genes which appear to encode PQS biosynthetic functions, although a transcriptional regulator and an apparent response effector were also represented. Two of the genes required for PQS synthesis (phnA and phnB) had previously been assumed to encode phenazine biosynthetic functions. The transcription of one of the genes required for PQS synthesis (PA2587/pqsH) was regulated by the LasI/R quorum-sensing system, thereby linking quorum sensing and PQS regulation. Others of the pleiotropic phenazine-minus mutations appear to inactivate novel components of the quorum-sensing regulatory network, including one regulator (np20) previously shown to be required for virulence in neutropenic mice. Originally published Journal of Bacteriology, Vol. 184, No. 23, Dec 2002
en_US
East Carolina University
http://jb.asm.org/cgi/content/abstract/184/23/6472
Author notified of opt-out rights by Cammie Jennings.
Pseudomonas aeruginosa
Quinolone signaling
Phenazine biosynthetic pathway
Functions Required for Extracellular Quinolone Signaling by Pseudomonas aeruginosa
Article
Journal of Bacteriology
184
23
6472-6480
oai:TheScholarship.intra.ecu.edu:10342/96492022-02-05T08:16:18Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:49:43Z
2022-02-04T13:49:43Z
2016-05
1945-4589
http://hdl.handle.net/10342/9649
10.18632/aging.100951
en_US
intragenic hypermethylation
MMP-9
melanoma
MMP�9 Overexpression is Associated with Intragenic Hypermethylation of MMP9 Gene in Melanoma
Article
8
5
933-944
oai:TheScholarship.intra.ecu.edu:10342/122052023-02-08T08:16:37Zcom_10342_74com_10342_73col_10342_527
Baumgartner, John
Pitzer, Josh E.
Roop, R. Martin II
Yurge, Svetlana N.
2023-02-07T19:05:08Z
2023-02-07T19:05:08Z
2002
0021-9258
http://hdl.handle.net/10342/12205
10.1016/j.jbc.2022.102377
en_US
formamidase
riboflavin biosynthesis
bacteria
A Novel Formamidase is Required for Riboflavin Biosynthesis in Invasive Bacteria
Article
Journal of Biological Chemistry
298
9
oai:TheScholarship.intra.ecu.edu:10342/56832021-03-03T21:07:39Zcom_10342_74com_10342_73col_10342_527
Martelli, Alberto M.
Evangelisti, Camilla
Chiarini, Francesca
Grimaldi, Cecilia
McCubrey, James A.
2016-06-22T16:42:03Z
2016-06-22T16:42:03Z
2010-08
Cancers; 2:3 p. 1576-1596
2072-6694
http://hdl.handle.net/10342/5683
pmc3837323
10.3390/cancers2031576
The cancer stem cell theory entails the existence of a hierarchically organized, rare population of cells which are responsible for tumor initiation, self-renewal/maintenance, and mutation accumulation. The cancer stem cell proposition could explain the high frequency of cancer relapse and resistance to currently available therapies. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway regulates a wide array of physiological cell functions which include differentiation, proliferation, survival, metabolism, autophagy, and motility. Dysregulated PI3K/Akt/mTOR signaling has been documented in many types of neoplasias. It is now emerging that this signaling network plays a key role in cancer stem cell biology. Interestingly, cancer stem cells displayed preferential sensitivity to pathway inhibition when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling pathways between neoplastic stem cells and healthy stem cells could be identified. In this review, we present the evidence which links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of cancer stem cells, both in solid and hematological tumors. We then highlight how targeting PI3K/Akt/mTOR signaling with small molecules could improve cancer patient outcome.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837323/
cancer stem cells
leukemic stem cells
PI3K/Akt/mTOR
proliferation
differentiation
targeted therapy
The Emerging Role of the Phosphatidylinositol 3-Kinase/ Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cell Biology
Article
Cancers
2
3
1576-1596
oai:TheScholarship.intra.ecu.edu:10342/56612021-03-03T21:05:55Zcom_10342_74com_10342_73col_10342_527
Curtis II, Alan Dale
Taslim, Najla
Reece, Shaun P.
Grebenciucova, Elena
Ray, Richard H.
Rosenbaum, Matthew D.
Wardle, Robert L.
Van Scott, Michael R.
Mannie, Mark D.
2016-06-16T17:52:53Z
2016-06-16T17:52:53Z
2014
PLoS ONE; 9:10 p. 1-17
1932-6203
http://hdl.handle.net/10342/5661
pmc4193844
10.1371/journal.pone.0110048
Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193844/
The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and Species
Article
PLoS ONE
9
10
1-17
oai:TheScholarship.intra.ecu.edu:10342/96392022-02-05T08:16:22Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:48:05Z
2022-02-04T13:48:05Z
2015-03-16
1949-2553
http://hdl.handle.net/10342/9639
10.18632/oncotarget.3295
en_US
PI3K isoforms
targeted therapy
autophagy
PI3K Pan-Inhibition Impairs More Efficiently Proliferation and Survival of T-Cell Acute Lymphoblastic Leukemia Cell Lines When Compared to Isoform-Selective PI3K Inhibitors
Article
Oncotarget
6
12
10399-10414
oai:TheScholarship.intra.ecu.edu:10342/33462021-03-03T20:54:33Zcom_10342_74com_10342_73col_10342_527
MacGregor, Carolyn H.
Arora, Shiwani K.
Hager, Paul W.
Dail, Mary Beth
Phibbs, Paul V. Jr.
2011-04-15T16:44:32Z
2011-05-17T01:40:05Z
2011-04-15T16:44:32Z
2011-05-17T01:40:05Z
1996-10
Journal of Bacteriology; 178:19 p. 5627-5635
http://hdl.handle.net/10342/3346
PMC178400
The gene (crc) responsible for catabolite repression control in Pseudomonas aeruginosa has been cloned and sequenced. Flanking the crc gene are genes encoding orotate phosphoribosyl transferase (pyrE) and RNase PH (rph). New crc mutants were constructed by disruption of the wild-type crc gene. The crc gene encodes an open reading frame of 259 amino acids with homology to the apurinic/apyrimidinic endonuclease family of DNA repair enzymes. However, crc mutants do not have a DNA repair phenotype, nor can the crc gene complement Escherichia coli DNA repair-deficient strains. The crc gene product was overexpressed in both P. aeruginosa and in E. coli, and the Crc protein was purified from both. The purified Crc proteins show neither apurinic/ apyrimidinic endonuclease nor exonuclease activity. Antibody to the purified Crc protein reacted with proteins of similar size in crude extracts from Pseudomonas putida and Pseudomonas fluorescens, suggesting a common mechanism of catabolite repression in these three species. Originally published Journal of Bacteriology, Vol. 178, No. 19, Oct 1996
en_US
East Carolina University
http://jb.asm.org/archive/1996.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Pseudomonas aeruginosa
Crc gene
Catabolite repression
The nucleotide sequence of the Pseudomonas aeruginosa pyrE-crc-rph region and the purification of the crc gene product.
Article
oai:TheScholarship.intra.ecu.edu:10342/117192022-11-09T08:16:53Zcom_10342_74com_10342_73col_10342_527
McCubrey, James Andrew
Abrams, Stephen L.
Steelman, Linda S.
2022-11-08T18:58:26Z
2022-11-08T18:58:26Z
2022-02-08
2218-273X
http://hdl.handle.net/10342/11719
10.3390/biom12020276
en_US
NAX compounds
berberine
mutant TP53 reactivators
APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells
Article
Biomolecules
12
2
oai:TheScholarship.intra.ecu.edu:10342/33692021-03-03T20:58:11Zcom_10342_74com_10342_73col_10342_527
Oglesby, Amanda G.
Farrow, John M. III
Lee, Joon-Hee
Tomaras, Andrew P.
Greenberg, E. Peter
Pesci, Everett C.
Vasil, Michael L.
2011-04-18T19:53:42Z
2011-05-17T01:40:06Z
2011-04-18T19:53:42Z
2011-05-17T01:40:06Z
2008-06-06
The Journal of Biological Chemistry; 283:23 p. 15558-15567
http://hdl.handle.net/10342/3369
PMC2414296
10.1074/jbc.M707840200
In iron-replete environments, the Pseudomonas aeruginosa Fur (ferric uptake regulator) protein represses expression of two small regulatory RNAs encoded by prrF1 and prrF2. Here we describe the effects of iron and PrrF regulation on P. aeruginosa physiology. We show that PrrF represses genes encoding enzymes for the degradation of anthranilate (i.e. antABC), a precursor of the Pseudomonas quinolone signal (PQS). Under ironlimiting conditions, PQS production was greatly decreased in a ∆ prrF1,2 mutant as compared with wild type. The addition of anthranilate to the growth medium restored PQS production to the ∆ prrF1,2 mutant, indicating that its defect in PQS production is a consequence of anthranilate degradation. PA2511 was
shown to encode an anthranilate-dependent activator of the ant genes and was subsequently renamed antR. AntR was not required for regulation of antA by PrrF but was required for optimal iron activation of antA. Furthermore, iron was capable of activating both antA and antR in a ∆ prrF1,2 mutant, indicating the presence of two distinct yet overlapping pathways for iron activation of antA (AntR-dependent and PrrF-dependent). Additionally, several quorum-sensing regulators, including PqsR, influenced antA expression, demonstrating that regulation of anthranilate metabolism is intimately woven into the
quorum-sensing network of P. aeruginosa. Overall, our data illustrate the extensive control that both iron regulation and quorum sensing exercise in basic cellular physiology, underlining how intermediary metabolism can affect the regulation of virulence factors in P. aeruginosa. Originally published Journal of Biological Chemistry, vol. 283, No. 23, June 2008
en_US
East Carolina University
http://www.jbc.org/content/283/23/15558
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Pseudomonas aeruginosa
Anthranilate
Quorum sensing
Iron environment
The Influence of Iron on Pseudomonas aeruginosa Physiology: A regulatory link between iron and quorum sensing
Article
The Journal of Biological Chemistry
283
23
15558-15567
oai:TheScholarship.intra.ecu.edu:10342/30002021-03-03T20:53:40Zcom_10342_74com_10342_73col_10342_527
Farrow, John M. III
Sund, Zoe M.
Ellison, Matthew L.
Wade, Dana S.
Coleman, James P.
Pesci, Everett C.
2010-11-10T15:52:44Z
2011-05-17T01:39:57Z
2010-11-10T15:52:44Z
2011-05-17T01:39:57Z
2008-11
Journal of Bacteriology; 190:21 p. 7043-7051
http://hdl.handle.net/10342/3000
PMC2580708
Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections in immunocompromised individuals. This gram-negative bacterium produces a battery of virulence factors that allow it to infect and survive in many different hostile environments. The control of many of these virulence factors falls under the influence of one of three P. aeruginosa cell-to-cell signaling systems. The focus of this study, the quinolone signaling system, functions through the Pseudomonas quinolone signal (PQS), previously identified as 2-heptyl-3-hydroxy-4-quinolone. This signal binds to and activates the LysR-type transcriptional regulator PqsR (also known as MvfR), which in turn induces the expression of the pqsABCDE operon. The first four genes of this operon are required for PQS synthesis, but the fifth gene, pqsE, is not. The function of the pqsE gene is not known, but it is required for the production of multiple PQS-controlled virulence factors and for virulence in multiple models of infection. In this report, we show that PqsE can activate PQS-controlled genes in the absence of PqsR and PQS. Our data also suggest that the regulatory activity of PqsE requires RhlR and indicate that a pqsE mutant can be complemented for pyocyanin production by a large excess of exogenous N-butyryl homoserine lactone (C4-HSL). Finally, we show that PqsE enhances the ability of Escherichia coli expressing RhlR to respond to C4-HSL. Overall, our data lead us to conclude that PqsE functions as a regulator that is independent of PqsR and PQS but dependent on the rhl quorum-sensing system. Originally published Journal of Bacteriology Vol. 190, No. 21.
en_US
East Carolina University
http://jb.asm.org/content/vol190/issue21/
Author notified of opt-out rights by Kent Nixon Myers prior to upload of this article.
Pseudomonas aeruginosa
Opportunistic pathogen
Quinolone signaling system
Transcription
Cellular regulation
Cell-to-cell signaling
PqsE Functions Independently of PqsR-Pseudomonas Quinolone Signal and Enhances the rhl Quorum-Sensing System
Article
oai:TheScholarship.intra.ecu.edu:10342/32422021-03-03T20:55:37Zcom_10342_74com_10342_73col_10342_527
Calfee, M. Worth
Shelton, John G.
McCubrey, James A.
Pesci, Everett C.
2011-02-17T15:57:51Z
2011-05-17T01:40:08Z
2011-02-17T15:57:51Z
2011-05-17T01:40:08Z
2005-02
Infection and Immunity; 73:2 p. 878-882
http://hdl.handle.net/10342/3242
PMC547021
Pseudomonas aeruginosa is a gram-negative bacterium that causes serious infections in immunocompromised individuals and cystic fibrosis patients. This opportunistic pathogen controls many of its virulence factors and cellular functions through the activity of three cell-to-cell signals, N-(3-oxododecanoyl)-L-homoserine lactone, N-butyryl-L-homoserine lactone, and the Pseudomonas quinolone signal (PQS). The activity of these signals is dependent upon their ability to dissolve in and freely diffuse through the aqueous solution in which P. aeruginosa happens to reside. Despite this, our data indicated that PQS was relatively insoluble in aqueous solutions, which led us to postulate that P. aeruginosa could be producing a PQS-solubilizing factor. In this report, we show that the P. aeruginosa-produced biosurfactant rhamnolipid greatly enhances the solubility of PQS in aqueous solutions. The enhanced solubility of PQS led to an increase in PQS bioactivity, as measured by both a gene induction assay and an apoptosis assay. This is the first demonstration of the importance of a bacterial surfactant in the solubilization and bioactivity of a cell-to-cell signal. Originally published Infection and Immunity, Vol. 73, No. 2, Feb 2005
en_US
East Carolina University
http://iai.asm.org/cgi/content/abstract/73/2/878
Pseudomonas quinolone signal
Biosurfactant
PQS solubility
Intercellular signals
Solubility and Bioactivity of the Pseudomonas Quinolone Signal Are Increased by a Pseudomonas aeruginosa-Produced Surfactant
Article
oai:TheScholarship.intra.ecu.edu:10342/62002021-03-03T21:14:14Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Lemasson, Isabelle
Fazio-Kroll, Ana Laura
Microbiology and Immunology
2017-06-01T12:14:43Z
2020-01-23T09:01:57Z
2017-05
2017-04-28
May 2017
2017-05-30T19:38:00Z
http://hdl.handle.net/10342/6200
The complex retrovirus Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of several diseases, including Adult T cell leukemia (ATL), a fatal hematological malignancy that affects mainly CD4+ T-cells. Freshly isolated ATL and HTLV-1 infected cells aggregate spontaneously in vitro. We have observed this same phenotype in T-cells exclusively expressing one of the viral proteins called HTLV-1 basic leucine zipper factor (HBZ). The hbz gene is uniquely encoded by the complementary strand of the HTLV-1 provirus and, in contrast to other HTLV-1 proteins, is constitutively expressed in ATL and HTLV-1-infected cells. High levels of aggregation in ATL cells have been correlated to an upregulation of the intercellular adhesion molecule-1 (ICAM-1). This protein is usually activated after T-cell stimulation and plays an important role in forming and stabilizing the immunological synapse. Interestingly, we found that cells expressing HBZ have an increase in ICAM-1 mRNA, which correlates with an increase in ICAM-1 at the cell surface. We confirmed by luciferase assay that HBZ expression stimulates ICAM-1 transcription. We found that blocking antibodies or peptides against ICAM-1 and its ligand, lymphocyte function-associated antigen 1 (LFA-1), dissociate the aggregates formed by HBZ-expressing cells, suggesting that ICAM-1 overexpression by HBZ mediates T-cell aggregation through interaction with LFA-1. Increased ICAM-1 expression at the cell surface is crucial for the formation of cell-to-cell contacts and efficient HTLV-1 transmission. To determine whether overexpression of ICAM-1 by HBZ plays a role in viral spread, we performed infection assays using a single-cycle, replication dependent reporter system. Interestingly, we found that HBZ expression significantly enhances HTLV-1 transmission. We confirmed that this effect involves the presence of LFA-1 on target cells. In addition, blocking the ICAM-1/LFA-1 interaction with an ICAM-1 antibody significantly reduced viral transmission. Therefore, ICAM-1 overexpression by HBZ plays a role in mediating viral transmission in our assays. A better understanding of the mechanisms used by HBZ to upregulate ICAM-1, induce cell-to-cell contact, and enhance virus transmission is important for future efforts to limit viral spread and prevent diseases in HTLV-1-infected individuals.
application/pdf
en
East Carolina University
Human T-lymphotropic virus 1
Protein HBZ
Viral transmission
NOVEL ROLE OF HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 ENCODED PROTEIN HBZ IN VIRAL TRANSMISSION THROUGH CELL-TO-CELL CONTACT
Doctoral Dissertation
text
Ph.D.
Doctoral
PHD-Microbiology & Immunology
East Carolina University
Microbiology and Immunology
Open Access
2019-05-01
oai:TheScholarship.intra.ecu.edu:10342/37272021-03-03T20:53:39Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
McCubrey, James A.
Chappell, William H.
Microbiology and Immunology
2012-01-18T20:13:16Z
2014-01-31T13:06:18Z
2011
http://hdl.handle.net/10342/3727
The development of prostate cancer from small regions of hyperplasia to invasive tumors requires genetic and epigenetic alterations of critical cellular components to aid in the development of cells more adapted for aberrant growth. Cell cycle control by the transcription factor p53 is necessary for the homeostatic proliferation and death of cells in response to DNA damage. Examination of prostate cancer cell lines harboring either wild-type (22Rv-1, LNCaP) or non-functional mutated p53 protein (DU145, PC3) responses to commonly used chemotherapeutic drugs demonstrated that p53 protein status dictated the apoptotic effectiveness a given drug would have on prostate cancer treatment. Moreover, restoration of functional p53 in p53-negative DU145 cells activated the Raf/MEK/ERK pathway through increased expression of a receptor tyrosine kinase, DDR1. Expression of NGAL, a small secreted extracellular protein belonging to the lipocalin super family, in early androgen receptor (AR) positive prostate cancer cell lines (22Rv-1, LNCaP) was demonstrated to increase these cells' invasiveness by their enhanced abilities to form colonies in soft agar. Conversely, reduced expression of NGAL in advanced AR negative prostate cancer cell lines (DU145, PC3) by use of a NGAL specific shRNA vector decreased their soft agar colony formation ability. In contrast to previously published studies, NGAL expression does not appear to augment drug sensitivity in these cell lines suggesting that NGAL's function in cancer is cell type specific. We also report here that the regulation of NGAL was mediated, in part, by NF-κB as a direct transcriptional target as previously reported and by p53 through some as of yet unknown mechanism. Detection of NGAL and NGAL:MMP-9 complexes in the urine of prostate patients, as well as others (glioblastoma, head & neck), indicated that NGAL could be potentially used as a biomarker for disease presence and progression. Taken together, our data suggests that p53 and NGAL function in the development and progression of prostate cancer. Â
Ph.D.
178 p.
dissertations, academic
East Carolina University
Oncology
Immunology
Biology
Chemotherapy
MMP-9
NGAL
p53
Prostate--Cancer
Soft agar
Biology, Genetics
Prostatic Neoplasms
Prostate-Specific Antigen
Protein-Tyrosine Kinases
LCN2 protein, human
RNA, Small Interfering
Acute-Phase Proteins
Proto-Oncogene Proteins
Lipocalins
Genetics
Neoplasms
Immunologic Techniques
Biological Markers
p53 and NGAL: dual regulatory roles in advanced prostate cancer
Doctoral Dissertation
oai:TheScholarship.intra.ecu.edu:10342/39072021-03-03T20:54:12Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Roop, Roy M., II.
Ojeda, Jenifer F.
Microbiology and Immunology
2012-05-20T15:27:02Z
2014-05-31T12:06:21Z
2012
http://hdl.handle.net/10342/3907
Brucella abortus is a Gram negative intracellular pathogen that causes the zoonotic disease brucellosis. Antibiotic treatment for brucellosis in humans is prolonged and sometimes followed by relapses. Currently, the United States employs prevention of the illness in humans through cattle vaccinations, eliminating the bacterium in its natural host. Unfortunately, these vaccine strains cause the disease in humans, and Brucella research ultimately aims to identify new vaccine targets as well as alternative treatment options. Brucella abortus resides in the phagosomal compartment of the host macrophage where essential nutrients such as iron are limited. Most bacteria need iron, and within the macrophage, heme is a likely source of iron due to the breakdown of red blood cells by the host macrophage. Heme transporters in Gram negative bacteria are highly conserved, and include components for outer membrane, periplasmic, and cytoplasmic membrane transport. BhuA has been previously characterized as the outer membrane heme transporter of Brucella abortus and here we report that BhuT, BhuU, and BhuV (BhuTUV) are the periplasmic and cytoplasmic heme transport components and that they are required in order for Brucella abortus to transport heme as an iron source. Utilization of heme as an iron source requires the breakdown of heme into ferrous iron, carbon monoxide, and biliverdin by a heme oxygenase. BhuO has been identified as a heme oxygenase in Brucella abortus , and although there seems to be more than one heme oxygenase in Brucella , this study shows that BhuO is needed for the use of heme as an iron source under iron starvation conditions in vitro. Further, both bhuTUV and bhuO are regulated in an iron-responsive manner. The iron responsive regulator Irr directly represses bhuO, which shares an operon with rirA . Then the rhizobial iron regulator RirA in turn represses the bhuTUV operon. Together, these regulators help to maintain iron homeostasis within the bacterial cell, protecting it from damaging hydroxyl radicals produced by Fenton chemistry.
Ph.D.
163 p.
dissertations, academic
East Carolina University
Microbiology
Biology
Biology, Molecular
Brucella
Heme
Iron
Irr
RirA
Biology, Microbiology
Molecular biology
Brucellosis
Brucella abortus
The bhuTUV and bhuO genes play vital roles in the ability of Brucella abortus to use heme as an iron source and are regulated in an iron-responsive manner by RirA and Irr
Doctoral Dissertation
oai:TheScholarship.intra.ecu.edu:10342/96482022-02-05T08:16:08Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:49:38Z
2022-02-04T13:49:38Z
2015-09-16
http://hdl.handle.net/10342/9648
en_US
synergistic apoptosis
acute lymphoblastic leukemia
targeted therapies
Co-Targeting of Bcl-2 and mTOR Pathway Triggers Synergistic Apoptosis in BH3 Mimetics Resistant Acute Lymphoblastic Leukemia
Article
Oncotarget
6
31
32089-32103
oai:TheScholarship.intra.ecu.edu:10342/76132021-12-01T09:01:54Zcom_10342_122com_10342_74com_10342_73col_10342_124col_10342_527
Rohlik, Denise L
Microbiology and Immunology
2020-02-04T15:19:08Z
2021-12-01T09:01:54Z
2019-12
2019-12-12
December 2019
2020-01-29T14:30:30Z
http://hdl.handle.net/10342/7613
Complement is a proteolytic cascade that upon activation plays a key effector role in the innate immune system and acts to prime the adaptive immune response. During normal homeostatic events, complement is tightly regulated for its roles in immune complex clearance, lysis of target cells, opsonization, and recruitment of leukocytes and monocytes to target areas. Several endogenous regulators are responsible for the control of complement activation, however when dysregulation occurs, aberrant complement activation has been linked to autoimmune, proinflammatory, and neurodegenerative diseases, including Alzheimer’s disease. Inhibition of the classical complement component C1 may ameliorate hallmarks of autoimmune and inflammatory disease.
The serine proteases within the C1 complex, C1r and C1s, are promising therapeutic targets for structure-based small-molecule drug development. We investigated the activity of a series of small-molecule compounds identified in a large-scale fragment library screen and those from a cheminformatics computational docking screen in which hit compounds were predicted to bind the C1r or C1s proteases. Using surface plasmon resonance and ELISA-based assays for hit validation, we analyzed the binding affinities and the inhibitory IC50’s of several compounds predicted to bind and inhibit the activation of C1r or C1s in a dose-dependent manner. In this study, we have identified four lead compounds (cmp-1611, cmp-1663, cmp-1696, cmp-1827) and their 10 active structural analogues that target and inhibit C1r activation.
Given their abilities to bind and inhibit C1r and favorable physicochemical properties, our lead compounds may provide a starting point for optimizing affinity and specificity necessary for developing novel routes of therapeutic upstream complement inhibition.
application/pdf
en
East Carolina University
Complement
classical pathway
small-molecule inhibitor
C1r
C1s
Development of small-molecule inhibitors of the initiating proteases, C1r and C1s, of the classical complement pathway
Master's Thesis
text
M.S.
Masters
MS-Biomedical Science
East Carolina University
Microbiology and Immunology
Open Access
2021-12-01
oai:TheScholarship.intra.ecu.edu:10342/56692021-03-03T21:08:01Zcom_10342_74com_10342_73col_10342_527
Abbott, Derek J.
Blanchfield, J. Lori
Martinson, David A.
Russell, Sean C.
Taslim, Najla
Curtis II, Alan Dale
Mannie, Mark D.
2016-06-16T19:24:52Z
2016-06-16T19:24:52Z
2011
BMC Immunology; 12: p. 72-72
1471-2172
http://hdl.handle.net/10342/5669
pmc3261124
10.1186/1471-2172-12-72
Background
Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.
Results
A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.
Conclusion
These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261124/
Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE)
Article
BMC Immunology
12
72-72
oai:TheScholarship.intra.ecu.edu:10342/124332023-03-23T14:39:35Zcom_10342_74com_10342_73col_10342_527
Garrigues, Ryan J.
Garcia, Brandon L.
et al
2023-03-23T14:39:35Z
2023-03-23T14:39:35Z
2022
0027-8424
10.1073/pnas.2117770119
http://hdl.handle.net/10342/12433
en_US
complement C1 j
lipoprotein
Borrelia burgdorferi
Lipoproteome Screening of the Lyme Disease Agent Identifies Inhibitors of Antibody-Mediated Complement Killing
Article
Proceedings of the National Academy of Sciences of the United States of America
119
13
oai:TheScholarship.intra.ecu.edu:10342/96502022-02-05T08:16:20Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
2022-02-04T13:49:50Z
2022-02-04T13:49:50Z
2020-01-14
2073-4409
http://hdl.handle.net/10342/9650
10.3390/cells9010205
en_US
Warburg Effect
Cancer Cells
Fibroblasts
The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts
Article
Cells
9
1
oai:TheScholarship.intra.ecu.edu:10342/55682021-03-03T21:07:55Zcom_10342_74com_10342_73col_10342_527
Gizak, Agnieszka
Grenda, Marcin
Mamczur, Piotr
Wisniewski, Janusz
Sucharski, Filip
Silberring, Jerzy
McCubrey, James A.
Wisniewski, Jacek R.
Rakus, Dariusz
2016-06-14T13:17:31Z
2016-06-14T13:17:31Z
2015-07
Oncotarget; 6:19 p. 17237-17250
1949-2553
http://hdl.handle.net/10342/5568
pmc4627304
Phosphoglycerate mutase (PGAM), a conserved, glycolytic enzyme has been found in nucleoli of cancer cells. Here, we present evidence that accumulation of PGAM in the nucleolus is a universal phenomenon concerning not only neoplastically transformed but also non-malignant cells. Nucleolar localization of the enzyme is dependent on the presence of the PGAM2 (muscle) subunit and is regulated by insulin/IGF-1–PI3K signaling pathway as well as drugs influencing ribosomal biogenesis. We document that PGAM interacts with several 40S and 60S ribosomal proteins and that silencing of PGAM2 expression results in disturbance of nucleolar structure, inhibition of RNA synthesis and decrease of the mitotic index of squamous cell carcinoma cells. We conclude that presence of PGAM in the nucleolus is a prerequisite for synthesis and initial assembly of new pre-ribosome subunits.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627304/
squamous cell carcinoma
PGAM2
rRNA
ribosome assembly
multifunctional enzyme
Insulin/IGF1-PI3K-dependent nucleolar localization of a glycolytic enzyme – phosphoglycerate mutase 2, is necessary for proper structure of nucleolus and RNA synthesis
Article
Oncotarget
6
19
17237-17250
oai:TheScholarship.intra.ecu.edu:10342/97532024-02-09T09:01:58Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Pesci, Everett C
Palethorpe, Samantha
Microbiology and Immunology
2022-02-11T17:11:01Z
2024-02-09T09:01:58Z
2021-12
2021-09-22
December 2021
2022-02-08T15:30:41Z
http://hdl.handle.net/10342/9753
The Gram-negative bacterium Acinetobacter baumannii is considered one of the most serious nosocomial pathogens worldwide. Predominantly responsible for ventilator-associated pneumonia, this insidious pathogen typically infects critically ill individuals and patients in long-term care. A. baumannii harbors a myriad of resistance mechanisms to aid its survival in both the environment and the host. Remarkably, A. baumannii does not encode an RpoS sigma factor homolog that is used to control the general stress response by the majority of Gram-negative bacteria. Instead, A. baumannii relies on an intricate regulatory network involving numerous two-component regulatory systems to respond to stress. Two key players that contribute to A. baumannii's "persist and resist" survival mechanisms are the BfmRS and PmrAB two-component regulatory systems. We have demonstrated that the response regulator BfmR can directly activate numerous stress-related pathways. We also provide evidence that the sensor kinase BfmS acts as a phosphatase to negatively regulate BfmR activity. Overall, we show that the BfmRS system harbors the characteristics of a master regulator by controlling the osmotic stress response, the oxidative stress response, the misfolded protein response, csu pili/fimbriae production, capsule polysaccharide biosynthesis, siderophore biosynthesis and transport, type IV pili production, and antibiotic resistance. Additionally, the PmrAB two-component system contributes to antibiotic resistance in A. baumannii. Clinically relevant mutations that arise in the pmrCAB operon often promote resistance to the last resort antibiotic colistin. We biochemically characterized the response regulator PmrA to identify its DNA-binding domain, in addition to the potential PmrA regulon. We also provide the first structural information for the PmrA N-terminal domain. Together, these data allowed us to analyze the structural and dynamic changes in two clinically relevant PmrA point mutants that alter the function of PmrA and promote colistin resistance. Understanding these regulatory mechanisms at a molecular level will allow us to explore novel ways to develop effective antimicrobial agents to combat this serious pathogen.
application/pdf
en
East Carolina University
BfmRS
colistin resistance
PmrA
response regulator
stress-response
trehalose
two-component system
Drug Resistance, Bacterial
Acinetobacter baumannii
Acinetobacter Infections
The respective roles of BfmRS and PmrA in stress responses and antibiotic resistance in Acinetobacter baumannii
Doctoral Dissertation
text
Ph.D.
Doctoral
PHD-Microbiology & Immunology
East Carolina University
Microbiology and Immunology
Restricted Campus Access Only
2023-12-01
oai:TheScholarship.intra.ecu.edu:10342/33192021-03-03T20:54:27Zcom_10342_74com_10342_73col_10342_527
Kang, Ho Young
Brickman, Timothy J.
Beaumont, Fiona C.
Armstrong, Sandra K.
2011-04-13T20:58:34Z
2011-05-17T01:40:07Z
2011-04-13T20:58:34Z
2011-05-17T01:40:07Z
1996-08
Journal of Bacteriology; 178:16 p. 4877-4884
http://hdl.handle.net/10342/3319
PMC178270
Bordetella bronchiseptica mutants BRM1, BRM6, and BRM9 fail to produce the native dihydroxamate siderophore alcaligin. A 4.5-kb BamHI-SmaI Bordetella pertussis genomic DNA fragment carried multiple genes required to restore alcaligin production to these siderophore-deficient mutants. Phenotypic complementation analysis using subclones of the 4.5-kb genomic region demonstrated that the closely linked BRM1 and BRM9 mutations were genetically separable from the BRM6 mutation, and both insertions exerted strong polar effects on expression of the downstream gene defined by the BRM6 mutation, suggesting a polycistronic transcriptional organization of these alcaligin biosynthesis genes. Subcloning and complementation experiments localized the putative Bordetella promoter to a 0.7-kb BamHI-SphI subregion of the cloned genomic DNA fragment. Nucleotide sequencing, phenotypic analysis of mutants, and protein expression by the 4.5-kb DNA fragment in Escherichia coli suggested the presence of three alcaligin system genes, namely, alcA, alcB, and alcC. The deduced protein products of alcA, alcB, and alcC have significant primary amino acid sequence similarities with known microbial siderophore biosynthesis enzymes. Primer extension analysis mapped the transcriptional start site of the putative alcaligin biosynthesis operon containing alcABC to a promoter region overlapping a proposed Fur repressor-binding site and demonstrated iron regulation at the transcriptional level. Originally published Journal of Bacteriology, Vol. 178, No. 16, Aug 1996
en_US
East Carolina University
http://jb.asm.org/archive/1996.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Alcaligin
Bordetella pertussis
Biosynthesis genes
Identification and characterization of iron-regulated Bordetella pertussis alcaligin siderophore biosynthesis genes.
Article
Journal of Bacteriology
178
16
4877-4884
oai:TheScholarship.intra.ecu.edu:10342/32312021-03-03T20:53:47Zcom_10342_74com_10342_73col_10342_527
Brodie, Ryan
Smith, Alex J.
Roper, Rachel L.
Tcherepanov, Vasily
Upton, Chris
2011-02-17T15:21:54Z
2011-05-17T01:39:59Z
2011-02-17T15:21:54Z
2011-05-17T01:39:59Z
2004-07-14
BMC Bioinformatics; 5:96 p. 1-9
http://hdl.handle.net/10342/3231
PMC481056
10.1186/1471-2105-5-96
Background: With ever increasing numbers of closely related virus genomes being sequenced, it has become desirable to be able to compare two genomes at a level more detailed than gene content because two strains of an organism may share the same set of predicted genes but still differ in their pathogenicity profiles. For example, detailed comparison of multiple isolates of the smallpox virus genome (each approximately 200 kb, with 200 genes) is not feasible without new bioinformatics tools. Results: A software package, Base-By-Base, has been developed that provides visualization tools to enable researchers to 1) rapidly identify and correct alignment errors in large, multiple genome alignments; and 2) generate tabular and graphical output of differences between the genomes at the nucleotide level. Base-By-Base uses detailed annotation information about the aligned genomes and can list each predicted gene with nucleotide differences, display whether variations occur within promoter regions or coding regions and whether these changes result in amino acid substitutions. Base-By-Base can connect to our mySQL database (Virus Orthologous Clusters; VOCs) to retrieve detailed annotation information about the aligned genomes or use information from text files. Conclusion: Base-By-Base enables users to quickly and easily compare large viral genomes; it highlights small differences that may be responsible for important phenotypic differences such as virulence. It is available via the Internet using Java Web Start and runs on Macintosh, PC and Linux operating systems with the Java 1.4 virtual machine. Originally published BMC Bioinformatics, Vol. 5, No. 96, July 2004
en_US
East Carolina University
http://www.biomedcentral.com/1471-2105/5/96
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Viral genomes
Nucleotide differences
Software usage
Base-By-Base: Single nucleotide-level analysis of whole viral genome alignments
Article
BMC Bioinformatics
5
96
1-9
oai:TheScholarship.intra.ecu.edu:10342/30812021-03-03T20:54:09Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
Steelman, Linda S.
Franklin, Richard A.
Abrams, Stephen L.
Chappell, William H.
Wong, Ellis W.T.
Lehmann, Brian D.
Terrian, David M.
Basecke, Jorg
Stivala, Franca
Libra, Massimo
Evangelisti, Camilla
Martelli, Alberto M.
2011-01-21T21:01:56Z
2011-05-17T01:40:01Z
2011-01-21T21:01:56Z
2011-05-17T01:40:01Z
2007
Advances in Enzyme Regulation; 47:1 p. 64-103
http://hdl.handle.net/10342/3081
PMC2696319
en_US
East Carolina University
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3T-4NBR8HF-1&_user=634873&_coverDate=12%2F31%2F2007&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000033758&_version=1&_urlVersion=0&_userid=634873&md5=819562c1e4c3462b24f2705832803fa4&searchtype=a
Hematopoietic drug resistance
Acute myeloid leukemia
RAF/MEK/ERK pathway
PI3K/AKT pathway
p53 pathway
Targeting the RAF/MEK/ERK, PI3K/AKT and P53 pathways in hematopoietic drug resistance
Article
oai:TheScholarship.intra.ecu.edu:10342/56902021-03-03T21:06:27Zcom_10342_74com_10342_73col_10342_527
Peloponese, Jean-Marie
Lemasson, Isabelle
Barbeau, Benoit
Mesnard, Jean-Michel
2016-06-22T20:03:12Z
2016-06-22T20:03:12Z
2011
Retrovirology; 8:Suppl 1 p. A135-A135
1742-4690
http://hdl.handle.net/10342/5690
pmc3112604
10.1186/1742-4690-8-S1-A135
Infection with the human T-cell leukemia virus type 1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia (ATL), a fatal malignancy characterized by the uncontrolled proliferation of virally infected CD4+ T cells. The HTLV-1 basic leucine zipper factor (HBZ) is believed to contribute to development and maintenance of ATL. Unlike the other HTLV-1 genes, the hbz gene is encoded on the complementary strand of the provirus and therefore is not under direct control of the promoter within the 5′ long terminal repeat (LTR) of the provirus. This promoter can undergo inactivating genetic or epigenetic changes during the course of ATL that eliminates expression of all viral genes except that of hbz. In contrast, repressive modifications are not known to occur on the hbz promoter located in the 3′ LTR, and hbz expression has been consistently detected in all ATL patient samples. Although Sp1 regulates basal transcription from the HBZ promoter, other factors that activate transcription remain undefined. In this study, we used a proviral reporter construct deleted of the 5′ LTR to show that HBZ upregulates its own expression through cooperation with JunD. Activation of antisense transcription was apparent in serum-deprived cells in which the level of JunD was elevated, and elimination of JunD expression by gene knockout or shRNA-mediated knockdown abrogated this effect. Activation through HBZ and JunD additionally required Sp1 binding at the hbz promoter. These data favor a model in which JunD is recruited to the promoter through Sp1, where it heterodimerizes with HBZ thereby enhancing its activity. Separately, hbz gene expression led to an increase in JunD abundance, and this effect correlated with emergence of features of transformed cells in immortalized fibroblasts. Overall, our results suggest that JunD represents a novel therapeutic target for the treatment of ATL.
http://jvi.asm.org/content/86/17/9070.full
JunD/HBZ enhances HBZ enhances HTLV-1 antisense transcription
Article
Retrovirology
8
Suppl 1
A135-A135
oai:TheScholarship.intra.ecu.edu:10342/31402021-03-03T20:54:03Zcom_10342_74com_10342_73col_10342_527
Tribble, Gena D.
Parker, Anita C.
Smith, C. Jeffrey
2011-01-28T19:54:18Z
2011-05-17T01:40:00Z
2011-01-28T19:54:18Z
2011-05-17T01:40:00Z
1997-04
Journal of Bacteriology; 179:8 p. 2731-2739
http://hdl.handle.net/10342/3140
PMC179024
The Bacteroides mobilizable transposon Tn4555 is a 12.2-kb molecule that encodes resistance to cefoxitin. Conjugal transposition is hypothesized to occur via a circular intermediate and is stimulated by coresident tetracycline resistance elements and low levels of tetracycline. In this work, the ends of the transposon were identified and found to consist of 12-bp imperfect inverted repeats, with an extra base at one end. In the circular form, the ends were separated by a 6-bp “coupling sequence� which was associated with either the left or the right transposon terminus when the transposon was inserted into the chromosome. Tn4555 does not duplicate its target site upon insertion. Using a conjugation-based transposition assay, we showed that the
coupling sequence originated from 6 bases of genomic DNA flanking either side of the transposon prior to excision. Tn4555 preferentially transposed into a 589-bp genomic locus containing a 207-bp direct repeat. Integration occurred before or after the repeated sequence, with one integration site between the two repeats. These observations are consistent with a transposition model based on site-specific recombination. In the bacteriophage lambda model for site-specific recombination, the bacteriophage recombines with the Escherichia
coli chromosome via a 7-bp “crossover� region. We propose that the coupling sequence of Tn4555 is analogous in function to the crossover region of lambda but that unlike the situation in lambda, recombination
occurs between regions of nonhomologous DNA. This ability to recombine into divergent target sites is also a feature of the gram-positive bacterial transposon Tn916. Originally published Journal of Bacteriology, Vol. 179, No. 8, Apr 1997
en_US
East Carolina University
http://jb.asm.org/archive/1997.dtl
Author notified of opt-out rights by Cammie Jennings
Mobilizable transposon
Conjugal transposition
Recombination
The Bacteroides mobilizable transposon Tn4555 integrates by a site-specific recombination mechanism similar to that of the gram-positive bacterial element Tn916
Article
Journal of Bacteriology
179
8
2731-2739
oai:TheScholarship.intra.ecu.edu:10342/34582021-03-03T20:54:40Zcom_10342_74com_10342_73col_10342_527
Brickman, Timothy J.
Armstrong, Sandra K.
2011-04-29T13:25:57Z
2011-05-17T01:40:07Z
2011-04-29T13:25:57Z
2011-05-17T01:40:07Z
1996-01
Journal of Bacteriology; 178:1 p. 54-60
http://hdl.handle.net/10342/3458
PMC177620
Chromosomal insertions defining Bordetella bronchiseptica siderophore phenotypic complementation group III mutants BRM3 and BRM5 were found to reside approximately 200 to 300 bp apart by restriction mapping of cloned genomic regions associated with the insertion markers. DNA hybridization analysis using B. bronchiseptica genomic DNA sequences flanking the cloned BRM3 insertion marker identified homologous Bordetella pertussis UT25 cosmids that complemented the siderophore biosynthesis defect of the group III B. bronchiseptica mutants. Subcloning and complementation analysis localized the complementing activity to a 2.8-kb B. pertussis genomic DNA region. Nucleotide sequencing identified an open reading frame predicted to encode a polypeptide exhibiting strong similarity at the primary amino acid level with several pyridoxal phosphate-dependent amino acid decarboxylases. Alcaligin production was fully restored to group III mutants by supplementation of iron-depleted culture media with putrescine (1,4-diaminobutane), consistent with defects in an ornithine decarboxylase activity required for alcaligin siderophore biosynthesis. Concordantly, the alcaligin biosynthesis defect of BRM3 was functionally complemented by the heterologous Escherichia coli speC gene encoding an ornithine decarboxylase activity. Enzyme assays confirmed that group III B. bronchiseptica siderophore-deficient mutants lack an ornithine decarboxylase activity required for the biosynthesis of alcaligin. Siderophore production by an analogous mutant of B. pertussis constructed by allelic exchange was undetectable. We propose the designation odc for the gene defined by these mutations that abrogate alcaligin siderophore production. Putrescine is an essential precursor of alcaligin in Bordetella spp. Originally published Journal of Bacteriology, Vol. 178, No. 1, Jan 1996
en_US
East Carolina University
http://jb.asm.org/archive/1996.dtl
Author notified of opt-out rights by Cammie Jennings prior to upload of this article.
Bordetella bronchiseptica
Siderophore
Ornithine decarboxylase
The ornithine decarboxylase gene odc is required for alcaligin siderophore biosynthesis in Bordetella spp.: putrescine is a precursor of alcaligin.
Article
oai:TheScholarship.intra.ecu.edu:10342/46582021-03-03T20:58:16Zcom_10342_122com_10342_74com_10342_73col_10342_123col_10342_527
Smith, C. Jeffrey
Cao, Yanlu
Microbiology and Immunology
2015-02-02T19:25:35Z
2017-02-07T22:22:34Z
2014
http://hdl.handle.net/10342/4658
Bacteroides fragilis is the most common anaerobe isolated from clinical infections and in this report we demonstrate a novel feature of the species that is critical to their success as an opportunistic pathogen. Among the Bacteroides spp. in the gut, B. fragilis has a unique ability to efficiently harvest complex N-linked glycans from the glycoproteins common to serum and serous fluid. This activity is mediated by a Sus-like outer membrane protein complex designated as Don. Using the abundant serum glycoprotein transferrin as a model it was shown that B. fragilis alone can rapidly and efficiently deglycosylate this protein in vitro and that transferrin glycans can provide the sole source of carbon and energy for growth in defined media. We then showed that transferrin deglycosylation occurs in vivo when B. fragilis is propagated in the rat tissue cage model of extraintestinal growth and that this ability provides a competitive advantage in vivo over strains lacking the don locus. Thus, Don functionally is an extraintestinal growth factor that may contribute to B. fragilis opportunistic infection. The regulation of don expression is controlled by two independent pathways. The first one was shown to be a typical ECF sigma/anti-sigma factor switch, commonly found in Sus-like Polysaccharide Utilization Loci (PULs), which responds to the presence of specific substrate. In the ECF sigma factor deletion mutant, [delta]donA, expression of the don PUL was completely abolished in the presence of substrate glycans, while the cognate anti-sigma deletion strain, [delta]donB, expressed the don genes even in the absence of substrate glycans. The donA overexpressing strain highly expressed the don PUL regardless of the substrate glycan presence. The second regulatory pathway is involved with a cis-encoded antisense sRNA which is associated within the don locus, DonS. DonS was shown to negatively regulate don expression. In contrast, expression of the don genes was induced two- to six-fold in the donS silencing mutant and highly repressed in the donS overexpressing strain. Notably, this sRNA controlled regulatory pathway is not commonly found associated with B. fragilis PULs. Only 14 of more than 50 PULs in B. fragilis possess DonS-like sRNAs, but at the present time their roles in commensal colonization and opportunistic infections is not understood.
Ph.D.
215 p.
dissertations, academic
East Carolina University
Microbiology
Medicine
Immunology
Abdominal abscesses
Bacteroides fragilis
Glycoproteins
Microbiota
Polysccharide utiliztion
Sus-like systems
Bacteroides Infections
Naphthalenesulfonates--chemistry
Bacteremia--microbiology
Bacteroides fragilis--metabolism
Function and regulation of the polysaccharide utilization locus, don, in the gut symbiont bacteroides fragilis
Doctoral Dissertation
oai:TheScholarship.intra.ecu.edu:10342/56722022-12-13T19:20:32Zcom_10342_74com_10342_73col_10342_527
McCubrey, James A.
Steelman, Linda S.
Chappell, William H.
Sun, Lin
Davis, Nicole Marie
Abrams, Stephen L.
Franklin, Richard A.
Cocco, Lucio
Evangelisti, Camilla
Chiarini, Francesca
Martelli, Alberto M.
Libra, Massimo
Candido, Saverio
Ligresti, Giovanni
Malaponte, Graziella
Mazzarino, Maria C.
Fagone, Paolo
Donia, Marco
Nicoletti, Ferdinando
Polesel, Jerry
Talamini, Renato
Bäsecke, Jörg
Mijatovic, Sanja
Maksimovic-Ivanic, Danijela
Milella, Michele
Tafuri, Agostino
Dulińska-Litewka, Joanna
Laidler, Piotr
D'Assoro, Antonino B.
Drobot, Lyudmyla B.
Umezawa, Kazuo
Montalto, Giuseppe
Cervello, Melchiorre
Demidenko, Zoya N.
2016-06-16T19:38:50Z
2016-06-16T19:38:50Z
2012-12
Oncotarget; 3:12 p. 1505-1521
1949-2553
http://hdl.handle.net/10342/5672
pmc3681490
Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681490/
Targeted Therapy
Therapy Resistance
Cancer Stem Cells
Raf
Akt
PI3K
mTOR
AMPK
Metformin
Advances in Targeting Signal Transduction Pathways
Article
Oncotarget
3
12
1505-1521
oai:TheScholarship.intra.ecu.edu:10342/107852022-07-19T07:16:06Zcom_10342_74com_10342_73col_10342_527
Abrams, Stephen L.
Akula, Shaw M.
Meher, Akshaya K.
Steelman, Linda S.
Gizak, Agnieszka
Duda, Przemysław
Rakus, Dariusz
Martelli, Alberto M.
Ratti, Stefano
Cocco, Lucio
Montalto, Giuseppe
Cervello, Melchiorre
Ruvolo, Peter
Libra, Massimo
Falzone, Luca
Candido, Saverio
McCubrey, James A.
2022-07-18T18:14:50Z
2022-07-18T18:14:50Z
2021-04
2073-4409
http://hdl.handle.net/10342/10785
10.3390/cells10040816
en_US
chemotherapeutic drugs
targeted therapy
breast cancer
GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals
Article
Cells
10
4
816
oai:TheScholarship.intra.ecu.edu:10342/30762021-03-03T20:54:02Zcom_10342_74com_10342_73col_10342_527
Rocha, Edson R.
Selby, Tina
Coleman, James P.
Smith, C. Jeffrey
2011-01-21T20:57:26Z
2011-05-17T01:40:02Z
2011-01-21T20:57:26Z
2011-05-17T01:40:02Z
1996-12
Journal of Bacteriology; 178:23 p. 6895-6903
http://hdl.handle.net/10342/3076
PMC178591
Survival of Bacteroides fragilis in the presence of oxygen was dependent on the ability of bacteria to synthesize
new proteins, as determined by the inhibition of protein synthesis after oxygen exposure. The B. fragilis protein
profile was significantly altered after either a shift from anaerobic to aerobic conditions with or without
paraquat or the addition of exogenous hydrogen peroxide. As determined by autoradiography after twodimensional
gel electrophoresis, approximately 28 newly synthesized proteins were detected in response to
oxidative conditions. These proteins were found to have a broad range of pI values (from 5.1 to 7.2) and
molecular weights (from 12,000 to 79,000). The hydrogen peroxide- and paraquat-inducible responses were
similar but not identical to that induced by oxygen as seen by two-dimensional gel protein profile. Eleven of the
oxidative response proteins were closely related, with pI values and molecular weights from 5.1 to 5.8 and from
17,000 to 23,000, respectively. As a first step to understanding the resistance to oxygen, a catalase-deficient
mutant was constructed by allelic gene exchange. The katB mutant was found to be more sensitive to the lethal
effects of hydrogen peroxide than was the parent strain when the ferrous iron chelator bipyridyl was added to
culture media. This suggests that the presence of ferrous iron in anaerobic culture media exacerbates the
toxicity of hydrogen peroxide and that the presence of a functional catalase is important for survival in the
presence of hydrogen peroxide. Further, the treatment of cultures with a sublethal concentration of hydrogen
peroxide was necessary to induce resistance to higher concentrations of hydrogen peroxide in the parent strain,
suggesting that this was an inducible response. This was confirmed when the bacterial culture, treated with
chloramphenicol before the cells were exposed to a sublethal concentration of peroxide, completely lost
viability. In contrast, cell viability was greatly preserved when protein synthesis inhibition occurred after
peroxide induction. Complementation of catalase activity in the mutant restored the ability of the mutant
strain to survive in the presence of hydrogen peroxide, showing that the catalase (KatB) may play a role in
oxidative stress resistance in aerotolerant anaerobic bacteria. Originally published Journal of Bacteriology, Vol. 178, No. 23, Dec. 1996
en_US
East Carolina University
http://jb.asm.org/archive/1996.dtl
Oxidative stress
Catalase
Hydrogen peroxide resistance
Oxidative stress response in an anaerobe, Bacteroides fragilis: a role for catalase in protection against hydrogen peroxide.
Article
dim///col_10342_527/100