Molecular characterization of the activation domain of the HTLV-1 HBZ protein and its interaction with the KIX domain of the cellular transcriptional coactivators p300 and CBP
Author
Cook, Pamela Renee
Abstract
The complex retrovirus human T-cell leukemia virus type I (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Deregulation of cellular transcription is thought to be a key event in virally-mediated T-cell transformation. The HTLV-1 basic leucine zipper factor (HBZ) originates from the 3' long terminal repeat (LTR) and is transcribed from the sense DNA strand relative to other viral genes. HBZ is the only viral gene known to be consistently expressed in ATL cells. HBZ is able to repress HTLV-1 transcription, in part, by binding to the homologous cellular coactivators p300 and CREB-binding protein (CBP). HBZ binds the kinase-inducible interaction (KIX) domain of p300/CBP via two φXXφφ motifs in the activation domain of HBZ (HBZ-AD). In this study, it was determined that HBZ-AD binds with high affinity to the KIX domain of p300/CBP with an apparent equilibrium dissociation constant (K<sub>d</sub>) of 3.2 ± 0.5 nM. The KIX domain contains two binding surfaces that are differentially targeted by various transcriptional regulatory proteins. One surface of KIX can bind the activation domain of the mixed lineage leukemia (MLL-AD) protein and the HTLV-1 transactivator Tax, among others. The other surface of KIX can contact the cellular transcription factors c-Myb or cyclic AMP (cAMP) response element binding protein (CREB). HBZ-AD was determined to bind the MLL-AD-binding surface of KIX and to compete with MLL-AD, Tax, and p53 for KIX binding. HBZ-AD was additionally found to significantly enhance the binding of the activation domain of c-Myb (c-Myb-AD) and CREB to KIX. HBZ was also shown to inhibit transcriptional activation mediated by MLL-AD and enhance activation mediated by c-Myb-AD. These results indicate that HBZ is able to alter gene expression by competing with one group of transcription factors for occupancy of KIX while enhancing the binding of other factors to a different surface on KIX.
Subject
Date
2010
Citation:
APA:
Cook, Pamela Renee.
(January 2010).
Molecular characterization of the activation domain of the HTLV-1 HBZ protein and its interaction with the KIX domain of the cellular transcriptional coactivators p300 and CBP
(Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship.
(http://hdl.handle.net/10342/3165.)
MLA:
Cook, Pamela Renee.
Molecular characterization of the activation domain of the HTLV-1 HBZ protein and its interaction with the KIX domain of the cellular transcriptional coactivators p300 and CBP.
Doctoral Dissertation. East Carolina University,
January 2010. The Scholarship.
http://hdl.handle.net/10342/3165.
September 30, 2023.
Chicago:
Cook, Pamela Renee,
“Molecular characterization of the activation domain of the HTLV-1 HBZ protein and its interaction with the KIX domain of the cellular transcriptional coactivators p300 and CBP”
(Doctoral Dissertation., East Carolina University,
January 2010).
AMA:
Cook, Pamela Renee.
Molecular characterization of the activation domain of the HTLV-1 HBZ protein and its interaction with the KIX domain of the cellular transcriptional coactivators p300 and CBP
[Doctoral Dissertation]. Greenville, NC: East Carolina University;
January 2010.
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Publisher
East Carolina University