Dimeric and tetrameric forms of muscle fructose-1,6- bisphosphatase play different roles in the cell
Wiśniewski, Janusz; Piróg, Michał; Hołubowicz, Rafał; Dobryszycki, Piotr; McCubrey, James A.; Rakus, Dariusz; Gizak, Agnieszka
Muscle fructose 1,6-bisphosphatase (FBP2), besides being a regulatory enzyme of glyconeogenesis also protects mitochondria against calcium stress and plays a key role in regulation of the cell cycle, promoting cardiomyocytes survival. However, in cancer cells, FBP2 acts as an anti-oncogenic/anti-proliferative protein. Here, we show that the physiological function of FBP2 depends both on its level of expression in a cell as well as its oligomerization state. Animal fructose-1,6-bisphosphatases are thought to function as tetramers. We present evidence that FBP2 exists in an equilibrium between tetramers and dimers. The dimeric form is fully active and insensitive to AMP, the main allosteric inhibitor of FBP2. Tetramerization induces the sensitivity of the protein to AMP, but it requires the presence of a hydrophobic central region in which leucine 190 plays a crucial role. Only the tetrameric form of FBP2 is retained in cardiomyocyte cell nucleus whereas only the dimeric form associates with mitochondria and protects them against stress stimuli, such as elevated calcium and H2O2 level. Remarkably, in hypoxic conditions, which are typical for many cancers, FBP2 ceases to interact with mitochondria and loses its pro-survival potential. Our results throw new light on the basis of the diverse role of FBP2 in cells.
Wiśniewski, Janusz, & Piróg, Michał, & Hołubowicz, Rafał, & Dobryszycki, Piotr, & McCubrey, James A., & Rakus, Dariusz, & Gizak, Agnieszka. (December 2017). Dimeric and tetrameric forms of muscle fructose-1,6- bisphosphatase play different roles in the cell. Oncotarget, (8:70), p.115420-115433. Retrieved from http://hdl.handle.net/10342/8173
Wiśniewski, Janusz, and Piróg, Michał, and Hołubowicz, Rafał, and Dobryszycki, Piotr, and McCubrey, James A., and Rakus, Dariusz, and Gizak, Agnieszka. "Dimeric and tetrameric forms of muscle fructose-1,6- bisphosphatase play different roles in the cell". Oncotarget. 8:70. (115420-115433.), December 2017. October 31, 2020. http://hdl.handle.net/10342/8173.
Wiśniewski, Janusz and Piróg, Michał and Hołubowicz, Rafał and Dobryszycki, Piotr and McCubrey, James A. and Rakus, Dariusz and Gizak, Agnieszka, "Dimeric and tetrameric forms of muscle fructose-1,6- bisphosphatase play different roles in the cell," Oncotarget 8, no. 70 (December 2017), http://hdl.handle.net/10342/8173 (accessed October 31, 2020).
Wiśniewski, Janusz, Piróg, Michał, Hołubowicz, Rafał, Dobryszycki, Piotr, McCubrey, James A., Rakus, Dariusz, Gizak, Agnieszka. Dimeric and tetrameric forms of muscle fructose-1,6- bisphosphatase play different roles in the cell. Oncotarget. December 2017; 8(70) 115420-115433. http://hdl.handle.net/10342/8173. Accessed October 31, 2020.