Oncotarget

Research Papers:

Dimeric and tetrameric forms of muscle fructose-1,6-bisphosphatase play different roles in the cell

Janusz Wiśniewski, Michał Piróg, Rafał Hołubowicz, Piotr Dobryszycki, James A. McCubrey, Dariusz Rakus and Agnieszka Gizak _

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Oncotarget. 2017; 8:115420-115433. https://doi.org/10.18632/oncotarget.23271

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Abstract

Janusz Wiśniewski1, Michał Piróg1, Rafał Hołubowicz2, Piotr Dobryszycki2, James A. McCubrey3, Dariusz Rakus1 and Agnieszka Gizak1

1Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw 50-335, Poland

2Department of Biochemistry, Wroclaw University of Science and Technology, Wroclaw 50-370, Poland

3Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

Correspondence to:

Agnieszka Gizak, email: agnieszka.gizak@uwr.edu.pl

Keywords: allostery; cardiomyocytes; mitochondria; ROS production; FBP

Abbreviations: FBP2, muscle fructose-1,6-bisphosphatase; FBP1, liver fructose-1,6-bisphosphatase; F-1,6-BP, fructose-1,6-bisphosphate

Received: October 19, 2017    Accepted: December 05, 2017    Published: December 15, 2017

ABSTRACT

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.


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