Journal article

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

Rahul Srivastava, Zhipeng Cao, Christina Nedeva, Samara Naim, Daniel Bachmann, Tatiana Rabachini, Lahiru Gangoda, Sanjay Shahi, Jason Glab, Joseph Menassa, Laura Osellame, Tao Nelson, Yuniel Fernandez-Marrero, Fiona Brown, Andrew Wei, Francine Ke, Lorraine O'Reilly, Marcel Doerflinger, Cody Allison, Andrew Kueh Show all

Proceedings of the National Academy of Sciences of USA | NATL ACAD SCIENCES | Published : 2019

Abstract

BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regu..

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Grants

Awarded by Swiss National Science Foundation


Funding Acknowledgements

We thank Julian Grusovin (Commonwealth Scientific and Industrial Research Organization), Dr. Grant Dewson (Walter and Eliza Hall Institute for Medical Research), and Prof. Mike Ryan (Monash University) for help and reagents and Prof. Jim Goding for reviewing the manuscript. This project was funded by La Trobe University Research Focus Area (H.P.) and the Swiss National Science Foundation (#31003A_173006 to T.K.). R.S. and Z.C. are supported by La Trobe University postgraduate scholarships. S.N. is supported by the Graduate School of Cellular and Biomedical Sciences of the University of Bern.