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Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15469-15474. doi: 10.1073/pnas.1904523116. Epub 2019 Jul 16.

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

Author information

1
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
2
Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
3
Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
4
Australian Center for Blood Diseases, Monash University, 3004 Melbourne, Australia.
5
Gastrointestinal Cancer Program, Peter MacCallum Cancer Centre, 3052 Melbourne, Australia.
6
Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland; thomas.kaufmann@pki.unibe.ch H.puthalakath@latrobe.edu.au.
7
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia; thomas.kaufmann@pki.unibe.ch H.puthalakath@latrobe.edu.au.

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-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.

KEYWORDS:

Bok; UMPS; apoptosis; chemoresistance; metabolism

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