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600139_Srivastava,R_2019.pdf (1.41 MB)

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

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posted on 2022-07-13, 01:31 authored by Rahul Srivastava, Zhipeng Cao, Christina Nedeva, Samara Naim, Daniel Bachmann, Tatiana Rabachini, Lahiru GangodaLahiru Gangoda, Sanjay ShahiSanjay Shahi, Jason Glab, Joseph MenassaJoseph Menassa, Laura Murray-RustLaura Murray-Rust, Tao NelsonTao Nelson, Yuniel Fernandez-Marrero, Fiona Brown, Andrew Wei, Francine Ke, Lorraine O'Reilly, Marcel Doerflinger, Cody Allison, Andrew Kueh, Rob Ramsay, Brian SmithBrian Smith, Suresh MathivananSuresh Mathivanan, Thomas Kaufmann, Hamsa PuthalakathHamsa Puthalakath
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.

Funding

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.

History

Publication Date

2019-07-30

Journal

Proceedings of the National Academy Of Sciences

Volume

116

Issue

31

Pagination

6p. (p. 15469-15474)

Publisher

National Academy of Sciences

ISSN

0027-8424

Rights Statement

© 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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