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


Srivastava, R; Cao, Z; Nedeva, C; Naim, S; Bachmann, D; Rabachini, T; Gangoda, L; Shahi, S; Glab, J; Menassa, J; Osellame, L; Nelson, T; Fernandez-Marrero, Y; Brown, F; Wei, A; Ke, F; O'Reilly, L; Doerflinger, M; Allison, C; Kueh, A; Ramsay, R; Smith, BJ; Mathivanan, S; Kaufmann, T; Puthalakath, H
2019-07-16
Proceedings of the National Academy of Sciences of the United States of America
Journal Article
116
31
15469-15474
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.
NAS
Blood Cells and Blood Cancer; Infectious Diseases and Immune Defence
10.1073/pnas.1904523116
31311867
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Creation Date 2019-07-26 09:44:17 Last Modified 2019-08-23 02:21:54