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 KuehRob Ramsay, Brian J. Smith, Suresh Mathivanan, Thomas Kaufmann, Hamsa Puthalakath

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)15469-15474
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number31
DOIs
Publication statusPublished - 30 Jul 2019

Keywords

  • apoptosis
  • Bok
  • chemoresistance
  • metabolism
  • UMPS

Cite this

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., ... Puthalakath, H. (2019). BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals. Proceedings of the National Academy of Sciences of the United States of America, 116(31), 15469-15474. https://doi.org/10.1073/pnas.1904523116