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BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals.
Srivastava, Rahul; Cao, Zhipeng; Nedeva, Christina; Naim, Samara; Bachmann, Daniel; Rabachini, Tatiana; Gangoda, Lahiru; Shahi, Sanjay; Glab, Jason; Menassa, Joseph; Osellame, Laura; Nelson, Tao; Fernandez-Marrero, Yuniel; Brown, Fiona; Wei, Andrew; Ke, Francine; O'Reilly, Lorraine; Doerflinger, Marcel; Allison, Cody; Kueh, Andrew; Ramsay, Rob; Smith, Brian J; Mathivanan, Suresh; Kaufmann, Thomas; Puthalakath, Hamsa.
Afiliação
  • Srivastava R; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Cao Z; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Nedeva C; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Naim S; Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
  • Bachmann D; Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
  • Rabachini T; Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
  • Gangoda L; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Shahi S; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Glab J; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Menassa J; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Osellame L; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Nelson T; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Fernandez-Marrero Y; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Brown F; Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
  • Wei A; Australian Center for Blood Diseases, Monash University, 3004 Melbourne, Australia.
  • Ke F; Australian Center for Blood Diseases, Monash University, 3004 Melbourne, Australia.
  • O'Reilly L; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Doerflinger M; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Allison C; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Kueh A; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Ramsay R; Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute for Medical Research, 3052 Melbourne, Australia.
  • Smith BJ; Gastrointestinal Cancer Program, Peter MacCallum Cancer Centre, 3052 Melbourne, Australia.
  • Mathivanan S; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Kaufmann T; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
  • Puthalakath H; Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland; thomas.kaufmann@pki.unibe.ch H.puthalakath@latrobe.edu.au.
Proc Natl Acad Sci U S A ; 116(31): 15469-15474, 2019 07 30.
Article em En | MEDLINE | ID: mdl-31311867
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Uridina / Proteínas Proto-Oncogênicas c-bcl-2 Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Uridina / Proteínas Proto-Oncogênicas c-bcl-2 Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article