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BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2022
- Publisher :
- La Trobe, 2022.
-
Abstract
- Significance It is believed that the Bcl-2 family protein Bok has a redundant role similar to Bax and Bak in regulating apoptosis. We report that this protein interacts with the key enzyme involved in uridine biosynthesis, uridine monophosphate synthetase, and positively regulates uridine biosynthesis and chemoconversion of 5-fluorouracil (5-FU). Bok-deficient cell lines are resistant to 5-FU. Bok down-regulation is a key feature of cell lines and primary colorectal tumor tissues that are resistant to 5-FU. Our data also show that through its impact on nucleotide metabolism, Bok regulates p53 level and cellular proliferation. Our results have implications for developing Bok as a biomarker for 5-FU resistance and for the development of BOK mimetics for sensitizing 5-FU-resistant cancers.<br />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.
- Subjects :
- 0301 basic medicine
Orotate Phosphoribosyltransferase
Orotidine-5'-Phosphate Decarboxylase
Regulator
Biology
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Bok
Mice
0302 clinical medicine
Protein Domains
Multienzyme Complexes
Biomarkers, Tumor
Uridine monophosphate synthetase
Animals
610 Medicine & health
UMPS
Uridine
Cell Proliferation
Uncategorized
Mammals
Multidisciplinary
Cell growth
Bcl-2 family
apoptosis
Signal transducing adaptor protein
chemoresistance
Cell cycle
Biological Sciences
Cell biology
030104 developmental biology
chemistry
Proto-Oncogene Proteins c-bcl-2
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer cell
Fluorouracil
Tumor Suppressor Protein p53
metabolism
DNA Damage
Protein Binding
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....c94d8ec59a137e8d6b83349b667f53d4
- Full Text :
- https://doi.org/10.26181/20226003