BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals.
Rahul SrivastavaZhipeng CaoChristina NedevaSamara NaimDaniel BachmannTatiana RabachiniLahiru GangodaSanjay ShahiJason GlabJoseph MenassaLaura OsellameTao NelsonYuniel Fernandez-MarreroFiona BrownAndrew WeiFrancine KeLorraine O'ReillyMarcel DoerflingerCody AllisonAndrew KuehRobert George RamsayBrian J SmithSuresh MathivananThomas KaufmannHamsa PuthalakathPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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.
Keyphrases
- cell cycle
- cell proliferation
- oxidative stress
- poor prognosis
- binding protein
- cell death
- protein protein
- gene expression
- transcription factor
- amino acid
- type diabetes
- electronic health record
- long non coding rna
- endoplasmic reticulum stress
- endothelial cells
- machine learning
- dna methylation
- genome wide
- cell cycle arrest
- artificial intelligence
- deep learning
- induced apoptosis
- anti inflammatory