E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53

Abstract

Spindle assembly checkpoint governs proper chromosomal segregation during mitosis to ensure genomic stability. At the cellular level, this event is tightly regulated by UBE2C, an E2 ubiquitin-conjugating enzyme that donates ubiquitin to the anaphase-promoting complex/cyclosome. This, in turn, facilitates anaphase-onset by ubiquitin-mediated degradation of mitotic substrates. UBE2C is an important marker of chromosomal instability and has been associated with malignant growth. However, the mechanism of its regulation is largely unexplored. In this study, we report that UBE2C is transcriptionally activated by the gain-of-function (GOF) mutant p53, although it is transcriptionally repressed by wild-type p53. We showed that wild-type p53-mediated inhibition of UBE2C is p21-E2F4-dependent and GOF mutant p53-mediated transactivation of UBE2C is NF-Y-dependent. We further explored that DNA damage-induced wild-type p53 leads to spindle assembly checkpoint arrest by repressing UBE2C, whereas mutant p53 causes premature anaphase exit by increasing UBE2C expression in the presence of 5-fluorouracil. Identification of UBE2C as a target of wild-type and GOF mutant p53 further highlights the contribution of p53 in regulation of spindle assembly checkpoint.

p53 gain‐of‐function mutations increase Cdc7‐dependent replication initiation

“…Soft agar assay was performed as described previously . Cells were allowed to form colonies for 2–3 weeks in presence of doxycycline (0.25 μg/ml).…”

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

“…The ubiquitin‐proteasome system is the main pathway responsible for the degradation of at least 80% of proteins in cells. [ 45 ] Ubiquitin is a small protein in the cells of higher organisms [ 46 ] that can be adenylated at specific sites and labeled to target proteins by the ubiquitin‐activating enzyme E1, [ 47 ] ubiquitin‐conjugating enzyme E2, [ 48 ] and E3 ubiquitin ligase. [ 49 ] The proteasome is a 26S protein complex with two 19S subunits and one 20S subunit.…”

Fabrication of an immunosensor for quantitative detection of breast cancer biomarker UBE2C

“…Therefore, it could be an important biomarker for clinical diagnosis of breast cancer. 3,18,19 Immunohistochemistry, 13,15,16 western blotting, 20 and quantitative real-time polymerase chain reaction (QRT-PCR) 21 are some of the molecular techniques which have been previously employed to detect UBE2C in breast cancer. However, these techniques are cumbersome, time-consuming, and lack the reusability of expensive reagents, which restricts their commercial use in clinical diagnosis.…”