title: 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.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India,; Advanced Molecular Diagnostics Laboratory, Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Swati
authors.initials: S
authors.lastname: Bajaj
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India.
authors.forename: Sk Kayum
authors.initials: SK
authors.lastname: Alam
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India.
authors.forename: Kumar Singha
authors.initials: KS
authors.lastname: Roy
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India.
authors.forename: Arindam
authors.initials: A
authors.lastname: Datta
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India,; Molecular Biology Research and Diagnostic Laboratory, Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata-700063, India.
authors.forename: Somsubhra
authors.initials: S
authors.lastname: Nath
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India,. Electronic address: susantarc@gmail.com.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; D016283:Proto-Oncogene Proteins p21(ras)
keywords: E2F transcription factor; mitosis; mitotic spindle; p53; ubiquitin-conjugating enzyme (E2 enzyme)