E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53
E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53
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DOI：
10.1074/jbc.m116.731398
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发表时间：
2016-07-01
影响因子：
4.8
通讯作者：
Roychoudhury, Susanta
中科院分区：
文献类型：
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作者：
Bajaj, Swati;Alam, Sk. Kayum;Roychoudhury, Susanta
纺锤体组装检查点控制有丝分裂过程中适当的染色体分离，以确保基因组的稳定性。在细胞水平上，这一事件受到UBE2C的严格调控，UBE2C是一种E2泛素结合酶，将泛素提供给后期促进复合物/环体。这反过来又通过泛素介导的有丝分裂底物降解促进了后期的开始。UBE2C是染色体不稳定性的重要标志，与恶性生长有关。然而，其调控机制在很大程度上是未知的。在这项研究中，我们报道了UBE2C在转录上被功能获得（GOF）突变体p53激活，尽管它在转录上被野生型p53抑制。我们发现野生型p53介导的UBE2C抑制是p21- e2f4依赖的，而GOF突变体p53介导的UBE2C转激活是nf - y依赖的。我们进一步探讨了DNA损伤诱导的野生型p53通过抑制UBE2C导致纺锤体组装检查点阻滞，而突变型p53在5-氟尿嘧啶存在下通过增加UBE2C表达导致早期后期退出。发现UBE2C是野生型和GOF突变体p53的靶点，进一步突出了p53在纺锤体组装检查点调控中的作用。
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.