Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1

摘要: The ubiquitin (Ub)–proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. is ubiquitinated destabilized by MDM2 several other Ub E3s, whereas it deubiquitinated stabilized Ub-specific protease (USP)7 USP10. Here we show that ovarian tumour domain-containing aldehyde-binding 1 (Otub1) novel regulator. Otub1 directly suppresses MDM2-mediated ubiquitination cells vitro. Overexpression drastically stabilizes activates p53, leading to apoptosis marked inhibition cell proliferation p53-dependent manner. These effects are independent its catalytic activity but require residue Asp88. Mutation Asp88 Ala (Otub1D88A) abolishes suppress ubiquitination. Further, wild-type mutant (Otub1C91S), not Otub1D88A, bind cognate E2, UbcH5, Ub-conjugating Otub1D88A or ablation endogenous siRNA markedly impaired stabilization activation response DNA damage. Together, these results reveal function for regulating