Positive Regulation of p53 Stability and Activity by the Deubiquitinating Enzyme Otubain 1

Sun, X. X., et al. EMBO J. 31, 576-592 (2011)

Speaker: Shun-Yi Chien (錢舜益)                                Time: 15:10~16:00, May 9, 2012

Commentator: Dr. Shu-Ying Wang (王淑鶯 博士)    Place: Room 601

Abstract

p53 acts as a tumor suppressor and is important for maintaining genomic stability and preventing cells from transformation. Activation of p53 in response to stress, such as UV, DNA damage, and irradiation, induces expression of various genes that mediate apoptosis, cell cycle arrest, senescence, autophagy, angiogenesis inhibition, and metabolism [1]. The oncoprotein MDM2 inhibits p53 transcriptional activity or promotes its ubiquitination and degradation through the proteasome [2]. However, ubiquitination of p53 can be reversed by deubiquitinating enzymes such as USP7 and USP10. The authors found that overexpression of the ovarian tumor domain-containg Ub aldehyde-binding protein 1 (Otub1) prolonged half-life of p53 in cells. Aberrant Otub1 significantly increased annexin V-positive cells, sub-G1 populations, and caspase 3-cleaved PARP in p53-proficient U2OS cells but not p53-null Saos2 cells. Co-immunoprecipitation assays showed Otub1 interacted with the DNA-binding domain of p53 via its N- and C-termini. Otub1 suppressed MDM2-mediated p53 ubiquitination in vitro. Mutation of Otub1 catalytic residue Cys91 abolished the ability to K48-linked polyUb chains, but not blocked MDM2-mediated p53 degradation. Surprisingly, mutation of Asp88 completely abolished the induction of p53, p21, and MDM2 proteins as well as their mRNA, and failed to suppress MDM2-mediated p53 degradation.Moreover, Otub1 bound to UbcH5 and suppressed UbcH5-dependent Ub chain formation independent of its catalytic activity. During DNA damage, Otub1 still localized in the cytoplasm and regulated p53 in cytosol. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.

References

1.       Vousden, K. H., et al. Blinded by the light: the growing complexity of p53. Cell 137, 413-431 (2009).

2.       Haupt, Y., et al. Mdm2 promotes the rapid degradation of p53. Nature 387, 296-299 (1997).