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World J Biol Chem. May 26, 2014; 5(2): 75-84
Published online May 26, 2014. doi: 10.4331/wjbc.v5.i2.75
Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1
Xiao-Xin Sun, Mu-Shui Dai
Xiao-Xin Sun, Mu-Shui Dai, Department of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, United States
Author contributions: Sun XX and Dai MS wrote the paper.
Supported by NIH/NCI, No. R00 CA127134 and No. R01 CA160474; and a Department of Defense, No. W81XWH-10-1-1029, to Dai MS; and A Grant from Medical Research Foundation (MRF) of Oregon, to Sun XX
Correspondence to: Mu-Shui Dai, MD, PhD, Department of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States. daim@ohsu.edu
Telephone: +1-503-4949917 Fax: +1-503-4944411
Received: November 29, 2013
Revised: January 11, 2014
Accepted: March 13, 2014
Published online: May 26, 2014
Processing time: 194 Days and 5.6 Hours
Abstract

Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes (DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme (E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.

Keywords: p53; MDM2; Ubiquitination; Deubiquitinating enzymes; Otub1; Cell cycle; Apoptosis

Core tip: p53 is tightly regulated by dynamic ubiquitination and deubiquitination. A number of deubiquitinating enzymes (DUBs) have been shown to regulate p53 stability and activity by either directly deubiquitinating p53 or indirectly deubiquitinating its regulators. We recently discovered that Otub1, an OTU family DUB, stabilizes and activates p53 via distinct and non-canonical mechanism wherein it suppresses the MDM2 cognate ubiquitin-conjugating enzymes UbcH5. Here we review the current progress made towards the understanding of the Otub1 functions as a potent E2 inhibitor and the underlying mechanisms.