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J. Biol. Chem., Vol. 279, Issue 12, 11696-11704, March 19, 2004

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Control of Human PIRH2 Protein Stability

INVOLVEMENT OF TIP60 AND THE PROTEASOME^*

Ian R. Logan, Vasileia Sapountzi, Luke Gaughan, David E. Neal, and Craig N. Robson¶

From the Northern Institute for Cancer Research, School of Surgical and Reproductive Sciences, Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom and the Oncology Centre, Addenbrooke Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom

Murine PIRH2 (mPIRH2) was recently identified as a RING finger-containing ubiquitin-protein isopeptide ligase that interacts with both p53 and the human androgen receptor. mpirh2 is a p53-responsive gene that is up-regulated by UV, and mPIRH2 protein has the capacity to polyubiquitylate p53, perhaps leading to p53 destruction. mpirh2 therefore has properties similar to those of the oncogene mdm2. Here, we have identified human PIRH2 (hPIRH2) as a TIP60-interacting protein. To investigate its regulation, we characterized hPIRH2 in parallel with hPIRH2 variants possessing mutations of conserved RING finger residues. We observed that wild-type hPIRH2 is an unstable protein with a short half-life and is a target for RING domain-dependent proteasomal degradation. Accordingly, we found that hPIRH2 was ubiquitylated in cells. The TIP60-hPIRH2 association appeared to regulate hPIRH2 stability; coexpression of TIP60 enhanced hPIRH2 protein stability and altered hPIRH2 subcellular localization. These results suggest that hPIRH2 activities can be controlled, at the post-translational level, in multiple ways.

Received for publication, November 20, 2003 , and in revised form, December 15, 2003.

^* This work was supported by grants from the Harker Foundation and Association for International Cancer Research (AICR)/National Cancer Research Institute (NCRI) and by NCRI PROMPT Grant G0100100/64424. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 44-191-222-7076; Fax: 44-191-222-8514; E-mail: C.N.Robson{at}ncl.ac.uk.

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