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Molecular and Cellular Biology, December 2007, p. 8284-8295, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00050-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ubiquitination and Degradation of Mutant p53{triangledown}

Natalia Lukashchuk and Karen H. Vousden*

Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, United Kingdom

Received 10 January 2007/ Returned for modification 9 March 2007/ Accepted 19 September 2007

While wild-type p53 is normally a rapidly degraded protein, mutant forms of p53 are stabilized and accumulate to high levels in tumor cells. In this study, we show that mutant and wild-type p53 proteins are ubiquitinated and degraded through overlapping but distinct pathways. While Mdm2 can drive the degradation of both mutant and wild-type p53, our data suggest that the ability of Mdm2 to function as a ubiquitin ligase is less important in the degradation of mutant p53, which is heavily ubiquitinated in an Mdm2-independent manner. Our initial attempts to identify ubiquitin ligases that are responsible for the ubiquitination of mutant p53 have suggested a role for the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein), although other unidentified ubiquitin ligases also appear to contribute. The contribution of Mdm2 to the degradation of mutant p53 may reflect the ability of Mdm2 to deliver the ubiquitinated mutant p53 to the proteasome.

* Corresponding author. Mailing address: The Beatson Institute for Cancer Research, Switchback Rd., Glasgow G61 1BD, United Kingdom. Phone: 44 (0)141 330 2424. Fax: 44 (0)141 943 0372. E-mail: k.vousden{at}beatson.gla.ac.uk

{triangledown} Published ahead of print on 1 October 2007.

Molecular and Cellular Biology, December 2007, p. 8284-8295, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00050-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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