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Molecular and Cellular Biology, December 2006, p. 8901-8913, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01156-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of p53 Localization and Activity by Ubc13{triangledown} ,{dagger}

Aaron Laine,1 Ivan Topisirovic,2 Dayong Zhai,3 John C. Reed,3 Katherine L. B. Borden,2 and Ze'ev Ronai1*

Signal Transduction,1 Apoptosis Programs, Burnham Institute for Medical Research, La Jolla, California 92037,3 Institute of Research in Immunovirology and Cancer, Université de Montréal, Pavillion Marcelle-Coutu, Chemin Polytechnique, Montreal H3T 1J4, Québec, Canada2

Received 27 June 2006/ Returned for modification 2 August 2006/ Accepted 15 September 2006

The abundance and activity of p53 are regulated largely by ubiquitin ligases. Here we demonstrate a previously undisclosed regulation of p53 localization and activity by Ubc13, an E2 ubiquitin-conjugating enzyme. While increasing p53 stability, Ubc13 decreases p53 transcriptional activity and increases its localization to the cytoplasm, changes that require its ubiquitin-conjugating activity. Ubc13 elicits K63-dependent ubiquitination of p53, which attenuates Hdm2-induced polyubiquitination of p53. Ubc13 association with p53 requires an intact C-terminal domain of p53 and is markedly stronger with a p53 mutant that cannot tetramerize. Expression of Ubc13 in vivo increases the pool of monomeric p53, indicating that Ubc13 affects tetramerization of p53. Significantly, wild-type but not mutant Ubc13 is associated with polysomes and enriches p53 within this fraction. In response to DNA damage, Ubc13 is no longer capable of facilitating p53 monomerization, in part due to a decrease in its own levels which is p53 dependent. Our findings point to a newly discerned mechanism important in the regulation of p53 organization, localization, and activity by Ubc13.

* Corresponding author. Mailing address: Signal Transduction Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 646-3185. Fax: (815) 366-8003. E-mail: ronai{at}burnham.org.

{triangledown} Published ahead of print on 25 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2006, p. 8901-8913, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01156-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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