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Molecular and Cellular Biology, February 2007, p. 1425-1432, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.00999-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression ^,

Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037,¹ Institut Pasteur, Départment de Biologie du Développement, Paris, France,² Université Pierre et Marie Curie-Paris 6, Paris, France,³ Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 rue d'Ulm, 75248 Paris Cedex 05, France⁴

Received 5 June 2006/ Returned for modification 11 July 2006/ Accepted 18 November 2006

The stability and activity of tumor suppressor p53 are tightly regulated and partially depend on the p53 proline-rich domain (PRD). We recently analyzed mice expressing p53 with a deletion of the PRD (p53^P). p53^P, a weak transactivator hypersensitive to Mdm2-mediated degradation, is unable to suppress oncogene-induced tumors. This phenotype could result from the loss of two motifs: Pin1 sites proposed to influence p53 stabilization and PXXP motifs proposed to mediate protein interactions. We investigated the importance of these motifs by generating mice encoding point mutations in the PRD. p53^TTAA contains mutations suppressing all putative Pin1 sites in the PRD, while p53^AXXA lacks PXXP motifs but retains one intact Pin1 site. Both mutant proteins accumulated in response to DNA damage, although the accumulation of p53^TTAA was partially impaired. Importantly, p53^TTAA and p53^AXXA are efficient transactivators and potent suppressors of oncogene-induced tumors. Thus, Pin1 sites in the PRD may modulate p53 stability but do not significantly affect function. In addition, PXXP motifs are not essential, but structure dictated by the presence of prolines, PXXXXP motifs that may mediate protein interactions, and/or the length of this region appears to be functionally significant. These results may explain why the sequence of the p53 PRD is so variable in evolution.

Published ahead of print on 11 December 2006.

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

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