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J. Biol. Chem., Vol. 281, Issue 45, 34096-34103, November 10, 2006

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Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function^*

Ian R. Watson, Alvaro Blanch, Dan C. C. Lin, Michael Ohh¹, and Meredith S. Irwin^¶2

From the Cancer Research Program and Division of Haematology-Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada and the Department of Laboratory Medicine and Pathobiology, ^¶Department of Paediatrics and Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (N) p73 isoforms. TAp73 possesses pro-apoptotic functions, while Np73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not Np73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53- and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent post-translational modification exclusively targeting the TA isoforms of p73.

Received for publication, April 17, 2006 , and in revised form, August 14, 2006.

^* This work was supported by the Terry Fox Foundation and the Canadian Cancer Society of the National Cancer Institute of Canada. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ A Canada Research Chair in Molecular Oncology.

² A Canada Research Chair in Cancer Biology. To whom correspondence should be addressed. Tel.: 416-813-7654 (ext. 2912); Fax: 416-813-5327; E-mail: meredith.irwin{at}sickkids.ca.

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