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J. Biol. Chem., Vol. 279, Issue 50, 52175-52182, December 10, 2004

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Aurora-A Abrogation of p53 DNA Binding and Transactivation Activity by Phosphorylation of Serine 215^*

Qiyuan Liu, Satoshi Kaneko, Lin Yang, Richard I. Feldman, Santo V. Nicosia, Jiandong Chen, and Jin Q. Cheng¶

From the Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612 and the Cancer Research Department, Berlex Biosciences, Richmond, California 94804

The tumor suppressor p53 is important in the decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 posttranslational modifications and association with other proteins have been implicated in the regulation of its stability and transactivation activity. Here we show that p53 is phosphorylated by the mitotic kinase Aurora-A at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (Brooks, C. L., and Gu, W. (2003) Curr. Opin. Cell Biol. 15, 164–171), the phosphorylation of p53 by Aurora-A at Ser-215 abrogates p53 DNA binding and transactivation activity. Downstream target genes of p53, such as p21^Cip/WAF1 and PTEN, were inhibited by Aurora-A in a Ser-215 phosphorylation-dependent manner (i.e. phosphomimic p53-S215D lost and non-phosphorylatable p53-S215A retained normal p53 function). As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and -irradiation, respectively. However, the effect of Aurora-A on p53 DNA binding and transactivation activity was not affected by phosphorylation of Ser-315, a recently identified Aurora-A phosphorylation site of p53 (Katayama, H., Sasai, K., Kawai, H., Yuan, Z. M., Bondaruk, J., Suzuki, F., Fujii, S., Arlinghaus, R. B., Czerniak, B. A., and Sen, S. (2004) Nat. Genet. 36, 55–62). Our data indicate that phosphorylation of p53 at Ser-215 by Aurora-A is a major mechanism to inactivate p53 and can provide a molecular insight for Aurora-A function.

Received for publication, June 17, 2004 , and in revised form, October 6, 2004.

^* This work was supported by grants from the National Cancer Institute and the Department of Defense (to J. Q. C.). 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: Dept. of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, 12901 Bruce B. Downs Blvd., MDC Box 11, Tampa, FL 33612. Tel.: 813-974-8595; Fax: 813-974-5536; E-mail: jcheng{at}hsc.usf.edu.

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