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J. Biol. Chem., Vol. 278, Issue 35, 32507-32516, August 29, 2003

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p21/CDKN1A Mediates Negative Regulation of Transcription by p53^*

Kristina Löhr, Constanze Möritz, Ana Contente and Matthias Dobbelstein 

From the Institut für Virologie, Philipps-Universität Marburg, Robert Koch Str. 17, 35037 Marburg, Germany

The tumor suppressor p53 regulates transcription positively and negatively, depending on the target gene. Whereas p53 induces transcription through direct interaction with promoter DNA, the mechanism of p53-mediated transcriptional repression is less well understood. Early reports described the alleviation of p53-mediated repression by inhibitors of apoptosis, suggesting that negative regulation of transcription might occur only in conjunction with programmed cell death. More recently, it has been proposed that certain genes, such as survivin, are repressed by direct association of p53 with their promoters, followed by recruitment of a repressor complex. We show here that p53-mediated negative regulation of transcription could occur independently of apoptosis. In contrast, the amino-terminal transactivation domain of p53 was required for negative regulation of transcription. Similarly, the p53 homologue p73 diminished the expression of survivin and stathmin, depending on its transactivation domain. Mutation of the putative p53 binding site within the survivin promoter did not impair its repression. These observations raised the hypothesis that activation of an effector gene might be required for repression by p53. Strikingly, when the p53-inducible p21/CDKN1A gene was deleted, p53 no longer repressed any one among 11 genes that it down-regulates otherwise. Most of these genes were also repressed by ectopic p21 in the absence of p53. Overexpressed c-Myc reduced the transcription of p21/CDKN1A and impaired p53-mediated repression but did not abolish repression by ectopic p21. Taken together, these results strongly suggest that increased expression of p21/CDKN1A is necessary and sufficient for the negative regulation of gene expression by p53.

Received for publication, December 9, 2002 , and in revised form, April 25, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft, the Wilhelm Sander-Stiftung, the Mildred Scheel Stiftung/Deutsche Krebshilfe, and the P. E. Kempkes Stiftung. C. M. was supported by the Fazit Stiftung and A. C. by the Fundação para a Ciência e a Tecnologia during this work. 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. Tel.: 49-6421-286-4318; Fax: 49-6421-286-8962; E-mail: dobbelst{at}mailer.uni-marburg.de.

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