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Molecular and Cellular Biology, April 2003, p. 2669-2679, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2669-2679.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene

Gerda Lagger,1 Angelika Doetzlhofer,1,{dagger} Bernd Schuettengruber,1 Eva Haidweger,1 Elisabeth Simboeck,1 Julia Tischler,1 Susanna Chiocca,2 Guntram Suske,3 Hans Rotheneder,1 Erhard Wintersberger,1 and Christian Seiser1*

Institute of Medical Biochemistry, Division of Molecular Biology, Vienna Biocenter, University of Vienna, A-1030 Vienna, Austria,1 European Institute of Oncology, Department of Experimental Oncology, 20141 Milan, Italy,2 Institute of Molecular Biology and Tumor Research, Phillips University of Marburg, Marburg, Germany3

Received 22 August 2002/ Returned for modification 15 October 2002/ Accepted 21 January 2003

The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is an important regulator of cell cycle progression, senescence, and differentiation. Genotoxic stress leads to activation of the tumor suppressor p53 and subsequently to induction of p21 expression. Here we show that the tumor suppressor p53 cooperates with the transcription factor Sp1 in the activation of the p21 promoter, whereas histone deacetylase 1 (HDAC1) counteracts p53-induced transcription from the p21 gene. The p53 protein binds directly to the C terminus of Sp1, a domain which was previously shown to be required for the interaction with HDAC1. Induction of p53 in response to DNA-damaging agents resulted in the formation of p53-Sp1 complexes and simultaneous dissociation of HDAC1 from the C terminus of Sp1. Chromatin immunoprecipitation experiments demonstrated the association of HDAC1 with the p21 gene in proliferating cells. Genotoxic stress led to recruitment of p53, reduced binding of HDAC1, and hyperacetylation of core histones at the p21 promoter. Our findings show that the deacetylase HDAC1 acts as an antagonist of the tumor suppressor p53 in the regulation of the cyclin-dependent kinase inhibitor p21 and provide a basis for understanding the function of histone deacetylase inhibitors as antitumor drugs.

* Corresponding author. Mailing address: Institute of Medical Biochemistry, Division of Molecular Biology, University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria. Phone: 431 4277 61770. Fax: 431 4277 9617. E-mail: cs{at}mol.univie.ac.at.

{dagger} Present address: House Ear Institute, Los Angeles, CA 90057-1922.

Molecular and Cellular Biology, April 2003, p. 2669-2679, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2669-2679.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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