The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene

Gerda Lagger, Angelika Doetzlhofer, Bernd Schuettengruber, Eva Haidweger, Elisabeth Simboeck, Julia Tischler, Susanna Chiocca, Guntram Suske, Hans Rotheneder, Erhard Wintersberger, Christian Seiser

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2669-2679
Number of pages11
JournalMolecular and cellular biology
Volume23
Issue number8
DOIs
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Lagger, G., Doetzlhofer, A., Schuettengruber, B., Haidweger, E., Simboeck, E., Tischler, J., Chiocca, S., Suske, G., Rotheneder, H., Wintersberger, E., & Seiser, C. (2003). The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Molecular and cellular biology, 23(8), 2669-2679. https://doi.org/10.1128/MCB.23.8.2669-2679.2003