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

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.

ACKNOWLEDGMENTS

We thank A. Matejowics for valuable help and C. Hauser for help with the chromatin immunoprecipitation assays, H. Nomura for the p21 reporter constructs, W. Krek for the initial idea and the p53 expression vector, G. Zupkovitz for Northern blot hybridization, and B. Vojtesek for p53 antibodies.

This project was supported by the Austrian FWF (grants P14909-GEN and P13068-GEN to C.S. and grants P10873-GEN and P13031-MOB to E.W.), Austrian National Bank grant 8414 to H.R., and the Herzfelder Stiftung to C.S.