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Estrogen receptors (ER) are ligand-dependent transcription factors that regulate growth, differentiation, and maintenance of cellular functions in a wide variety of tissues. We report here that p21WAF1/CIP1, a cyclin-dependent kinase (Cdk) inhibitor, cooperates with CBP to regulate the ERα-mediated transcription of endogenous target genes in a promoter-specific manner. The estrogen-induced expression of the progesterone receptor and WISP-2 mRNA transcripts in MCF-7 cells was enhanced by p21WAF1/CIP1, whereas that of the cyclin D1 mRNA was reduced and the pS2 mRNA was not affected. Chromatin immunoprecipitation assays revealed that p21WAF1/CIP1 was recruited simultaneously with ERα and CBP to the endogenous progesterone receptor gene promoter in an estrogen-dependent manner. Experiments in which the p21WAF1/CIP1 protein was knocked down by RNA interference showed that the induction of the expression of the gene encoding the progesterone receptor required p21WAF1/CIP1, in contrast with that of the cyclin D1 and pS2 genes, p21WAF1/CIP1 induced not only cell cycle arrest in breast cancer cells but also milk fat globule protein and lipid droplets, indicators of the differentiated phenotype, as well as cell flattening and increase of the volume of the cytoplasm. These results indicate that p21WAF1/CIP1, in addition to its Cdk-regulatory role, behaves as a transcriptional coactivator in a gene-specific manner implicated in cell differentiation. [ABSTRACT FROM AUTHOR]