p21^WAF1/CIP1 Selectively Controls the Transcriptional Activity of Estrogen Receptor α

Abstract

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 p21 WAF1/CIP1 , a cyclin-dependent kinase (Cdk) inhibitor, cooperates with CBP to regulate the ER␣-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 p21 WAF1/CIP1 , whereas that of the cyclin D1 mRNA was reduced and the pS2 mRNA was not affected. Chromatin immunoprecipitation assays revealed that p21 WAF1/CIP1 was recruited simultaneously with ER␣ and CBP to the endogenous progesterone receptor gene promoter in an estrogen-dependent manner. Experiments in which the p21 WAF1/CIP1 protein was knocked down by RNA interference showed that the induction of the expression of the gene encoding the progesterone receptor required p21 WAF1/CIP1 , in contrast with that of the cyclin D1 and pS2 genes. p21 WAF1/CIP1induced 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 p21 WAF1/CIP1 , in addition to its Cdk-regulatory role, behaves as a transcriptional coactivator in a gene-specific manner implicated in cell differentiation.

Multiple Functions of Kip-Related Protein5 Connect Endoreduplication and Cell Elongation

“…] see Dotto, 2000;Perkins, 2002;Chen et al, 2009). p21 has been described to act both as a repressor and as a coactivator of the expression of genes (Poole et al, 2004;Fritah et al, 2005;Sestáková et al, 2010). Thus, the transcription function of p21 could be conserved in its Arabidopsis homolog KRP5 and provide a molecular link between the onset of endoreduplication and cell growth or differentiation.…”

Molecular cloning and characterization of the human WISP-2/CCN5 gene promoter reveal its upregulation by oestrogens

“…Furthermore, the upregulation of WISP-2/CCN5 under oestrogen treatment could be independent of DNA synthesis (Inadera 2003) although it has been demonstrated that hWISP-2 is important for proliferation in MCF-7 cells (Banerjee et al 2003(Banerjee et al , 2005. Recently, we demonstrated that hWISP-2/CCN5 mRNA transcripts were enhanced by p21 WAF1/CIP1 in MCF-7 cells treated by oestrogens (Fritah et al 2005). In these cells, the expression of p21 WAF1/CIP1 induced cell cycle arrest and changes suggestive of mammary differentiation.…”

“…It has been reported that hWISP-2/CCN5 expression is induced by oestrogens in the MCF-7 cell line (Inadera et al 2002, Banerjee et al 2003, Fritah et al 2005. We wondered whether oestrogens regulate hWISP-2/CCN5 expression in two other ER-positive human breast cancer cell lines: T47D…”

“…ChIP assays were performed largely as previously described (Fritah et al 2005). Briefly, a small portion (1%) of the crosslinked, sheared chromatin solution was saved as input DNA and the remainder was used for immunoprecipitation by using specific anti-ERa antibody (AER-311; Upstate), anti-CBP antibody (A-22; Santa Cruz) or anti-p21 antibody (SX118; Pharmingen, BD Biosciences, Lincoln Park, NJ).…”

The orphan nuclear receptor SHP inhibits apoptosis during the monocytic differentiation by inducing p21WAF1

“…pSUPER/p21 siRNA400 was kindly donated by Dr. Michele Sabbah (Fritah et al, 2005). pGL2B/hSHP-Luc (-2.2 kb) was kindly provided by Dr. Heung Sik Choi (Chonman National University, Korea).…”