title: p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha.
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 p21WAF1/CIP1, a cyclin-dependent kinase (Cdk) inhibitor, cooperates with CBP to regulate the ERalpha-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 ERalpha 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U482, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
authors.forename: Asmaà
authors.initials: A
authors.lastname: Fritah
authors.forename: Cécile
authors.initials: C
authors.lastname: Saucier
authors.forename: Jan
authors.initials: J
authors.lastname: Mester
authors.forename: Gérard
authors.initials: G
authors.lastname: Redeuilh
authors.forename: Michèle
authors.initials: M
authors.lastname: Sabbah
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003593:Cytoplasm / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; C051838:TFF1 protein, human; D015534:Trans-Activators; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D004958:Estradiol; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
references.citation: Mol Cell Biol. 1996 Jun;16(6):2554-60
references.pmid: 8649362
references.citation: Nature. 1996 Sep 5;383(6595):99-103
references.pmid: 8779723
references.citation: Curr Opin Genet Dev. 1996 Feb;6(1):56-64
references.pmid: 8791491
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11540-5
references.pmid: 8876171
references.citation: Carcinogenesis. 1996 Nov;17(11):2279-84
references.pmid: 8968038
references.citation: Tumour Biol. 1997;18(1):22-9
references.pmid: 8989922
references.citation: Science. 1997 Jan 24;275(5299):523-7
references.pmid: 8999795
references.citation: Mol Cell Biol. 1997 Apr;17(4):2030-7
references.pmid: 9121451
references.citation: J Biol Chem. 1997 Apr 18;272(16):10882-94
references.pmid: 9099745
references.citation: Am J Clin Pathol. 1997 Jun;107(6):684-91
references.pmid: 9169666
references.citation: Mol Cell Biol. 1997 Jul;17(7):4059-69
references.pmid: 9199341
references.citation: Endocr Rev. 1997 Aug;18(4):502-19
references.pmid: 9267762
references.citation: Mol Endocrinol. 1997 Oct;11(11):1593-607
references.pmid: 9328342
references.citation: Nature. 1997 Oct 16;389(6652):753-8
references.pmid: 9338790
references.citation: Genes Dev. 1998 Feb 1;12(3):331-42
references.pmid: 9450928
references.citation: J Biol Chem. 1998 Apr 24;273(17):10696-701
references.pmid: 9553133
references.citation: Nature. 1998 May 21;393(6682):284-9
references.pmid: 9607768
references.citation: Mol Cell Biol. 1998 Oct;18(10):6131-41
references.pmid: 9742130
references.citation: Biochem J. 1998 Dec 15;336 ( Pt 3):639-46
references.pmid: 9841876
references.citation: J Biol Chem. 1999 Aug 13;274(33):23480-90
references.pmid: 10438527
references.citation: Oncogene. 1999 Sep 23;18(39):5381-92
references.pmid: 10498892
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11217-22
references.pmid: 10500157
references.citation: Nat Rev Mol Cell Biol. 2001 Jun;2(6):422-32
references.pmid: 11389466
references.citation: J Biol Chem. 2001 Aug 3;276(31):29200-9
references.pmid: 11369759
references.citation: J Biol Chem. 2001 Oct 5;276(40):36865-8
references.pmid: 11459854
references.citation: J Biol Chem. 2001 Oct 5;276(40):37280-3
references.pmid: 11487586
references.citation: Genes Dev. 2001 Oct 1;15(19):2598-612
references.pmid: 11581164
references.citation: Physiol Rev. 2001 Oct;81(4):1535-65
references.pmid: 11581496
references.citation: EMBO J. 2001 Dec 3;20(23):6816-25
references.pmid: 11726517
references.citation: J Biol Chem. 2002 Feb 15;277(7):5209-18
references.pmid: 11717311
references.citation: Science. 2002 Apr 19;296(5567):550-3
references.pmid: 11910072
references.citation: Nature. 2002 Aug 8;418(6898):654-7
references.pmid: 12167865
references.citation: Oncogene. 2002 Aug 22;21(37):5773-82
references.pmid: 12173048
references.citation: EMBO J. 2002 Oct 15;21(20):5457-66
references.pmid: 12374746
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Endocrinology. 2002 Dec;143(12):4583-91
references.pmid: 12446585
references.citation: Mol Cell Biol. 2003 Jan;23(1):335-48
references.pmid: 12482985
references.citation: Mol Cell. 2003 Mar;11(3):695-707
references.pmid: 12667452
references.citation: Int J Biochem Cell Biol. 2003 Jul;35(7):1034-51
references.pmid: 12672473
references.citation: Mol Cell Endocrinol. 2003 Mar 28;201(1-2):165-75
references.pmid: 12706304
references.citation: Biochem Biophys Res Commun. 2003 Sep 19;309(2):272-8
references.pmid: 12951045
references.citation: J Biol Chem. 1999 Nov 26;274(48):34186-95
references.pmid: 10567390
references.citation: J Biol Chem. 2000 Apr 7;275(14):10477-83
references.pmid: 10744738
references.citation: J Cell Biol. 2000 Apr 17;149(2):281-92
references.pmid: 10769022
references.citation: J Biol Chem. 2000 Jun 23;275(25):18794-800
references.pmid: 10764767
references.citation: Mol Endocrinol. 2000 Jul;14(7):972-85
references.pmid: 10894148
references.citation: Mol Cell. 2000 Jun;5(6):939-48
references.pmid: 10911988
references.citation: Biochem Biophys Res Commun. 2000 Aug 18;275(1):108-14
references.pmid: 10944450
references.citation: Mol Pharmacol. 2000 Sep;58(3):584-90
references.pmid: 10953052
references.citation: Cell. 2000 Dec 8;103(6):843-52
references.pmid: 11136970
references.citation: Pathol Int. 2001 Feb;51(2):94-9
references.pmid: 11169147
references.citation: Breast Cancer Res. 2000;2(5):360-6
references.pmid: 11250729
references.citation: Genes Dev. 2001 May 1;15(9):1140-51
references.pmid: 11331609
references.citation: J Biol Chem. 2003 Oct 10;278(41):39509-16
references.pmid: 12888559
references.citation: J Biol Chem. 2004 Jun 18;279(25):26184-91
references.pmid: 15078875
references.citation: Cancer Res. 2004 Jun 15;64(12):4122-30
references.pmid: 15205322
references.citation: Cancer Res. 1983 Sep;43(9):3998-4006
references.pmid: 6871841
references.citation: J Cell Biol. 1985 Mar;100(3):965-73
references.pmid: 3972906
references.citation: J Biol Chem. 1990 Apr 5;265(10):5722-30
references.pmid: 2180933
references.citation: In Vitro Cell Dev Biol. 1990 Aug;26(8):803-14
references.pmid: 2394675
references.citation: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):390-4
references.pmid: 1988939
references.citation: Nucleic Acids Res. 1991 May 11;19(9):2499
references.pmid: 2041787
references.citation: Cancer Res. 1991 Aug 1;51(15):3867-73
references.pmid: 1855205
references.citation: J Cell Physiol. 1992 Mar;150(3):534-44
references.pmid: 1537883
references.citation: Nucleic Acids Res. 1992 Jun 11;20(11):2902
references.pmid: 1614888
references.citation: Cell. 1994 Oct 7;79(1):107-17
references.pmid: 7923369
references.citation: Cell. 1994 Nov 18;79(4):551-5
references.pmid: 7954821
references.citation: Science. 1994 Dec 2;266(5190):1524-7
references.pmid: 7985022
references.citation: Science. 1995 Feb 17;267(5200):1018-21
references.pmid: 7863327
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4352-6
references.pmid: 7753810
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5451-5
references.pmid: 7777529
references.citation: EMBO J. 1995 Aug 1;14(15):3741-51
references.pmid: 7641693
references.citation: J Biol Chem. 1995 Oct 13;270(41):24237-45
references.pmid: 7592630
references.citation: Cell. 1995 Dec 15;83(6):835-9
references.pmid: 8521507
references.citation: Genes Dev. 1996 Jan 15;10(2):142-53
references.pmid: 8566748