Transcriptional activation by the oestrogen receptor alpha is modulated through inhibition of cyclin-dependent kinases.
We have investigated the interaction between the expression of p21(WAF1/CIP1/SDI1), a stoichiometric inhibitor of Cdk, and the transcriptional activity of the oestrogen receptor alpha (ER(alpha). Transient transfection experiments demonstrated that the expression of p21(WAF1/CIP1/SDI1) amplified the transcriptional activation by ER(alpha). A dominant negative mutant of Cdk2 also enhanced the ER(alpha) transcriptional activity, indicating that the underlying mechanism relies on the inhibition of Cdk2 activity and cell cycle arrest. In agreement with this conclusion, experiments with p21(WAF1/CIP1/SDI1) mutants demonstrated that the domain involved in the binding of p21(WAF1/CIP1/SDI1) to Cdks was indispensable for the modulation of ER(alpha) activity. In addition, we show that expression of p21(WAF1/CIP1/SDI1) alleviates the block on CBP function mediated by Cdk2 and in turn stimulates transcriptional activation by ER(alpha) in a CBP-histone acetyltransferase (HAT)-dependent manner. These results suggest a novel mechanism by which p21(WAF1/CIP1/SDI1) functions as an enhancer of ER(alpha) activity through the modulation of CBP function.
Redeuilh
Gérard
G
Institut National de la Santé et de la Recherche Médicale U 482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Attia
Annette
A
Mester
Jan
J
Sabbah
Michèle
M
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D042846:CDC2-CDC28 Kinases; D019556:COS Cells; D050882:CREB-Binding Protein; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D016213:Cyclins / Q000502:physiology*; D047628:Estrogen Receptor alpha; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D056920:Nuclear Receptor Coactivator 1; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases