Cyclin-dependent kinase activity is required for progesterone receptor function: novel role for cyclin A/Cdk2 as a progesterone receptor coactivator.
Our studies examining the role of the cell cycle-regulated kinase cyclin A/Cdk2 in progesterone receptor (PR) action have demonstrated that cyclin-dependent kinase activity is required for PR function and that cyclin A/Cdk2 functions as a PR coactivator. Although Cdk2 can phosphorylate PR, elimination of these phosphorylation sites has little effect ... on the ability of cyclin A/Cdk2 to stimulate PR activity. PR interacts with cyclin A and recruits cyclin A/Cdk2 to progestin-responsive promoters, stimulating transcription. Inhibition of Cdk2 activity abolishes progesterone-dependent activation of PR target genes in part through inhibition of PR-dependent recruitment of steroid receptor coactivator 1 (SRC-1) and subsequent histone H4 acetylation at the target promoter. In vitro studies revealed that the interaction between SRC-1 and PR is dependent upon phosphorylation of SRC-1. This heretofore-unknown mechanism provides a potential means for integrating the regulation of PR activity with cell cycle progression. Moreover, the ability of PR to recruit cyclin A/Cdk2 to target promoters provides locally elevated levels of kinase, which can preferentially facilitate phosphorylation-dependent interactions and enzymatic activities of coactivators at the target promoter.
Mesh Terms:
Acetylation, Animals, Blotting, Western, CDC2-CDC28 Kinases, COS Cells, Cell Cycle, Cell Line, Chromatin Immunoprecipitation, Cyclin A, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Genes, Reporter, Genetic Vectors, Glutathione Transferase, HeLa Cells, Histone Acetyltransferases, Histones, Humans, Immunoprecipitation, Lysine, Models, Genetic, Nuclear Receptor Coactivator 1, Phosphorylation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Biosynthesis, Protein Kinase Inhibitors, Purines, Receptors, Progesterone, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Two-Hybrid System Techniques
Acetylation, Animals, Blotting, Western, CDC2-CDC28 Kinases, COS Cells, Cell Cycle, Cell Line, Chromatin Immunoprecipitation, Cyclin A, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Genes, Reporter, Genetic Vectors, Glutathione Transferase, HeLa Cells, Histone Acetyltransferases, Histones, Humans, Immunoprecipitation, Lysine, Models, Genetic, Nuclear Receptor Coactivator 1, Phosphorylation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Biosynthesis, Protein Kinase Inhibitors, Purines, Receptors, Progesterone, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Two-Hybrid System Techniques
Mol. Cell. Biol.
Date: Jan. 01, 2005
PubMed ID: 15601848
View in: Pubmed Google Scholar
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