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Molecular and Cellular Biology, January 2005, p. 264-277, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.264-277.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cyclin-Dependent Kinase Activity Is Required for Progesterone Receptor Function: Novel Role for Cyclin A/Cdk2 as a Progesterone Receptor Coactivator

Ramesh Narayanan,1 Abayomi A. Adigun,1 Dean P. Edwards,2 and Nancy L. Weigel1*

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas,1 Department of Pathology and Program in Molecular Biology, University of Colorado Health Science Center, Denver, Colorado2

Received 15 July 2004/ Returned for modification 20 August 2004/ Accepted 6 October 2004

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.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6234. Fax: (713) 790-1275. E-mail: nweigel{at}bcm.tmc.edu.

Molecular and Cellular Biology, January 2005, p. 264-277, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.264-277.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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