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Molecular and Cellular Biology, December 2000, p. 8667-8675, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Regulation of the Functional Interaction between Cyclin D1 and the Estrogen Receptor

Justin Lamb,1 Mohamed H. Ladha,1 Christine McMahon,1 Robert L. Sutherland,2 and Mark E. Ewen1,*

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115,1 and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia2

Received 28 June 2000/Returned for modification 24 July 2000/Accepted 31 August 2000

We report that the functional interaction between cyclin D1 and the estrogen receptor (ER) is regulated by a signal transduction pathway involving the second messenger, cyclic AMP (cAMP). The cell-permeable cAMP analogue 8-bromo-cAMP caused a concentration-dependent enhancement of cyclin D1-ER complex formation, as judged both by coimmunoprecipitation and mammalian two-hybrid analysis. This effect was paralleled by increases in ligand-independent ER-mediated transcription from an estrogen response element containing reporter construct. These effects of 8-bromo-cAMP were antagonized by a specific protein kinase A (PKA) inhibitor, indicating that the signaling pathway involved was PKA dependent. Further, we show that culture of MCF-7 cells on a cellular substratum of murine preadipocytes also enhanced the functional interaction between cyclin D1 and ER in a PKA-dependent manner. These findings demonstrate a collaboration between cAMP signaling and cyclin D1 in the ligand-independent activation of ER-mediated transcription in mammary epithelial cells and show that the functional associations of cyclin D1 are regulated as a function of cellular context.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute and Harvard Medical School, D728, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2206. Fax: (617) 632-5417. E-mail: mark_ewen{at}dfci.harvard.edu.

Molecular and Cellular Biology, December 2000, p. 8667-8675, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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