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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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