Regulation of the functional interaction between cyclin D1 and the estrogen receptor.
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.
Lamb
J
J
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ladha
M H
MH
McMahon
C
C
Sutherland
R L
RL
Ewen
M E
ME
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D019938:Cyclin D1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism
D008024:Ligands; D011960:Receptors, Estrogen; D019938:Cyclin D1; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004958:Estradiol