Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element.
Estrogens induce cell proliferation in target tissues by stimulating progression through the G(1) phase of the cell cycle. Induction of cyclin D1 expression is a critical feature of the mitogenic action of estrogen. We have determined a region between -96 and -29 in the cyclin D1 promoter that confers regulation by estrogens in the human mammary carcinoma cells MCF-7. This region encompasses a unique known transcription factor binding site with a sequence of a potential cAMP response element (CRE-D1). The induction is strictly hormone dependent and requires the DNA binding domain as well as both AF-1 and AF-2 domains of the estrogen receptor (ER) alpha. Destruction of the CRE-D1 motif caused complete loss of estrogen responsiveness. Both c-Jun and ATF-2 transactivated the cyclin D1 promoter in transient transfection experiments, and a clear additional increase was detected when ER was cotransfected with either c-Jun or with c-Jun and ATF-2 but not with ATF-2 alone. Furthermore, the expression of a dominant negative variant of c-Jun, TAM67, completely abolished the induction of the cyclin D1 promoter both in the absence and presence of ER. We show that ATF-2 homodimers and ATF-2/c-Jun heterodimers, but not c-Jun homodimers, were able to bind the CRE of the cyclin D1 promoter. To interpret these results, we propose a mechanism in which ATF-2/c-Jun heterodimers bind to the CRE-D1 element and mediate the activation of cyclin D1 promoter by the ER. This mechanism represents a pathway by which estrogens control the proliferation of target cells.
Sabbah
M
M
Institut National de la Santé et de la Recherche Médicale U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Courilleau
D
D
Mester
J
J
Redeuilh
G
G
D051698:Activating Transcription Factor 2; D000242:Cyclic AMP / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004967:Estrogens; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D014157:Transcription Factors; D019938:Cyclin D1; D000242:Cyclic AMP