Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression.
Induction of cyclin D1 gene transcription by estrogen receptor alpha (ERalpha) plays an important role in estrogen-mediated proliferation. There is no classical estrogen response element in the cyclin D1 promoter, and induction by ERalpha has been mapped to an alternative response element, a cyclic AMP-response element at -57, with possible participation of an activating protein-1 site at -954. The action of ERbeta at the cyclin D1 promoter is unknown, although evidence suggests that ERbeta may inhibit the proliferative action of ERalpha. We examined the response of cyclin D1 promoter constructs by luciferase assay and the response of the endogenous protein by Western blot in HeLa cells transiently expressing ERalpha, ERalphaK206A (a derivative that is superactive at alternative response elements), or ERbeta. In each case, ER activation at the cyclin D1 promoter is mediated by both the cyclic AMP-response element and the activating protein-1 site, which play partly redundant roles. The activation by ERbeta occurs only with antiestrogens. Estrogens, which activate cyclin D1 gene expression with ERalpha, inhibit expression with ERbeta. Strikingly, the presence of ERbeta completely inhibits cyclin D1 gene activation by estrogen and ERalpha or even by estrogen and the superactive ERalphaK206A. The observation of the opposing action and dominance of ERbeta over ERalpha in activation of cyclin D1 gene expression has implications for the postulated role of ERbeta as a modulator of the proliferative effects of estrogen.
Liu
Meng-Min
MM
Department of Medicine, University of California, San Francisco, California 94112-1640, USA.
Albanese
Chris
C
Anderson
Carol M
CM
Hilty
Kristin
K
Webb
Paul
P
Uht
Rosalie M
RM
Price
Richard H
RH
Pestell
Richard G
RG
Kushner
Peter J
PJ
D019943:Amino Acid Substitution; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011960:Receptors, Estrogen / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D017362:Cyclic AMP Response Element-Binding Protein; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D008156:Luciferases