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Differential Roles for Signal Transducers and Activators of Transcription 5a and 5b in PRL Stimulation of ER and ERß Transcription

Department of Physiology and Biophysics (J.F., C.T., G.G.), University of Illinois at Chicago, Chicago, Illinois 60612; Department of Physiology (K.P., M.B., O.-K.P.-S.), University of Kentucky, Lexington, Kentucky 40536; Department of Hemopoietic Factors (T.K.), University of Tokyo, Tokyo 108-8639, Japan; Departments of Medicine, Molecular and Cell Biology, and Immunology (L.-Y.Y.-L.), Baylor College of Medicine, Houston, Texas 77030-3411; and Department of Biologie Cellulaire (J.D.), Institut National de Recherche Agronomique, Jouy-en-Josas, F-78350 France

Address all correspondence and requests for reprints to: Geula Gibori, 835 South Wolcott, M/C 901, Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612. E-mail: ggibori{at}uic.edu

PRL has been shown to stimulate mRNA expression of both ER and ERß in the rat corpus luteum and decidua of pregnancy. To investigate whether PRL may stimulate ER expression at the level of transcription and which transcription factors may mediate this stimulation, we have cloned the 5'-flanking regions of both rat ER genes. A constitutively active PRL receptor (PRL-R_CA) stimulated both ER and ERß promoter activity, indicating that PRL is acting to stimulate ER transcription. Putative signal transducer and activator of transcription (Stat)5 response elements were identified at -189 in the ER promoter and at -330 in the ERß promoter. Mutation of these response elements or overexpression of dominant negative Stat5 prevented stimulation of ER and ERß promoter activity, indicating that PRL regulation of ER expression requires both intact Stat5 binding sites as well as functional Stat5. Interestingly, either Stat5a or Stat5b could stimulate ER transcription while stimulation of ERß occurred only in the presence of Stat5b. Through mutational analysis, a single nucleotide difference between the ER and ERß Stat5 response elements was shown to be responsible for the lack of Stat5a-mediated stimulation of ERß. These findings indicate that PRL stimulation of ER expression occurs at the level of transcription and that PRL regulation of ER can be mediated by either Stat5a or Stat5b, while regulation of ERß appears to be mediated only by Stat5b.

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