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Progesterone Receptor Repression of Prolactin/Signal Transducer and Activator of Transcription 5-Mediated Transcription of the ß-Casein Gene in Mammary Epithelial Cells

Department of Pathology (A.C.B., E.K.G.-H., S.A.L., H.W., S.M.A., D.P.E.), Program in Molecular Biology (S.M.A., D.P.E.) and Department of Microbiology (J.S.), University of Colorado Health Sciences Center, Aurora, Colorado 80045; Baylor College of Medicine (S.L.W., J.M.R., D.P.E.), Department of Molecular and Cellular Biology, Houston, Texas 77030; and Division of Medical Biochemistry (W.D.), Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria

Address all correspondence and requests for reprints to: Dean P. Edwards, Ph.D., Baylor College of Medicine, Department of Molecular/Cellular Biology, One Baylor Plaza, Room 145E, Mail Box BCM-130, Houston, Texas 77030. E-mail: deane{at}bcm.tmc.edu.

Prolactin (PRL) and glucocorticoids act synergistically to stimulate transcription of the ß-casein milk protein gene. Signal transducer and activator of transcription 5 (Stat5) mediates PRL-dependent trans-activation, and glucocorticoid potentiation occurs through cross talk between glucocorticoid receptor (GR) and Stat5 at the ß-casein promoter. In the mouse, progesterone withdrawal leads to terminal differentiation and secretory activation of the mammary gland at parturition, indicating progesterone’s role in repressing milk protein gene expression during pregnancy. To investigate the mechanism of the inhibitory action of progesterone, experiments were performed with cell culture systems reconstituted to express progesterone receptor (PR), the PRL receptor/Stat5 signaling pathway, and GR, enabling evaluation of PR, GR, and Stat5 interactions at the ß-casein promoter. With COS-1, normal murine mammary gland, HC-11, and primary mammary epithelial cells, progestin-PR directly repressed the PRL receptor/Stat5a signaling pathway’s mediation of PRL-induced ß-casein transcription. Progestin-PR also inhibited glucocorticoid-GR enhancement of PRL induced trans-activation of ß-casein. Inhibition depended on a functional PR DNA binding domain and specific PR-DNA interactions at the ß-casein promoter. Chromatin immunoprecipitation assays in HC-11 cells revealed recruitment of PR and Stat5a to the ß-casein promoter by progestin or PRL, respectively. Recruitment was disrupted by cotreatment with progestin and PRL, suggesting a mutual interference between activated PR and Stat5a. Without PRL, progestin-PR also recruited Stat5a to the ß-casein promoter, suggesting that recruitment of an unactivated form of Stat5a may contribute to inhibition of ß-casein by progesterone. These results define a negative cross talk between PR and Stat5a/GR that may contribute to the physiological role of progesterone to repress lactogenic hormone induction of the ß-casein gene in the mammary gland during pregnancy.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  PR

Ligands:   Dexamethasone  |  R5020

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