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p38 Mitogen-Activated Protein Kinase Stimulates Estrogen-Mediated Transcription and Proliferation through the Phosphorylation and Potentiation of the p160 Coactivator Glucocorticoid Receptor-Interacting Protein 1

Molecular and Cellular Biology Program (D.E.F., E.N.N.-S.), Center for Bioenvironmental Research (D.E.F., E.N.N.-S., L.I.M., J.A.M., M.E.B.), Department of Surgery (C.B.W., M.E.B.), Department of Medicine-Section of Hematology and Medical Oncology (C.M.D., S.E., B.M.C.-B., V.A.S., Y.Z., T.J.C., M.E.B.), Tulane Cancer Center (C.M.D., V.A.S., Y.Z., M.E.B.), and the Department of Pharmacology (J.A.M.), Tulane University Health Science Center, New Orleans, Louisiana 70112; the Metabolic Research Unit (G.N.L., P.J.K.), Department of Medicine (P.J.K.), University of California, San Francisco, California 94143; and the Department of Biochemistry and Molecular Biology (A.B., B.G.R.), Medical College of Ohio, Toledo, Ohio 43614

Address all correspondence and requests for reprints to: Matthew E. Burow, Tulane University School of Medicine, Department of Medicine-Section of Hematology and Medical Oncology, 1430 Tulane Avenue, SL-78, New Orleans, Louisiana 70112. E-mail: mburow{at}tulane.edu.

Nuclear hormone receptors, such as the estrogen receptors (ERs), are regulated by specific kinase signaling pathways. Here, we demonstrate that the p38 MAPK stimulates both ER- and ERß-mediated transcription in MCF-7 breast carcinoma, Ishikawa endometrial adenocarcinoma, and human embryonic kidney 293 cells. Inhibition of this potentiation using the p38 inhibitor, RWJ67657, blocked estrogen-mediated transcription and proliferation. Activated ERs promote gene expression in part through the recruitment of the p160 class of coactivators. Because no direct p38 phosphorylation sites have been determined on either ER or ß, we hypothesized that p38 could target the p160 class of coactivators. We show for the first time using pharmacological and molecular techniques that the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) is phosphorylated and potentiated by the p38 MAPK signaling cascade in vitro and in vivo. S736 was identified as a necessary site for p38 induction of GRIP1 transcriptional activation. The C terminus of GRIP1 was also demonstrated to contain a p38-responsive region. Taken together, these results indicate that p38 stimulates ER-mediated transcription by targeting the GRIP1 coactivator.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Coregulators:   GRIP1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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