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This version published online on January 12, 2006
Molecular Endocrinology, doi:10.1210/me.2004-0075
Molecular Endocrinology Vol. 0, No. 2006 200400751-
doi:10.1210/me.2004-0075
Copyright © 2006 by the Endocrine Society.
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Submitted on February 22, 2004
Accepted on January 4, 2006

p38 MAPK Stimulates Estrogen-Mediated Transcription and Proliferation Through the Phosphorylation and Potentiation of the p160 Coactivator GRIP1

Daniel E. Frigo, Aninda Basu, Erica N. Nierth-Simpson, Christopher B. Weldon, Christine M. Dugan, Steven Elliott, Bridgette M. Collins-Burow, Virgilio A. Salvo, Yun Zhu, Lilia I. Melnik, Gabriela N. Lopez, Peter J. Kushner, Tyler J. Curiel, Brian G. Rowan, John A. McLachlan, and Matthew E. Burow*

Molecular and Cellular Biology Program, Center for Bioenvironmental Research, Department of Surgery, Department of Medicine-Section of Hematology and Medical Oncology, Tulane Cancer Center, and the Department of Pharmacology, Tulane University Health Science Center, New Orleans, LA 70112, the Metabolic Research Unit, Department of Medicine, University of California, San Francisco, California 94143, and the Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, OH 43614

* To whom correspondence should be addressed. 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{alpha}- and ER{beta}-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{alpha} or {beta}, 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.
Key words: ER • DDT • HEK 293 • Ishikawa • MAPK • MCF-7 • p38 • GRIP1

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Coregulators:   GRIP1
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen



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