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Molecular Endocrinology, doi:10.1210/me.2002-0378
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Molecular Endocrinology 17 (4): 628-642
Copyright © 2003 by The Endocrine Society

Mitogen-Activated Protein Kinase Regulates Nuclear Association of Human Progesterone Receptors

Ming Qiu, Abby Olsen, Emily Faivre, Kathryn B. Horwitz and Carol A. Lange

Department of Medicine (M.Q., A.O., E.F., C.A.L.), Division of Hematology, Oncology, and Transplant, Department of Pharmacology, and The University of Minnesota Cancer Center, Minneapolis, Minnesota 55455; and Department of Medicine (K.B.H.), The Molecular Biology Program, and The Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262

Address all correspondence and requests for reprints to Carol A. Lange, Ph.D., Department of Medicine, University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455. E-mail: Lange047{at}tc.umn.edu.

Breast cancers often have increased MAPK activity; this pathway may drive breast cancer cell growth by targeting steroid hormone receptors. MAPK phosphorylates human progesterone receptors (PRs) on Ser294, thus regulating several aspects of PR activity. To study the role of PR Ser294 phosphorylation on subcellular distribution, we stably expressed wild-type (wt) or S294A (Ser294 to Ala) PR-B in several cell types. PRs phosphorylated on Ser294 were nuclear. Activation of MAPK induced Ser294 phosphorylation and rapid nuclear translocation of wt, but not S294A, PR-B; both receptors concentrated in the nucleus after progestin treatment. The MAPK kinase inhibitor, U0126, blocked epidermal growth factor but not progestin-induced Ser294 phosphorylation and translocation of wt PR, indicating a novel mechanism for nuclear localization. After progestin treatment, wt PR-B underwent ligand-dependent down-regulation, while S294A PR-B persisted in nuclei. Prolonged treatment with U0126 or the nuclear export inhibitor, leptomycin B, promoted nuclear accumulation of wt PR-B and blocked ligand-dependent PR down-regulation, suggesting that PR degradation occurs in the cytoplasm and requires MAPK-dependent nuclear export. Stabilization of PRs by leptomycin B also blocked PR transcriptional activity, indicating a link between nucleocytoplasmic shuttling, receptor stability, and function. These results support a regulatory role for MAPK in nuclear steroid hormone receptor subcellular localization and coupling to multiple PR functions.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR
Ligands:   R5020



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