Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors.
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.
Qiu
Ming
M
Department of Medicine, University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.
Olsen
Abby
A
Faivre
Emily
E
Horwitz
Kathryn B
KB
Lange
Carol A
CA
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011397:Promegestone / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D002070:Butadienes; D015853:Cysteine Proteinase Inhibitors; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D009097:Multienzyme Complexes; D009570:Nitriles; D011980:Receptors, Progesterone; C113580:U 0126; C097314:progesterone receptor B; C067713:lactacystin; D012694:Serine; D004815:Epidermal Growth Factor; D011397:Promegestone; D020929:Mitogen-Activated Protein Kinase Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine; C038753:leptomycin B