Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation.
Estrogen receptors are phosphoproteins which can be activated by ligands, kinase activators, or phosphatase inhibitors. Our previous study showed that p38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and MEKK1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (Thr(311)), located in helix 1 of the hormone-binding domain. The mutation of threonine-311 to alanine did not affect estrogen binding of the receptor but compromised its interaction with coactivators. Suppression of p38 activity or mutation of the site inhibited the estrogen-induced receptor nuclear localization as well as its transcriptional activation by estrogens and MEKK1. The inhibition of the p38 signal pathway by a specific chemical inhibitor blocked the biological activities of estrogens in regulating endogenous gene expression as well as endometrial cancer cell growth. Our studies demonstrate the role of estrogen receptor phosphorylation induced by the natural ligand in estrogen receptor's cellular distribution and its significant contribution to the growth-stimulating activity of estrogens in endometrial cancer cells.
Lee
Heehyoung
H
Department of Pathology, University of South Florida College of Medicine, and Program of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida 33612-4799, USA.
Bai
Wenlong
W
D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000502:physiology; D000230:Adenocarcinoma / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D016889:Endometrial Neoplasms / Q000503:physiopathology; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D006801:Humans; D008024:Ligands; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021382:Protein Sorting Signals; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D021382:Protein Sorting Signals; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D013912:Threonine; D004958:Estradiol; C038752:leptomycin A; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human