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Molecular and Cellular Biology, August 2002, p. 5835-5845, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5835-5845.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Estrogen Receptor Nuclear Export by Ligand-Induced and p38-Mediated Receptor Phosphorylation

Heehyoung Lee and Wenlong Bai*

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

Received 29 January 2002/ Returned for modification 7 March 2002/ Accepted 9 May 2002

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 (Thr311), 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.

* Corresponding author. Mailing address: Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 11, Tampa, FL 33612-4799 Phone: (813) 974-0563. Fax: (813) 974-5536. E-mail: wbai{at}hsc.usf.edu.

Molecular and Cellular Biology, August 2002, p. 5835-5845, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5835-5845.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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