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Protein Phosphatase 5 Is a Negative Regulator of Estrogen Receptor-Mediated Transcription

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine (K.I., T.T., K.H.-I., M.M., S.I.), and Department of Molecular Biology (T.T.), Saitama Medical School, Hidaka-shi, Saitama 350-1241, Japan, Department of Geriatric Medicine (S.O., Y.O., S.I.), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; and Institute of Molecular and Cellular Biosciences (S.K.), University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan

Address all correspondence and requests for reprints to: Satoshi Inoue, Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan. E-mail: INOUE-GER{at}h.u-tokyo.ac.jp.

Estrogen receptors (ERs) are transcription factors that can be modulated by both estrogen-dependent and growth factor-dependent phosphorylation. A yeast two-hybrid screening identified a serine/threonine protein phosphatase (PP5) as an interactant of ERß (1–481), a dominant negative ERß mutant. Glutathione S-transferase pull-down assays, mammalian two-hybrid assays, and immunoprecipitation studies showed that PP5 directly binds to both ER and ERß via its tetratricopeptide repeat domain. E domains of ER and ERß, without containing activation domain core regions in transcription activation function 2, were required for the binding to PP5. In ER-positive breast cancer MCF7 cells, estrogen- and epidermal growth factor-dependent phosphorylation of ER on serine residue 118, a major phosphorylation site of the receptor, was reduced by expressing PP5 but enhanced by PP5 antisense oligonucleotide. Estrogen-induced transcriptional activities of both ER and ERß and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide. A truncated PP5 mutant consisting only of its tetratricopeptide repeat domain acted as a dominant negative PP5 that enhanced serine residue 118 phosphorylation of ER and transactivations by ER and ERß. We present the first evidence that PP5 functions as an inhibitory regulator of ER phosphorylation and transcriptional activation in vivo.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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