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J. Biol. Chem., Vol. 283, Issue 35, 24039-24046, August 29, 2008

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Unlocking Repression of the Human Luteinizing Hormone Receptor Gene by Trichostatin A-induced Cell-specific Phosphatase Release^*

From the Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510

Our previous studies demonstrated that the histone deacetylase inhibitor, trichostatin A (TSA), induces derepression of the human luteinizing hormone receptor (LHR) gene by de-recruitment of the pRB homologue p107 repressor from the promoter in JAR and MCF-7 cancer cells. TSA initiates a mechanism whereby the phosphatidylinositol 3-kinase/protein kinase (PKC) cascade phosphorylates Sp1 at Ser-641, which is essential for the release of the repression of LHR transcription. The present studies have revealed that dissociation of serine/threonine protein phosphatases PP2A and PP1 from the LHR promoter mediates TSA-induced activation of LHR gene transcription in a cell-specific manner. Changes in chromatin structure induced by TSA cause the release of PP2A in JAR cells or of PP1 in MCF-7 cells, which is associated with Sp1 directly or through histone deacetylase 1/2, respectively, at the promoter. This favors the phosphorylation of Sp1 mediated by the phosphatidylinositol 3-kinase/PKC pathway, which in turn causes the release of the p107 inhibitor from Sp1 and marked transcriptional activation of the LHR. These findings reveal the importance of phosphatases in the control of LHR transcription, where the balance between phosphatidylinositol 3-kinase/PKC and phosphatases could be critical for up- and down-regulation of LHR gene expression in physiological and pathological settings.

Received for publication, March 7, 2008 , and in revised form, July 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health (Intramural Research Program of the NICHD). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be address: Bldg. 49, Rm. 6A-36, 49 Convent Dr., MSC 4510, National Institutes of Health, Bethesda, MD 20892-4510. Tel.: 301-496-2021; E-mail: dufaum{at}mail.nih.gov.

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