Unlocking repression of the human luteinizing hormone receptor gene by trichostatin A-induced cell-specific phosphatase release.
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 zeta (PKCzeta) 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/PKCzeta 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/PKCzeta and phosphatases could be critical for up- and down-regulation of LHR gene expression in physiological and pathological settings.
Zhang
Ying
Y
Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH, 49 Convent Drive, Bethesda, MD 20892-4510, USA.
Liao
Mingjuan
M
Dufau
Maria L
ML
D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011974:Receptors, LH / Q000096:biosynthesis* / Q000235:genetics; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D002843:Chromatin; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C493844:RBL1 protein, human; D011974:Receptors, LH; D050720:Retinoblastoma-Like Protein p107; D016329:Sp1 Transcription Factor; C012589:trichostatin A; D019869:Phosphatidylinositol 3-Kinases; D051744:Protein Kinase C-epsilon; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2