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TRICHOSTATIN A INDUCED DEREPRESSION OF THE HUMAN LUTEINIZING HORMONE RECEPTOR GENE BY CELL‐SPECIFIC PHOSPHATASE RELEASE FROM THE PROMOTER
Author(s) -
Zhang Ying,
Liao Mingjuan,
Dufau Maria L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.782.13
Subject(s) - trichostatin a , derepression , histone deacetylase , psychological repression , histone deacetylase inhibitor , repressor , promoter , chemistry , microbiology and biotechnology , protein phosphatase 2 , phosphatase , biology , transcription factor , histone , phosphorylation , gene expression , gene , biochemistry
The histone deacetylase inhibitor, Trichostatin A (TSA), induces de‐repression of the human Luteinizing Hormone receptor (hLHR) 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/PKCzeta cascade phosphorylates Sp1 at Ser641, which is essential for the release of the repression of LHR transcription. These studies have revealed a critical role of serine/threonine protein phosphatases PP2A and PP1 in TSA‐induced activation of LHR gene transcription in a cell type‐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 HDAC, respectively at the promoter. This favors the phophorylation of Sp1 mediated by the PI3K/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 PI3K/PKCzeta and phosphatases could be critical for up‐ and down‐regulation of LHR gene expression in physiological and pathological settings.