Premium
PI3K/PKCzeta‐induced Phosphorylation of Sp1 and p107 Inhibitor Release Has a Critical Role in HDAC Inhibitor‐Induced Depression of Transcription of the Luteinizing Hormone Receptor (LHR) Gene
Author(s) -
Zhang Ying,
Liao Mingjuan,
Dufau Maria
Publication year - 2006
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.20.5.lb48-c
Subject(s) - derepression , phosphorylation , repressor , promoter , chemistry , psychological repression , transcription (linguistics) , regulation of gene expression , gene expression , microbiology and biotechnology , gene , biology , biochemistry , linguistics , philosophy
We have demonstrated that silencing of the LHR gene transcription is mediated via a proximal Sp1 site at its promoter. TSA induced histone acetylation and gene activation that prevailed in absence of changes of Sp1/Sp3 expression, their binding activity or disassociation of an HDAC/mSin3A complex from the Sp1site. This indicated a different mechanism involved in TSA‐induced derepression. The current studies have revealed that PI3K/PKCzeta‐mediated Sp1 phosphorylation accounts for the Sp1‐site dependent LHR gene activation. TSA caused marked phosphorylation of Sp1 in JAR cells. Blockade of PI3K or PKCzeta activity by inhibitors or kinase‐deficient mutants abolished the TSA effect on the LHR gene, and Sp1 phosphorylation. PKCzeta was shown to associate with Sp1and this association was enhanced by TSA. Sp1 phosphorylation was required for release of pRb homologue p107 from the LHR gene promoter while p107 acts as a repressor of the LHR gene. Inhibition of PKCzeta activity blocked the dissociation of p107 from the LHR gene promoter, and markedly reduced Sp1 phosphorylation and transcription. These results have demonstrated that phosphorylation of Sp1 by PI3K/PKCzeta is critical for TSA‐activated LHR gene expression. These studies have revealed a novel mechanism of TSA action through derecruitment of a repressor from the LHR gene promoter in a PI3K/PKCzeta‐induced Sp1 phosphorylation‐dependent manner.