Open AccessProtein Kinase Cα-Induced Derepression of the Human Luteinizing Hormone Receptor Gene Transcription through ERK-Mediated Release of HDAC1/Sin3A Repressor Complex from Sp1 Sites
Author(s) -
Min Liao,
Ying Zhang,
Maria L. Dufau
Publication year - 2008
Publication title -
molecular endocrinology
Language(s) - English
Resource type - Journals
eISSN - 1944-9917
pISSN - 0888-8809
DOI - 10.1210/me.2008-0035
Subject(s) - derepression , biology , repressor , microbiology and biotechnology , mapk/erk pathway , promoter , hdac1 , phosphorylation , sp1 transcription factor , transcription factor , gene silencing , regulation of gene expression , psychological repression , histone , gene expression , gene , histone deacetylase , biochemistry
LH receptor (LHR) gene transcription is subject to repression/derepression through various modes and multiple effectors. Epigenetic silencing and activation of the LHR is achieved through coordinated regulation at both histone and DNA levels. The LHR gene is subject to repression by deacetylation and methylation at its promoter region, where a HDAC/mSin3A repressor complex is anchored at Sp1 sites. The present studies revealed that protein kinase C (PKC) alpha/ERK signaling is important for the activation of LHR promoter activity, and the increase of endogenous transcripts induced by phorbol-12-myristate-13-acetate (PMA) in HeLa cells. Whereas these effects were attributable to PKCalpha activity, the ERK pathway was the downstream effector in LHR activation. PMA caused a significant enhancement of Sp1 phosphorylation at serine residue (s), which was blocked by PKCalpha or ERK inhibition. The interaction of activated phosphorylated ERK with Sp1 and ERK's association with the LHR promoter points to Sp1 as a direct target of ERK. After Sp1 phosphorylation, the HDAC1/mSin3A repressor complex dissociated from Sp1 sites, histone 3 was acetylated, and transcription factor II B and RNA polymerase II were recruited. In addition, overexpression of a constitutively active PKCalpha (PKCalpha CA) strongly activated LHR transcription in MCF-7 cells (devoid of PKCalpha), induced Sp1 phosphorylation at serine residue (s) and caused derecruitment of HDAC1/mSin3A complex from the promoter. These effects were negated by cotransfection of a dominant-negative PKCalpha. In conclusion, these studies have revealed a novel regulatory signaling mechanism of transcriptional control in which the LHR is derepressed through PKCalpha/ERK-mediated Sp1 phosphorylation, causing the release of HDAC1/mSin3A complex from the promoter.