PKC alpha‐Induced Derepression of the Human Luteinizing Hormone Receptor (LHR) through ERK‐Mediated Sp1 Phosphorylation

Abstract

Transcription of the LHR is subject to repression/derepression through various modes and multiple effectors. The present studies revealed that PKCα/ERK signaling is essential for activation of the LHR gene induced by phorbol‐12‐myristate‐13‐acetate (PMA) in Hela cells. While this effect was attributable to PKCα activity, the ERK pathway was the downstream effector in LHR activation. PMA caused significant enhancement of Sp1 phosphorylation at serine residue(s), which was blocked by inhibition of PKCα or ERK. The interaction of activated phospho‐ERK with Sp1 and ERK's association with the LHR promoter points to Sp1 as a direct target of ERK. Following Sp1 phosphorylation the HDAC/mSin3A repressor complex dissociated from Sp1 sites, histone 3 was acetylated, and TFIIB and Pol II were recruited. In addition, overexpression of a constitutively active PKCα (PKCαCA) which strongly activated LHR transcription in MCF‐7 cells (devoid of PKCα), induced Sp1 phosphorylation at serine residue(s) and caused de‐recruitment of the HDAC1/mSin3A complex from the promoter. These effects were negated by co‐transfection of dominant negative PKCα. These studies have revealed a novel regulatory signaling mechanism of transcriptional control in which the LHR is derepressed through PKCα/ERK‐mediated Sp1 phosphorylation, causing the release of HDAC1/mSin3A complex from the promoter.