ATRA activates and PDGF-BB represses the SM22α promoter through KLF4 binding to, or dissociating from, its cis-DNA elements

Abstract

Krüppel-like factor 4 (KLF4) is implicated in all-trans retinoic acid (ATRA)-induced and platelet-derived growth factor-BB (PDGF-BB)-repressed SM22α expression in vascular smooth muscle cells (VSMCs). However, its exact mechanism of action remains unclear. We determined how KLF4 plays different roles in ATRA- and PDGF-BB-dependent regulation of the SM22α gene. ATRA and PDGF-BB induced KLF4 expression but exhibited an opposite effect on SM22α expression and VSMC proliferation. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22α promoter. ATRA increased the binding of KLF4 to site 2, whereas PDGF-BB decreased the binding of KLF4 to site 1. ATRA stimulated KLF4 acetylation by inducing KLF4 phosphorylation and increasing its interaction with p300 via activating c-Jun NH(2)-terminal kinase (JNK) and p38 pathways, and acetylated KLF4 increased its binding activity to site 2. PDGF-BB stimulated KLF4 deacetylation by inducing KLF4 dephosphorylation and increasing its interaction with histone deacetylase 2 (HDAC2) via activating extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways, and deacetylated KLF4 dissociated from site 1. In VSMCs, ATRA activates and PDGF-BB represses SM22α expression through KLF4 binding to, or dissociating from, its different cis-elements in an acetylation-dependent manner.