Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters.

Content Provider	Semantic Scholar
Author	Yoshida, Tadashi Gan, Qiong Shang, Yueting Owens, Gary K.
Copyright Year	2007
Abstract	A hallmark of smooth muscle cell (SMC) phenotypic switching is suppression of SMC marker gene expression. Although myocardin has been shown to be a key regulator of this process, the role of its related factors, MKL1 and MKL2, in SMC phenotypic switching remains unknown. The present studies were aimed at determining if: 1) MKL factors contribute to the expression of SMC marker genes in cultured SMCs; and 2) platelet-derived growth factor-BB (PDGF-BB)-induced repression of SMC marker genes is mediated by suppression of MKL factors. Results of gain- and loss-of-function experiments showed that MKL factors regulated the expression of single and multiple CArG [CC(AT-rich)(6)GG]-containing SMC marker genes, such as smooth muscle (SM) alpha-actin and telokin, but not CArG-independent SMC marker genes such as smoothelin-B. Treatment with PDGF-BB reduced the expression of CArG-containing SMC marker genes, as well as myocardin expression in cultured SMCs, while it had no effect on expression of MKL1 and MKL2. However, of interest, PDGF-BB induced the dissociation of MKL factors from the CArG-containing region of SMC marker genes, as determined by chromatin immunoprecipitation assays. This dissociation was caused by the competition between MKL factors and phosphorylated Elk-1 at early time points, but subsequently by the reduction in acetylated histone H4 levels at these promoter regions mediated by histone deacetylases, HDAC2, HDAC4, and HDAC5. Results provide novel evidence that PDGF-BB-induced repression of SMC marker genes is mediated through combinatorial mechanisms, including downregulation of myocardin expression and inhibition of the association of myocardin/MKL factors with CArG-containing SMC marker gene promoters.
Starting Page	95
Ending Page	118
Page Count	24
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://ajpcell.physiology.org/content/early/2006/09/20/ajpcell.00449.2006.full.pdf
Alternate Webpage(s)	http://ajpcell.physiology.org/content/ajpcell/292/2/C886.full.pdf
Alternate Webpage(s)	http://ajpcell.physiology.org/content/ajpcell/early/2006/09/20/ajpcell.00449.2006.full.pdf
Alternate Webpage(s)	http://ajpcell.physiology.org/content/ajpcell/292/2/c886.full.pdf
PubMed reference number	16987998v1
Volume Number	292
Issue Number	2
Journal	American journal of physiology. Cell physiology
Language	English
Access Restriction	Open
Subject Keyword	Blood Platelets Down-Regulation Gene Expression HDAC4 protein, human HDAC5 protein, human Histones MKL2 gene MYOCD gene Muscle Cells Myocytes, Smooth Muscle Platelet-Derived Growth Factor Promoter Regions, Genetic Repression, Psychology SMTN gene Smooth muscle (tissue) Streptomycin chromatin immunoprecipitation histone deacetylase 2
Content Type	Text
Resource Type	Article