Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression.

Liu Y, Sinha S, McDonald OG, Shang Y, Hoofnagle MH, Owens GK
J Biol Chem. 2005 280 (10): 9719-27

PMID: 15623517 · DOI:10.1074/jbc.M412862200

Platelet-derived growth factor BB (PDGF-BB) has been shown to be an extremely potent negative regulator of smooth muscle cell (SMC) differentiation. Moreover, previous studies have demonstrated that the Kruppel-like transcription factor (KLF) 4 potently represses the expression of multiple SMC genes. However, the mechanisms whereby KLF4 suppresses SMC gene expression are not known, nor is it clear whether KLF4 contributes to PDGF-BB-induced down-regulation of SMC genes. The goals of the present studies were to determine the molecular mechanisms by which KLF4 represses expression of SMC genes and whether it contributes to PDGF-BB-induced suppression of these genes. Results demonstrated that KLF4 markedly repressed both myocardin-induced activation of SMC genes and expression of myocardin. KLF4 was rapidly up-regulated in PDGF-BB-treated, cultured SMC, and a small interfering RNA to KLF4 partially blocked PDGF-BB-induced SMC gene repression. Both PDGF-BB and KLF4 markedly reduced serum response factor binding to CArG containing regions within intact chromatin. Finally, KLF4, which is normally not expressed in differentiated SMC in vivo, was rapidly up-regulated in vivo in response to vascular injury. Taken together, results indicate that KLF4 represses SMC genes by both down-regulating myocardin expression and preventing serum response factor/myocardin from associating with SMC gene promoters, and suggest that KLF4 may be a key effector of PDGF-BB and injury-induced phenotypic switching of SMC.

MeSH Terms (19)

3T3 Cells Animals Aorta Becaplermin Chlorocebus aethiops Chromatin COS Cells DNA-Binding Proteins Gene Expression Regulation Kruppel-Like Transcription Factors Mice Muscle, Smooth, Vascular Nuclear Proteins Platelet-Derived Growth Factor Proto-Oncogene Proteins c-sis Rats Trans-Activators Transcription Factors Transfection

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