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

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  • Author(s): Liu Y;Liu Y; Sinha S; McDonald OG; Shang Y; Hoofnagle MH; Owens GK
  • Source:
    The Journal of biological chemistry [J Biol Chem] 2005 Mar 11; Vol. 280 (10), pp. 9719-27. Date of Electronic Publication: 2004 Dec 28.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9258 (Print) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      DNA-Binding Proteins/*physiology ; Muscle, Smooth, Vascular/*physiology ; Nuclear Proteins/*antagonists & inhibitors ; Nuclear Proteins/*genetics ; Trans-Activators/*antagonists & inhibitors ; Trans-Activators/*genetics ; Transcription Factors/*physiology; 3T3 Cells ; Animals ; Aorta ; Becaplermin ; COS Cells ; Chlorocebus aethiops ; Chromatin/genetics ; Gene Expression Regulation/drug effects ; Kruppel-Like Factor 4 ; Kruppel-Like Transcription Factors ; Mice ; Muscle, Smooth, Vascular/drug effects ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-sis ; Rats ; Transfection
    • Abstract:
      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.
    • Grant Information:
      P01HL19242 United States HL NHLBI NIH HHS; R01HL38854 United States HL NHLBI NIH HHS; R37HL57353 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Chromatin)
      0 (DNA-Binding Proteins)
      0 (Klf4 protein, mouse)
      0 (Klf4 protein, rat)
      0 (Kruppel-Like Factor 4)
      0 (Kruppel-Like Transcription Factors)
      0 (Nuclear Proteins)
      0 (Platelet-Derived Growth Factor)
      0 (Proto-Oncogene Proteins c-sis)
      0 (Trans-Activators)
      0 (Transcription Factors)
      0 (myocardin)
      1B56C968OA (Becaplermin)
    • Publication Date:
      Date Created: 20041230 Date Completed: 20050419 Latest Revision: 20220310
    • Publication Date:
      20221213
    • Accession Number:
      10.1074/jbc.M412862200
    • Accession Number:
      15623517