SUMOylation of KLF4 acts as a switch in transcriptional programs that control VSMC proliferation

Exp Cell Res. 2016 Mar 1;342(1):20-31. doi: 10.1016/j.yexcr.2016.03.001. Epub 2016 Mar 2.

Abstract

The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue due to its major implications for the prevention of pathological vascular conditions. The objective of this work was to assess the function of small ubiquitin-like modifier (SUMO)ylated Krϋppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in cultured cells and in animal models with balloon injury. We found that under basal conditions, binding of non-SUMOylated KLF4 to p300 activated p21 (p21(WAF1/CIP1))transcription, leading to VSMC growth arrest. PDGF-BB promoted the interaction between Ubc9 and KLF4 and the SUMOylation of KLF4, which in turn recruited transcriptional corepressors to the p21 promoter. The reduction in p21 enhanced VSMC proliferation. Additionally, the SUMOylated KLF4 did not affect the expression of KLF4, thereby forming a positive feedback loop enhancing cell proliferation. These results demonstrated that SUMOylated KLF4 plays an important role in cell proliferation by reversing the transactivation action of KLF4 on p21 induced with PDGF-BB.

Keywords: KLF4; Proliferation; SUMOylation; Ubc9; VSMC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Femoral Artery / injuries
  • Femoral Artery / pathology
  • Gene Expression Regulation*
  • Humans
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-sis / physiology
  • Rats, Sprague-Dawley
  • Sumoylation*
  • Transcription, Genetic
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Vascular Diseases / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytoskeletal Proteins
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Klf4 protein, rat
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins c-sis
  • Becaplermin
  • Ubiquitin-Conjugating Enzymes