ERK5 regulates muscle cell fusion through Klf transcription factors

Dev Cell. 2011 Feb 15;20(2):192-205. doi: 10.1016/j.devcel.2010.12.005.

Abstract

In skeletal muscle differentiation, muscle-specific genes are regulated by two groups of transcription factors, the MyoD and MEF2 families, which work together to drive the differentiation process. Here, we show that ERK5 regulates muscle cell fusion through Klf transcription factors. The inhibition of ERK5 activity suppresses muscle cell fusion with minimal effects on the expression of MyoD, MEF2, and their target genes. Promoter analysis coupled to microarray assay reveals that Klf-binding motifs are highly enriched in the promoter regions of ERK5-dependent upregulated genes. Remarkably, Klf2 and Klf4 expression are also upregulated during differentiation in an ERK5-dependent manner, and knockdown of Klf2 or Klf4 specifically suppresses muscle cell fusion. Moreover, we show that Sp1 transcription factor links ERK5 to Klf2/4, and that nephronectin, a Klf transcriptional target, is involved in muscle cell fusion. Therefore, an ERK5/Sp1/Klf module plays a key role in the fusion process during skeletal muscle differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Morphogenetic Protein 2 / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Fusion
  • Cell Line
  • Extracellular Matrix Proteins / metabolism
  • Fibroblast Growth Factor 2 / pharmacology
  • Gene Expression Profiling
  • Insulin-Like Growth Factor I / pharmacology
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Molecular Sequence Data
  • Muscle Cells / cytology*
  • Muscle Cells / drug effects
  • Muscle Cells / enzymology*
  • Muscle Development / drug effects
  • Muscle Development / genetics
  • MyoD Protein / metabolism
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / drug effects
  • Sp1 Transcription Factor / metabolism
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Bone Morphogenetic Protein 2
  • Extracellular Matrix Proteins
  • Klf2 protein, mouse
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • MyoD Protein
  • Sp1 Transcription Factor
  • nephronectin
  • Fibroblast Growth Factor 2
  • Insulin-Like Growth Factor I
  • Mitogen-Activated Protein Kinase 7

Associated data

  • GEO/GSE25827