title: ERK5 regulates muscle cell fusion through Klf transcription factors.
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.
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sunadome
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Miki
authors.initials: M
authors.lastname: Ebisuya
authors.forename: Kunio
authors.initials: K
authors.lastname: Kondoh
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sehara-Fujisawa
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002459:Cell Fusion; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D020869:Gene Expression Profiling; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics; D017570:MyoD Protein / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D055396:Bone Morphogenetic Protein 2; D016326:Extracellular Matrix Proteins; C498314:Klf2 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017570:MyoD Protein; D016329:Sp1 Transcription Factor; C432915:nephronectin; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D048054:Mitogen-Activated Protein Kinase 7