title: Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation.
abstract: Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARγ act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation.
authors.affiliation: 1] Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan [2] Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nobusue
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.affiliation: 1] Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0076, Japan.
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: 1] Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0076, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.affiliation: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oki
authors.affiliation: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sumikawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Chiyoda
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka 812-8582, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: 1] Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0076, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kano
mesh_terms: D041721:3T3-L1 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015151:Immunoblotting; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D059008:Time-Lapse Imaging; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D000199:Actins; C511173:Mrtfa protein, mouse; D047495:PPAR gamma; D015534:Trans-Activators; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein