Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

Hiroyuki Nobusue, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Yuko Sumikawa, Tatsuyuki Chiyoda, Koichi Akashi, Hideyuki Saya () and Koichiro Kano ()
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Hiroyuki Nobusue: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University
Nobuyuki Onishi: Institute for Advanced Medical Research, Keio University School of Medicine
Takatsune Shimizu: Institute for Advanced Medical Research, Keio University School of Medicine
Eiji Sugihara: Institute for Advanced Medical Research, Keio University School of Medicine
Yoshinao Oki: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University
Yuko Sumikawa: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University
Tatsuyuki Chiyoda: Institute for Advanced Medical Research, Keio University School of Medicine
Koichi Akashi: Kyushu University Graduate School of Medical Science
Hideyuki Saya: Institute for Advanced Medical Research, Keio University School of Medicine
Koichiro Kano: Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4368

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