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; Koichiro Kano

doi:10.1038/ncomms4368

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, Koichiro Kano

Research output: Contribution to journal › Article › peer-review

138 Citations (Scopus)

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.

Original language	English
Article number	3368
Pages (from-to)	3368
Number of pages	1
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4368
Publication status	Published - 2014
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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@article{9cab125f710a4acda13583fc99428a16,

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. ",

author = "Hiroyuki Nobusue and Nobuyuki Onishi and Takatsune Shimizu and Eiji Sugihara and Yoshinao Oki and Yuko Sumikawa and Tatsuyuki Chiyoda and Koichi Akashi and Hideyuki Saya and Koichiro Kano",

note = "Funding Information: We thank T. Hara for the retroviral expression vector pRePS; T. Kitamura for the retroviral expression vector pMXs-puro; O. Sampetrean, S. Kuninaka, and H. Naoe for discussion; RM. Yonamine, X. Wang, H. Ito, N. Yanagihara, and N. Hirose for technical assistance; and K. Arai for secretarial assistance. We are grateful to the Collaborative Research Resources, School of Medicine, Keio University for technical support and reagents. This work was partly supported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan (HS) and a grant from Okinawa Research and Industrialization for the Forefront Medical Care (KK).",

year = "2014",

doi = "10.1038/ncomms4368",

language = "English",

volume = "5",

pages = "3368",

journal = "Nature communications",

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T1 - Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

AU - Nobusue, Hiroyuki

AU - Onishi, Nobuyuki

AU - Shimizu, Takatsune

AU - Sugihara, Eiji

AU - Oki, Yoshinao

AU - Sumikawa, Yuko

AU - Chiyoda, Tatsuyuki

AU - Akashi, Koichi

AU - Saya, Hideyuki

AU - Kano, Koichiro

N1 - Funding Information: We thank T. Hara for the retroviral expression vector pRePS; T. Kitamura for the retroviral expression vector pMXs-puro; O. Sampetrean, S. Kuninaka, and H. Naoe for discussion; RM. Yonamine, X. Wang, H. Ito, N. Yanagihara, and N. Hirose for technical assistance; and K. Arai for secretarial assistance. We are grateful to the Collaborative Research Resources, School of Medicine, Keio University for technical support and reagents. This work was partly supported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan (HS) and a grant from Okinawa Research and Industrialization for the Forefront Medical Care (KK).

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

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