Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation
Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation
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DOI：
10.1038/ncomms4368
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发表时间：
2014-02-01
影响因子：
16.6
通讯作者：
Kano, Koichiro
中科院分区：
文献类型：
--
作者：
Nobusue, Hiroyuki;Onishi, Nobuyuki;Kano, Koichiro
细胞分化是通过激活和抑制特定转录因子来调节的。分化的标志是细胞形状的明显变化，这是由肌动蛋白细胞骨架的动力学决定的。在这里，我们表明，调节转录辅激活因子MKL 1（巨核细胞白血病1）肌动蛋白细胞骨架动力学驱动脂肪细胞分化介导的过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ），一个主转录调节脂肪形成。脂肪细胞分化的诱导通过下调RhoA-ROCK信号传导导致肌动蛋白应力纤维的破坏。随后单体G-肌动蛋白的快速增加导致G-肌动蛋白与MKL 1的相互作用，这阻止了MKL 1的核转位，并允许PPAR γ的表达，随后是脂肪形成分化。此外，我们发现MKL 1和PPAR γ在脂肪细胞分化过程中以相互拮抗的方式发挥作用。因此，我们的研究结果提供了新的机制之间的关系，细胞分化过程中的细胞形状和转录调控的动态洞察。
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 gamma (PPAR gamma), 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 PPAR gamma followed by adipogenic differentiation. Moreover, we found that MKL1 and PPAR gamma 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.