Regulation of MKL1 via Actin Cytoskeleton Dynamics Drives Adipocyte Differentiation

Nat Commun. 2014 Feb 26;5:3368. doi: 10.1038/ncomms4368.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Actin Cytoskeleton / metabolism*
  • Actins / genetics
  • Actins / metabolism
  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Animals
  • Cell Differentiation*
  • Cell Line
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Immunoblotting
  • Kinetics
  • Mice
  • Microscopy, Fluorescence
  • NIH 3T3 Cells
  • Oligonucleotide Array Sequence Analysis
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Protein Binding
  • Protein Transport
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time-Lapse Imaging
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein

Substances

  • Actins
  • MKL1 protein, mouse
  • PPAR gamma
  • Trans-Activators
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein

Associated data

  • GEO/GSE52334