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Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization

Keigo Araki1, Keiko Kawauchi, Hiroaki Hirata

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Elife
|December 5, 2013
PubMed

Insights

Tumor necrosis factor-alpha (TNF-α) triggers skeletal muscle degeneration by causing retinoblastoma protein (Rb) to disrupt sarcomere organization. This study reveals a new non-nuclear role for Rb in maintaining muscle structure.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Muscle Physiology

Background:

  • Skeletal muscle degeneration is a common complication of chronic diseases like cancer.
  • Pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is a key mediator of cancer-related muscle wasting.

Purpose of the Study:

  • To investigate the novel role of retinoblastoma protein (Rb) in skeletal muscle degeneration.
  • To elucidate the mechanism by which TNF-α induces sarcomeric disorganization in muscle.

Main Methods:

  • Treatment of human skeletal muscle myotubes (HSMMs) with TNF-α.
  • Analysis of cyclin-dependent kinase 4 (CDK4) and Rb phosphorylation and localization.
  • Expression of nuclear exporting signal (NES)-fused Rb and identification of binding partners using biochemical assays.

Main Results:

  • TNF-α treatment upregulated CDK4 and induced Rb phosphorylation, leading to its cytoplasmic translocation.
  • Induced expression of NES-Rb disrupted sarcomeric organization.
  • Cytoplasmic Rb was found to bind with mammalian diaphanous-related formin 1 (mDia1), an actin nucleation factor.

Conclusions:

  • Retinoblastoma protein (Rb) has a novel non-nuclear function in maintaining sarcomeric organization.
  • TNF-α induces skeletal muscle degeneration by promoting Rb's cytoplasmic localization and subsequent disruption of sarcomere structure via mDia1 interaction.
Keywords:
CDKphosphorylationretinoblastoma proteinsarcomeric organization

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