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Active Ras-induced effects on skeletal myoblast differentiation and apoptosis are independent of constitutive

M Karasarides1, K Dee, D Schulman

  • 1Department of Cell Biology, Learner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.

Cell Biology International
|March 1, 2006
PubMed

Insights

Constitutively active Ras mutants impair skeletal myoblast differentiation and apoptosis. A novel pathway, distinct from MAPK, NF-kappaB, or PI3-kinase, mediates these effects, offering new therapeutic targets.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Skeletal Muscle Research

Background:

  • Ras proteins are key regulators of cell signaling pathways.
  • Aberrant Ras signaling is implicated in various diseases, including cancer.
  • Understanding Ras function in skeletal myoblasts is crucial for muscle development and disease.

Purpose of the Study:

  • To investigate the cellular and molecular effects of different constitutively active H-Ras mutants in skeletal myoblasts.
  • To compare the signaling pathways activated by G12V:H-Ras and F156L:H-Ras.
  • To identify the signaling pathways responsible for impaired differentiation and apoptosis in Ras-expressing myoblasts.

Main Methods:

  • Establishment of 23A2 skeletal myoblast cell lines stably expressing G12V:H-Ras or F156L:H-Ras.
  • Assessment of cell morphology, differentiation, and apoptosis.
  • Analysis of signaling pathway activation (PI3-kinase, MAPK, NF-kappaB) and pharmacological inhibition studies.

Main Results:

  • G12V:H-Ras induced transformed morphology, abrogated differentiation and apoptosis, and activated PI3-kinase, MAPK, and NF-kappaB.
  • F156L:H-Ras did not induce transformed morphology but impaired differentiation and apoptosis without activating MAPK and NF-kappaB.
  • Constitutive PI3-kinase signaling was common to both mutants but not responsible for the observed differentiation/apoptosis defects.

Conclusions:

  • Constitutively active Ras proteins differentially affect skeletal myoblast phenotype and signaling.
  • A signaling pathway independent of MAPK, NF-kappaB, and PI3-kinase mediates the impaired differentiation and apoptosis.
  • This novel pathway represents a potential therapeutic target for conditions involving Ras dysregulation in skeletal muscle.

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