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Differential effects of Ras signaling through NFkappaB on skeletal myogenesis

N Mitin1, A J Kudla, S F Konieczny

  • 1Department of Biological Sciences, Purdue University, West Lafayette, Indiana, IN 47907-1392, USA.

Oncogene
|April 21, 2001
PubMed

Insights

Oncogenic Ras (H-Ras G12V) blocks skeletal muscle development. This study shows Ras inhibits myogenesis independently of NF-kappaB signaling, implicating other pathways in this Ras-induced differentiation defect.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Skeletal myogenesis is crucial for muscle development and function.
  • Oncogenic Ras proteins are known to disrupt normal cellular processes, including differentiation.
  • Previous studies implicated MEK/MAPK, RalGDS, and Rac/Rho pathways in Ras-mediated inhibition of myogenesis, with limited roles found.

Purpose of the Study:

  • To investigate the role of Nuclear Factor kappa B (NF-kappaB) activation in Ras-induced inhibition of skeletal myogenesis.
  • To determine if NF-kappaB is a necessary mediator for the differentiation-defective phenotype caused by oncogenic Ras (H-Ras G12V).

Main Methods:

  • Utilized C3H10T1/2-MyoD cells expressing H-Ras G12V and effector-loop variants.
  • Assessed NF-kappaB transcriptional activity during differentiation.
  • Measured cyclin D1 levels and cell cycle progression.
  • Employed IkappaBalpha SR, an inhibitor of NF-kappaB, to evaluate its effect on Ras-induced myogenesis inhibition and TNFalpha-induced differentiation.

Main Results:

  • H-Ras G12V expression led to high NF-kappaB transcriptional activity in differentiating cells.
  • All tested Ras proteins blocked myogenesis, but only H-Ras G12V increased cyclin D1 and maintained cell cycle progression.
  • NF-kappaB inhibition via IkappaBalpha SR did not rescue the differentiation defect caused by Ras.
  • IkappaBalpha SR induced differentiation in TNFalpha-treated or RelA/p65-expressing cells, confirming NF-kappaB's role in other contexts.

Conclusions:

  • NF-kappaB is a downstream target of Ras, but its activation is not essential for Ras-mediated inhibition of skeletal myogenesis.
  • H-Ras G12V blocks myogenesis through a pathway independent of NF-kappaB.
  • These findings suggest that Ras utilizes unidentified signaling pathways to inhibit skeletal myogenesis.

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