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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
Published on: June 15, 2017
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
Summary
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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