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Differential effects of Ras signaling through NFκB on skeletal myogenesis

Oncogene volume 20, pages 1276–1286 (2001)Cite this article

Abstract

Oncogenic Ras (H-Ras G12V) inhibits skeletal myogenesis through multiple signaling pathways. Previously, we demonstrated that the major downstream effectors of Ras (i.e., MEK/MAPK, RalGDS and Rac/Rho) play a minor, if any, role in the differentiation-defective phenotype of Ras myoblasts. Recently, NFκB, another Ras signaling target, has been shown to inhibit myogenesis presumably by stimulating cyclin D1 accumulation and cell cycle progression. In this study, we address the involvement of NFκB activation in the Ras-induced inhibition of myogenesis. Using H-Ras G12V and three G12V effector-loop variants, we detect high levels of NFκB transcriptional activity in C3H10T1/2-MyoD cells treated with differentiation medium. Myogenesis is blocked by all Ras proteins tested, yet only in the case of H-Ras G12V are cyclin D1 levels increased and cell cycle progression maintained. Expression of IκBα SR, an inhibitor of NFκB, does not reverse the differentiation-defective phenotype of Ras expressing cultures, but does induce differentiation in cultures treated with tumor necrosis factor (TNFα) or in cultures expressing the RelA/p65 subunit of NFκB. These data confirm that NFκB is a target of Ras and suggest that the cellular actions of NFκB require additional signals that are discriminated by the Ras effector-loop variants. Results with IκBα SR convincingly demonstrate that H-Ras G12V does not rely on NFκB activity to block myogenesis, an observation that continues to implicate another unidentified signaling pathway(s) in the inhibition of skeletal myogenesis by Ras.

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Acknowledgements

We thank A Baldwin for the 3×NFκ B-Luc reporter and RelA/p65 expression plasmids, S Tapscott for 10T1/2-MyoD-ER cells, D Ballard for the IκBα SR expression plasmid and D Guttridge for helpful suggestions and for generously communicating unpublished results. This work was supported by Public Health Service Grant AR41115-07 (to SF Konieczny) and a grant awarded to EJ Taparowsky from the Indiana Elks. A Kudla was supported by an American Heart Association Postdoctoral Fellowship 9804743W and by Public Health Service Grant T32 CA09634.

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  1. Arthur J Kudla

    Present address: , RHeoGene 706 Forest Street Charlottesville, 22903, VA, USA

  2. Natalia Mitin and Arthur J Kudla: N Mitin and A Kudla to be treated as co-first authors

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

    Natalia Mitin, Stephen F Konieczny & Elizabeth J Taparowsky

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Mitin, N., Kudla, A., Konieczny, S. et al. Differential effects of Ras signaling through NFκB on skeletal myogenesis. Oncogene 20, 1276–1286 (2001). https://doi.org/10.1038/sj.onc.1204223

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