Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase
| Autor: | Seonmin Lee, Min Jin Lim, Eunyoung Tak, Sung-Soo Kim, Feng Hong, Tae Gyu Choi, Sung Goo Chang, Jisun Lee, Kyu Jin Choi, Young Joo Kim, Jin Man Cho, Joohun Ha |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Cellular differentiation Farnesyltransferase Nitric Oxide Synthase Type II Muscle Development Nitric Oxide Cell Line Proto-Oncogene Proteins p21(ras) Phosphatidylinositol 3-Kinases chemistry.chemical_compound Animals Phosphatidylinositol RNA Small Interfering Molecular Biology PI3K/AKT/mTOR pathway Membrane Glycoproteins biology Kinase Myocardium NF-kappa B NADPH Oxidases Cell Differentiation Cell Biology Farnesol Salicylates Rats Cell biology Biochemistry chemistry NADPH Oxidase 2 biology.protein RNA Interference Signal transduction Signal Transduction |
| Zdroj: | Cell Research. 20:919-934 |
| ISSN: | 1748-7838 1001-0602 |
| DOI: | 10.1038/cr.2010.92 |
| Popis: | Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-kappaB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-kappaB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/Mek/Erk pathway. |
| Databáze: | OpenAIRE |
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