STUDY OF SIGNALTRANSDUCTION PATHWAY FOR TERMINAL DIFFERENTIATION OF RHABDOMYOSARCOMA CELLS

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The mammalian target of rapamycin (mTOR) has been shown to link growth factor signaling and posttranscriptional control of translation of proteins that are frequently involved in cell cycle progression. Transcriptional control for expression of growth-related genes has been well studied and reported. We demonstrated that Insulin-like Growth Factor I (IGF-I) induces N-Myc in neuroblastoma cells, at the RNA level and establish a clear correlation between N-Myc induction and activation of p44/42 MAPK signaling. Posttranscriptional control for gene expression, however, has not been fully understood. The mTOR has been recently revealed to be a protein kinase that phosphorylates the eukaryotic initiation factor (eIF)-4E repressor protein, PHAS-I.This protein controls the translation of a specific subset of mRNAs including those encoding highly growth-related proteins. We demonstrated that mTOR is a critical target for downregulation of c-Myc through the posttranscriptional control and growth inhibition of rhabdomyosarcoma cells by rapamycin.Further, the role of this pathway in cell survival has not been demonstrated. Here, we report that rapamycin, specific inhibitor of mTOR kinase, induces G1 cell cycle arrest and apoptosis in rhabdomyosarcoma cells. Protection from apoptosis was conferred by expression of a mutant mTOR resistant to rapamycin, demonstrating mTOR as the critical target for inducing cell death and indirectly indicating that mTOR transduces a survival signal in rhabdomyosarcoma cells.Our study is thought to lead to further insight for understanding of signaltransduction pathways under growth factor receptors that control proliferation, survival and differentiation of normal cells as well as cancer cells leading developing new anti-cancer agents for children with catastrophic diseases.