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STUDY OF SIGNALTRANSDUCTION PATHWAY FOR TERMINAL DIFFERENTIATION OF RHABDOMYOSARCOMA CELLS

横纹肌肉瘤细胞终末分化信号传导途径的研究

基本信息

批准号：
11470174
负责人：
HOSOI Hajime
金额：
$ 4.22万
依托单位：
KYOTO PREFECTURAL UNIVERSITY OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

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.

哺乳动物雷帕霉素靶蛋白（mTOR）已被证明与生长因子信号传导和经常参与细胞周期进程的蛋白质翻译的转录后控制有关。生长相关基因表达的转录调控已经得到了很好的研究和报道。我们证明了胰岛素样生长因子I（IGF-I）在RNA水平诱导神经母细胞瘤细胞中的N-Myc，并在N-Myc诱导和p44/42 MAPK信号传导的激活之间建立了明确的相关性。然而，基因表达的转录后调控尚未完全理解。mTOR是一种蛋白激酶，它磷酸化真核起始因子（eIF）-4E阻遏蛋白PHAS-I。这种蛋白质控制特定mRNA亚组的翻译，包括那些编码高度生长相关蛋白的mRNA。我们证明mTOR是雷帕霉素通过转录后调控和抑制横纹肌肉瘤细胞生长而下调c-Myc的关键靶点，此外，该途径在细胞存活中的作用尚未得到证实。在这里，我们报告雷帕霉素，特异性抑制剂mTOR激酶，诱导横纹肌肉瘤细胞G1期细胞周期阻滞和凋亡。雷帕霉素抗性突变mTOR的表达可以保护细胞免于凋亡，这表明mTOR是诱导细胞死亡的关键靶点，并间接表明mTOR在横纹肌肉瘤细胞中转导生存信号。我们的研究被认为有助于进一步了解控制增殖的生长因子受体下的信号转导途径，正常细胞和癌细胞的存活和分化，从而为患有灾难性疾病的儿童开发新的抗癌药物。