AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression.

摘要: Prior work demonstrates that AKT activity regulates sensitivity of cells to G(1) arrest induced by mammalian target rapamycin (mTOR) inhibitors such as and CCI-779. To investigate this, a novel high-throughput microarray polysome analysis was performed identify genes whose mRNA translational efficiency differentially affected following mTOR inhibition. The also allowed the assessment steady-state transcript levels. We identified two transcripts, cyclin D1 c-myc, which exhibited differential expression in an AKT-dependent manner: High levels activated resulted rapamycin-induced down-regulation expression, whereas low up-regulation expression. ectopically express these proteins we exploited finding p27(kip1) efficiently translated face inhibition irrespective activity. Thus, 5'-untranslated region fused c-myc coding regions constructs were expressed cells. In transfected cells, or not decreased rapamycin. Most importantly, this completely converted sensitive phenotype resistant arrest. Furthermore, patterns observed mouse xenograft model vivo treatment with These results critical downstream molecular targets is regulated required for rapamycin/CCI-779 sensitivity.