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mTOR Mammalian Target of Rapamycin (哺乳动物雷帕霉素靶蛋白)A central regulator of cell growth and metabolism (控制细胞的生长和代谢) Protein SynthesisGrowth ProliferationAngiogenesisBioenergeticsmTOR(哺乳动物雷帕霉素靶蛋白)NutrientsGrowth Factorsglucose, amino acids, etc IGF, EGF, VEGF etcmTOR is an intracellular serine-threonine kinase (丝氨酸-苏氨酸激酶) mTOR is downstream of growth factor/nutrient and PI3k/AKT signalling pathway (信号通路中的下游分子)mTOR is a central regulator of protein synthesisActivated by mutations in cancerMutations in cancerPI3KAKTeif-4eS6kRASRASAKTmTOR Pathway ActivationGrowth FactorsRegulators of mTOR activity mTOR activating mTOR deactivatingMutations of PI3K, Akt, Ras, GFRs, TSC1/2, PTEN..) may result in inappropriate activation of the pathway and loss of control of functions normally regulated by mTORActivation of mTOR can result in loss of cell growth control and enhanced cell metabolism in cancer cells (无限制的癌细胞生长和扩散)VEGFIGFEGFPTENProteinSynthesisPI3KABLLKB1ERTSC2AMPKTSC1mTOR Cell Growth ProliferationBioenergeticsAngiogenesismTOR Activation↑Increased synthesis of multiple proteins, including:Hypoxia-Inducible Factors (HIFs, 低氧诱导 因子): ↑expression of angiogenic growth factors (eg, VEGF/ PDGF) (RCC)Cyclin D1: promotes progression through the cell cycle (MCL)Proteins necessary to transport nutrients (amino acids and glucose) into the cellmTOR-Linked Pathway Activation in Selected Cancersp-Akt, 42%PTEN, 15%–41%HER2, 30%–36%PI3-K, 18%–26%ALK p-AktNF-kBCyclin D1LymphomaBreastEGFR, 32%–60%p-Akt, 23%–50%Ras, 30%PTEN, 24%TSC1/TSC2IGF-1/IGF-1RVHLLungNETTGFa/TGFb1, 60%–100%VHL, 30%–50%IGF-1/IGF-IR, 39%-69%p-Akt, 38%PTEN, 31%TSC1/TSC2NF-kB, 33%Ras, 50%p-Akt, 46%PTEN, 35%PI3-K, 20%–32%EGFR, 70%Renal CellColorectalRapamycin (sirolimus)-雷帕霉素 Isolated in 1975 on the island of Rapa Nui Approved for prevention of kidney transplant rejection in the US and Europe Found to have broad anticancer activity against a panel of human cancer cell lines by the U.S. NCI in the 1980s Rapamycin derivatives w
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