18 3 2006 6 Chinese Bulletin of Life Sciences Vol. 18, No. 3 Jun., 2006 1004-0374(2006)03-0261-05 mtor 210009 mtor mtor mtor mtor R329.2 + 8; R730.23 A mtor signaling pathway and cancer ZHENG Jie (Institute of Molecular Pathology, School of Basic Medical Science, Southeast University, Nanjing 210009, China) Abstract: mtor signaling pathway recently emerges from horizons. mtor pathway is conservative in evolution and controls the cell growth via protein synthesis. The dysregulation of mtor pathway is recognized to be associated with several hamartoma syndromes and cancers. Rapamycin and its derivatives selectively inhibit mtor kinase activity. These new findings are very important in regulations of the cell growth and cancer targeting therapy. Key words: mtor; rapamycin; hamartoma; cancer (mammalian target of rapamycin, mtor) / mtor mtor mtor 1 mtor TOR 1991 (rapamycin) TOR TOR mtor TOR 95% mtor / 289kDa mtor PIKK (phosphoinositide kinase-related kinase) TOR TOR [1] PIKK (PtdIns3K-related kinase family) ATM (ataxia-telangiectasia mutated) ATR (ataxia-telangiectasia and Rad3-related) DNA-PKcs (DNA-dependent protein kinase) mtor mtor raptor (regulatory-associated protein of 2005-11-14 2005-12-14 (1954 )
262 mtor) mtor rictor (rapamycin-insensitive companion of mtor) GβL (WD-repeat protein Gβ-like) mtor rictor AKT AKT mtor/rictor AKT [2~3] 2 mtor 10 TOR mtor ( 1) mtor S6 (S6 kinase, S6K) 4E 1(4E binding protein, 4EBP1) 4EBPl S6K1 S6 S6K (a tract of pyrimidines motif) mrna mrna 4EBP1 mtor 4E (elf-4e)4ebp1 mtor 4EBP1 elf-4e 4EBP1 elf-4e elf-4e D1 Rb -1 (hypoxia inducible factor-1, HIF-1) c-myc (vascular endothelial growth factor VEGF) CLIP-170 mtor 4EBP1 S6K mtor G 1 S mtor mtor G l 1 mtor
mtor 263 (insulin-like growth factor, IGF); mtor PI3K/AKT LKB1/AMPK 1 (insulin receptor, IR) IR IR IR (insulin receptor substrate, IRS) PI3K PI3K PI3K PtdIinsP2(phospha tidylinositol P2) PtdIinsP3 AKT PtdIinsP3 1(PDK-1) AKT, AKT PI3K AKT mtor 2(tuberous sclerosis complex 2 TSC2) TSC1 mtor TSC1/TSC2 GTP Rheb(Ras-homolog enriched in brain) Rheb mtor, TSC1/TSC2 AKT TSC2 Ser 939 Thr 1462 TSC1/TSC2 mtor TSC1/TSC2 PI3K/AKT PTEN (phosphatase and tensin homolog deleted on chromosome ten) PI3K AKT PI3K (phosphatidylinositol, PI) 3 AKT / PTEN AKT PI3K AKT / PDKl AKT PDKl TSC1/TSC2 mtor S6K TSC1/TSC2 mtor ( 1) TSC1/ TSC2 mtor TSC1/TSC2 5'AMP (5'AMP-activated protein kinase, AMPK) mtor ATP S6K 4EBP1 PI3K AMPK TSC2 mtor ATP/AMP ( 1) AMPK (energy-starvation) AMPK AMPK ATP ATP, AMPK ATP ADP [4] TSC1 TSC2 mtor ( ATP) mtor Peutz-Jeghers LKB1 / LKB1 AMPK LKB1 S6K 4EBP1 LKB1 mtor 3 mtor mtor 3.1 mtor (LKB1 PTEN TSC1/TSC2) mtor TSC1/TSC2 (hamartoma) (tuberous sclerosis) [1,5] PTEN 10q23 (LOH) PTEN PTEN (somatic mutation) [6] (germ line)pten
264 (Cowden disease CD) LDD (Lhermitte-Duclos disease) PS (proteus syndrome) BRRS (Bannayan-Riley-Ruvalcaba syndrome) [7] PTEN- (PTEN-hamartoma tumor syndromes, PTHSs) PTEN AKT mtor PTEN mtor LKB1 Peutz-Jeghers [1], 40 90% 3.2 mtor S6K1 4EBPl mtor S6K1 [6,8], S6K1 4EBPl elf-4e 4EBPl [9] elf-4e 4EBPl elf-4e [10] PTEN [6,11] PTEN [12] AKT AKT AKT PTEN AKT AKT PTEN AKT PETN AKT PTEN P13K/ AKT PTEN p53, LKB1 [6] LKB1 LKB1 (-/+) LKB1 [13] mtor 4 mtor mtor [14] 4.1 20 70 FK506 FK506 FKBP12(12-kDa immunophilin FK506-binding protein) mtor FRB(FKBPl2-rapamycin binding) mtor [15] FK506/FKBP12 20 70 CCI- 779 RAD001 AP23573 [2,16] [17] PTEN PTEN/P13K/AKT/mTOR [18] AKT S6K1 [19] PTEN AKT mtor S6K1 4EBPl mtor [20] Gleevec abl-bcr Gleevec Gleevec [21]
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