Chinese Bulletin of Life Sciences. mtor mtor mtor. mtor signaling pathway and cancer. ZHENG Jie

Transcript

1 Chinese Bulletin of Life Sciences Vol. 18, No. 3 Jun., (2006) mtor mtor mtor mtor mtor R ; R A mtor signaling pathway and cancer ZHENG Jie (Institute of Molecular Pathology, School of Basic Medical Science, Southeast University, Nanjing , 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 (1954 )

2 262 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

3 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

4 264 (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] FK506 FK506 FKBP12(12-kDa immunophilin FK506-binding protein) mtor FRB(FKBPl2-rapamycin binding) mtor [15] FK506/FKBP 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]

5 mtor 265 [6] 4.2 [22] VEGF HIF TOR mtor mtor (ADP ATP) Peutz-Jeghers LKB1 AMPK [1] AMPK 5 mtor [1] Inoki K, Corradetti M N, Guan K L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet, 2005, 37 (1): 19~24 [2] Guertin D A, Sabatini D M. An expanding role for mtor in cancer. Trends Mol Med, 2005, 11(8): 353~361 [3] Sarbassov D D, Guertin D A, Ali S M, et al. Phosphorylation and regulation of Akt/PKB by the rictor mtor complex. Science, 2005, 307(5712): 1098~1101 [4] Hardie D G. The AMP-activated protein kinase pathwaynew players upstream and downstream. J Cell Sci, 2004, 117 (Pt 23): 5479~5487 [5] Martin D E,Hall M N. The expanding TOR signaling network. Curr Opin Cell Biol, 2005, 17(2): 158~166 [6] Law B K. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol, 2005, 56(1): 47~60 [7] Shaw R J, Bardeesy N, Manning B D, et al. The LKB1 tumor suppressor negatively regulates mtor signaling. Cancer Cell, 2004, 6(1): 91~99 [8] Grewe M, Gansauge F, Schmid R M, et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res, 1999, 59(15): 3581~3587 [9] Rosenwald I B, Chen J J, Wang S, et al. Upregulation of protein synthesis initiation factor eif-4e is an early event during colon carcinogenesis. Oncogene, 1999, 18(15): 2507~2517 [10] Rousseau D, Gingras A C, Pause A, et al. The eif4e binding proteins 1 and 2 are negative regulators of cell growth. Oncogene, 1996, 13(11): 2415~2420 [11] Vivanco I, Sawyers C L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer, 2002, 2(7): 489~501 [12] Podsypanina K, Ellenson L H, Nemes A, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA, 1999, 96(4): 1563~1568 [13] Nakau M, Miyoshi H, Seldin M F, et al. Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res, 2002, 62(16): 4549~4553 [14] Chan S. Targeting the mtor: a new approach to treating cancer. Br J Cancer, 2004, 91(8): 1420~1424 [15] Hay N, Sonenberg N. Upstream and downstream of mtor. Genes Dev, 2004, 18(16): 1926~1945 [16] Bjornsti M A, Houghton P J. The TOR pathway: a target for cancer therapy. Nat Rev Cancer, 2004, 4(5): 335~348 [17] Rowinsky E K. Targeting the molecular target of rapamycin (mtor). Curr Opin Oncol, 2004, 16(6): 564~575 [18] Shi Y J, Gera J, Hu L P, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI Cancer Res, 2002, 62(17): 5027~5034 [19] Noh W C, Mondesire W H, Peng J, et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res, 2004, 10(3): 1013~1023 [20] Gera J F, Mellinghoff I K, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mtor) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem, 2004, 279(4): 2737~2746 [21] Mohi M G, Boulton C, Gu T L, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA, 2004, 101(9): 3130~3135 [22] Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med, 2002, 8(2): 128~135