Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner

Aoki, 1998, The akt kinase: Molecular determinants of oncogenicity, Proc. Natl. Acad. Sci. USA, 95, 14950, 10.1073/pnas.95.25.14950 Chen, 2001, Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene, Genes Dev., 15, 2203, 10.1101/gad.913901 Chen, 2006, The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/− mice, Genes Dev., 20, 1569, 10.1101/gad.1395006 Di Cristofano, 1998, Pten is essential for embryonic development and tumour suppression, Nat. Genet., 19, 348, 10.1038/1235 Downward, 2003, Targeting RAS signalling pathways in cancer therapy, Nat. Rev. Cancer, 3, 11, 10.1038/nrc969 Fingar, 2004, mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E, Mol. Cell. Biol., 24, 200, 10.1128/MCB.24.1.200-216.2004 Gera, 2004, AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression, J. Biol. Chem., 279, 2737, 10.1074/jbc.M309999200 Gingras, 1998, 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway, Genes Dev., 12, 502, 10.1101/gad.12.4.502 Hahn-Windgassen, 2005, Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity, J. Biol. Chem., 280, 32081, 10.1074/jbc.M502876200 Harada, 2001, p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD, Proc. Natl. Acad. Sci. USA, 98, 9666, 10.1073/pnas.171301998 Harrington, 2005, Restraining PI3K: mTOR signalling goes back to the membrane, Trends Biochem. Sci., 30, 35, 10.1016/j.tibs.2004.11.003 Hay, 2005, The Akt-mTOR tango and its relevance to cancer, Cancer Cell, 8, 179, 10.1016/j.ccr.2005.08.008 Hay, 2004, Upstream and downstream of mTOR, Genes Dev., 18, 1926, 10.1101/gad.1212704 Hennessy, 2005, Exploiting the PI3K/AKT pathway for cancer drug discovery, Nat. Rev. Drug Discov., 4, 988, 10.1038/nrd1902 Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat. Cell Biol., 4, 648, 10.1038/ncb839 Kang, 2005, Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic, Proc. Natl. Acad. Sci. USA, 102, 802, 10.1073/pnas.0408864102 Lawlor, 2001, PKB/Akt: A key mediator of cell proliferation, survival and insulin responses?, J. Cell Sci., 114, 2903, 10.1242/jcs.114.16.2903 Li, 2004, Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity, Mol. Cell. Biol., 24, 7965, 10.1128/MCB.24.18.7965-7975.2004 Luo, 1996, Rapamycin resistance tied to defective regulation of p27kip1, Mol. Cell. Biol., 12, 6744, 10.1128/MCB.16.12.6744 Majumder, 2003, Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: The MPAKT model, Proc. Natl. Acad. Sci. USA, 100, 7841, 10.1073/pnas.1232229100 Manning, 2002, Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway, Mol. Cell, 10, 151, 10.1016/S1097-2765(02)00568-3 Manning, 2005, Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2, Genes Dev., 19, 1773, 10.1101/gad.1314605 Mayo, 2001, A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus, Proc. Natl. Acad. Sci. USA, 98, 11598, 10.1073/pnas.181181198 Parsons, 2003, PTEN and cancer, Methods Mol. Biol., 222, 147 Peng, 2003, Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2, Genes Dev., 17, 1352, 10.1101/gad.1089403 Podsypanina, 1999, Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems, Proc. Natl. Acad. Sci. USA, 96, 1563, 10.1073/pnas.96.4.1563 Rajasekhar, 2003, Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes, Mol. Cell, 12, 889, 10.1016/S1097-2765(03)00395-2 Robey, 2005, Mitochondrial hexokinases: Guardians of the mitochondria, Cell Cycle, 4, 654, 10.4161/cc.4.5.1678 Samuels, 2004, High frequency of mutations of the PIK3CA gene in human cancers, Science, 304, 554, 10.1126/science.1096502 Sansal, 2004, The biology and clinical relevance of the PTEN tumor suppressor pathway, J. Clin. Oncol., 22, 2954, 10.1200/JCO.2004.02.141 Sarbassov, 2005, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science, 307, 1098, 10.1126/science.1106148 Schmidt, 2002, Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D, Mol. Cell. Biol., 22, 7842, 10.1128/MCB.22.22.7842-7852.2002 Sinn, 1987, Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo, Cell, 49, 465, 10.1016/0092-8674(87)90449-1 Stahl, 2002, The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2, J. Immunol., 168, 5024, 10.4049/jimmunol.168.10.5024 Suzuki, 1998, High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice, Curr. Biol., 8, 1169, 10.1016/S0960-9822(07)00488-5 Thomas, 2006, mTOR and cancer: Reason for dancing at the crossroads?, Curr. Opin. Genet. Dev., 16, 78, 10.1016/j.gde.2005.12.003 Wyszomierski, 2005, A knotty turnabout?: Akt1 as a metastasis suppressor, Cancer Cell, 8, 437, 10.1016/j.ccr.2005.11.006 Yu, 2001, Specific protection against breast cancers by cyclin D1 ablation, Nature, 411, 1017, 10.1038/35082500 Zhang, 2000, Regulation of cellular growth by the Drosophila target of rapamycin dTOR, Genes Dev., 14, 2712, 10.1101/gad.835000 Zhang, 2003, Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR, J. Clin. Invest., 112, 1223, 10.1172/JCI200317222 Zhou, 2001, HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation, Nat. Cell Biol., 3, 973, 10.1038/ncb1101-973 Zou, 2002, Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence, Genes Dev., 16, 2923, 10.1101/gad.1033002