Oncogenic PI3K deregulates transcription and translation (original) (raw)
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science304, 554 (2004). The first study to describe point mutations in the gene that encodes p110α in various solid tumours. ArticleCASPubMed Google Scholar
Bachman, K. E. et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther.3, 772–775 (2004). ArticleCASPubMed Google Scholar
Campbell, I. G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res.64, 7678–7681 (2004). ArticleCASPubMed Google Scholar
Broderick, D. K. et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res.64, 5048–5050 (2004). ArticleCASPubMed Google Scholar
Lee, J. W. et al. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene24, 1477–1480 (2005). ArticleCASPubMed Google Scholar
Levine, D. A. et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res.11, 2875–2878 (2005). ArticleCASPubMed Google Scholar
Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res.65, 2554–2559 (2005). ArticleCASPubMed Google Scholar
Wang, Y., Helland, A., Holm, R., Kristensen, G. B. & Borresen-Dale, A. L. PIK3CA mutations in advanced ovarian carcinomas. Hum. Mutat.25, 322 (2005). ArticleCASPubMed Google Scholar
Hartmann, C., Bartels, G., Gehlhaar, C., Holtkamp, N. & von Deimling, A. PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol.109, 639–642 (2005). ArticleCASPubMed Google Scholar
Vanhaesebroeck, B. & Waterfield, M. D. Signaling by distinct classes of phosphoinositide 3-kinases. Exp. Cell Res.253, 239–254 (1999). ArticleCASPubMed Google Scholar
Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nature Rev. Immunol.3, 317–330 (2003). ArticleCAS Google Scholar
Wymann, M. P., Zvelebil, M. & Laffargue, M. Phosphoinositide 3-kinase signalling — which way to target? Trends Pharmacol. Sci.24, 366–376 (2003). ArticleCASPubMed Google Scholar
Deane, J. A. & Fruman, D. A. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu. Rev. Immunol.22, 563–598 (2004). ArticleCASPubMed Google Scholar
Okkenhaug, K. & Vanhaesebroeck, B. New responsibilities for the PI3K regulatory subunit p85α. Sci. STKE65, PE1 (2001). Google Scholar
Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature370, 527–532 (1994). ArticleCASPubMed Google Scholar
Rodriguez-Viciana, P., Warne, P. H., Vanhaesebroeck, B., Waterfield, M. D. & Downward, J. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J.15, 2442–2451 (1996). ArticleCASPubMedPubMed Central Google Scholar
Corvera, S. & Czech, M. P. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol.8, 442–446 (1998). ArticleCASPubMed Google Scholar
Balendran, A. et al. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr. Biol.9, 393–404 (1999). ArticleCASPubMed Google Scholar
Persad, S. et al. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem.276, 27462–27469 (2001). ArticleCASPubMed Google Scholar
Toker, A. & Newton, A. C. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J. Biol. Chem.275, 8271–8274 (2000). ArticleCASPubMed Google Scholar
Feng, J., Park, J., Cron, P., Hess, D. & Hemmings, B. A. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J. Biol. Chem.279, 41189–41196 (2004). ArticleCASPubMed Google Scholar
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science307, 1098–1101 (2005). ArticleCASPubMed Google Scholar
Wishart, M. J. & Dixon, J. E. PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol.12, 579–585 (2002). ArticleCASPubMed Google Scholar
Maehama, T., Taylor, G. S. & Dixon, J. E. PTEN and myotubularin: novel phosphoinositide phosphatases. Annu. Rev. Biochem.70, 247–279 (2001). ArticleCASPubMed Google Scholar
Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl Cancer Inst.91, 1922–1932 (1999). ArticleCASPubMed Google Scholar
Simpson, L. & Parsons, R. PTEN: life as a tumor suppressor. Exp. Cell Res.264, 29–41 (2001). ArticleCASPubMed Google Scholar
Staal, S. P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl Acad. Sci. USA84, 5034–5037 (1987). ArticleCASPubMedPubMed Central Google Scholar
Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science276, 1848–1850 (1997). Reports the isolation and identification of the v-P3k oncoprotein, a retroviral and tumorigenic homologue of p110α. ArticleCASPubMed Google Scholar
Bellacosa, A., Testa, J. R., Staal, S. P. & Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science254, 274–277 (1991). CASPubMed Google Scholar
Aoki, M. et al. The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity. J. Biol. Chem.275, 6267–6275 (2000). ArticleCASPubMed Google Scholar
Aoki, M., Batista, O., Bellacosa, A., Tsichlis, P. & Vogt, P. K. The akt kinase: molecular determinants of oncogenicity. Proc. Natl Acad. Sci. USA95, 14950–14955 (1998). ArticleCASPubMedPubMed Central Google Scholar
Borlado, L. R. et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J.14, 895–903 (2000). ArticleCASPubMed Google Scholar
Janssen, J. W., Schleithoff, L., Bartram, C. R. & Schulz, A. S. An oncogenic fusion product of the phosphatidylinositol 3-kinase p85b subunit and HUMORF8, a putative deubiquitinating enzyme. Oncogene16, 1767–1772 (1998). ArticleCASPubMed Google Scholar
Jimenez, C. et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J.17, 743–753 (1998). ArticleCASPubMedPubMed Central Google Scholar
Jucker, M. et al. Expression of a mutated form of the p85α regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia16, 894–901 (2002). ArticleCASPubMed Google Scholar
Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res.61, 7426–7429 (2001). CASPubMed Google Scholar
Katoh, M. Human FOX gene family (Review). Int. J. Oncol.25, 1495–1500 (2004). CASPubMed Google Scholar
Vogt, P. K., Jiang, H. & Aoki, M. Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle4, 908–913 (2005). ArticleCASPubMed Google Scholar
Tran, H., Brunet, A., Griffith, E. C. & Greenberg, M. E. The many forks in FOXO's road. Sci. STKE172, RE5 (2003). Google Scholar
Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature404, 782–787 (2000). ArticleCASPubMed Google Scholar
Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell117, 211–223 (2004). Shows that FOXO1 repressesp21cip1gene expression in a complex with Smad. The oncoprotein Fox G1 binds to this complex and inhibits its repressive activity. ArticleCASPubMed Google Scholar
Schmidt, M. et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol. Cell. Biol.22, 7842–7852 (2002). ArticleCASPubMedPubMed Central Google Scholar
Ramaswamy, S., Nakamura, N., Sansal, I., Bergeron, L. & Sellers, W. R. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell2, 81–91 (2002). ArticleCASPubMed Google Scholar
Biggs, W. H., Meisenhelder, J., Hunter, T., Cavenee, W. K. & Arden, K. C. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl Acad. Sci. USA96, 7421–7426 (1999). ArticleCASPubMedPubMed Central Google Scholar
Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell96, 857–868 (1999). ArticleCASPubMed Google Scholar
Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature398, 630–634 (1999). ArticleCASPubMed Google Scholar
Takaishi, H. et al. Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B. Proc. Natl Acad. Sci. USA96, 11836–11841 (1999). ArticleCASPubMedPubMed Central Google Scholar
Tang, E. D., Nunez, G., Barr, F. G. & Guan, K. L. Negative regulation of the forkhead transcription factor FKHR by Akt. J. Biol. Chem.274, 16741–16746 (1999). ArticleCASPubMed Google Scholar
Brownawell, A. M., Kops, G. J., Macara, I. G. & Burgering, B. M. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol. Cell. Biol.21, 3534–3546 (2001). ArticleCASPubMedPubMed Central Google Scholar
Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol.156, 817–828 (2002). ArticleCASPubMedPubMed Central Google Scholar
Rena, G., Prescott, A. R., Guo, S., Cohen, P. & Unterman, T. G. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem. J.354, 605–612 (2001). ArticleCASPubMedPubMed Central Google Scholar
Zhao, X. et al. Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms. Biochem. J.378, 839–849 (2004). ArticleCASPubMedPubMed Central Google Scholar
Obsil, T., Ghirlando, R., Anderson, D. E., Hickman, A. B. & Dyda, F. Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Biochemistry42, 15264–15272 (2003). ArticleCASPubMed Google Scholar
Perrot, V. & Rechler, M. M. The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription. Mol. Endocrinol.19, 2283–2298 (2005). ArticleCASPubMed Google Scholar
Aoki, M., Jiang, H. & Vogt, P. K. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc. Natl Acad. Sci. USA101, 13613–13617 (2004). ArticleCASPubMedPubMed Central Google Scholar
Huang, H. et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc. Natl Acad. Sci. USA102, 1649–1654 (2005). ArticleCASPubMedPubMed Central Google Scholar
Plas, D. R. & Thompson, C. B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J. Biol. Chem.278, 12361–12366 (2003). ArticleCASPubMed Google Scholar
Matsuzaki, H., Daitoku, H., Hatta, M., Tanaka, K. & Fukamizu, A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc. Natl Acad. Sci. USA100, 11285–11290 (2003). ArticleCASPubMedPubMed Central Google Scholar
Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell117, 225–237 (2004). Reports that IκB is the kinase responsible for inactivation of FOXO3a in cancer cells that lack elevated levels of phospho-AKT. ArticleCASPubMed Google Scholar
Karin, M., Cao, Y., Greten, F. R. & Li, Z. W. NF-κB in cancer: from innocent bystander to major culprit. Nature Rev. Cancer2, 301–310 (2002). ArticleCAS Google Scholar
Nakanishi, C. & Toi, M. Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nature Rev. Cancer5, 297–309 (2005). ArticleCAS Google Scholar
Ozes, O. N. et al. NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature401, 82–85 (1999). ArticleCASPubMed Google Scholar
Romashkova, J. A. & Makarov, S. S. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature401, 86–90 (1999). ArticleCASPubMed Google Scholar
Kane, L. P., Mollenauer, M. N., Xu, Z., Turck, C. W. & Weiss, A. Akt-dependent phosphorylation specifically regulates Cot induction of NF-κ B-dependent transcription. Mol. Cell. Biol.22, 5962–5974 (2002). ArticleCASPubMedPubMed Central Google Scholar
Madrid, L. V., Mayo, M. W., Reuther, J. Y. & Baldwin, A. S. Jr. Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-κ B through utilization of the Iκ B kinase and activation of the mitogen-activated protein kinase p38. J. Biol. Chem.276, 18934–18940 (2001). ArticleCASPubMed Google Scholar
Sizemore, N., Leung, S. & Stark, G. R. Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit. Mol. Cell. Biol.19, 4798–4805 (1999). ArticleCASPubMedPubMed Central Google Scholar
Sizemore, N., Lerner, N., Dombrowski, N., Sakurai, H. & Stark, G. R. Distinct roles of the Iκ B kinase α and β subunits in liberating nuclear factor κ B (NF-κ B) from Iκ B and in phosphorylating the p65 subunit of NF-κ B. J. Biol. Chem.277, 3863–3869 (2002). ArticleCASPubMed Google Scholar
Asano, T. et al. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells. Oncogene23, 8571–8580 (2004). ArticleCASPubMed Google Scholar
Liptay, S. et al. Mitogenic and antiapoptotic role of constitutive NF-κB/Rel activity in pancreatic cancer. Int. J. Cancer105, 735–746 (2003). ArticleCASPubMed Google Scholar
Kim, S. et al. Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-α/nuclear factor-κB (NF-κB)-inducing kinase/NF-κB pathway is linked to a default IκB-α autoregulatory loop. J. Biol. Chem.279, 4285–4291 (2004). ArticleCASPubMed Google Scholar
Vasudevan, K. M., Gurumurthy, S. & Rangnekar, V. M. Suppression of PTEN expression by NF-κ B prevents apoptosis. Mol. Cell. Biol.24, 1007–1021 (2004). ArticleCASPubMedPubMed Central Google Scholar
Wanzel, M. et al. Akt and 14-3-3ε regulate Miz1 to control cell-cycle arrest after DNA damage. Nature Cell Biol.7, 30–41 (2005). ArticleCASPubMed Google Scholar
Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol.3, 973–982 (2001). ArticleCASPubMed Google Scholar
Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA98, 11598–11603 (2001). ArticleCASPubMedPubMed Central Google Scholar
Boyle, W. J. et al. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell64, 573–584 (1991). ArticleCASPubMed Google Scholar
de Groot, R. P., Auwerx, J., Bourouis, M. & Sassone-Corsi, P. Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. Oncogene8, 841–847 (1993). CASPubMed Google Scholar
Nikolakaki, E., Coffer, P. J., Hemelsoet, R., Woodgett, J. R. & Defize, L. H. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. Oncogene8, 833–840 (1993). CASPubMed Google Scholar
Gregory, M. A., Qi, Y. & Hann, S. R. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J. Biol. Chem.278, 51606–51612 (2003). ArticleCASPubMed Google Scholar
Rubinfeld, B. et al. Binding of GSK3β to the APC–β-catenin complex and regulation of complex assembly. Science272, 1023–1026 (1996). ArticleCASPubMed Google Scholar
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature378, 785–789 (1995). ArticleCASPubMed Google Scholar
Wei, W., Jin, J., Schlisio, S., Harper, J. W. & Kaelin, W. G. Jr. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell8, 25–33 (2005). Shows that GSK3 mediated phosphorylation marks c-Jun for proteasomal degradation, a mechanism that is no longer in place for oncogenic v-Jun. ArticleCASPubMed Google Scholar
Jiang, B. H. et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ.12, 363–369 (2001). CASPubMed Google Scholar
Hamilton, G. S. & Steiner, J. P. Immunophilins: beyond immunosuppression. J. Med. Chem.41, 5119–5143 (1998). ArticleCASPubMed Google Scholar
Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot.28, 721–726 (1975). ArticleCAS Google Scholar
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell78, 35–43 (1994). ArticleCASPubMed Google Scholar
Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature369, 756–758 (1994). ArticleCASPubMed Google Scholar
Chiu, M. I., Katz, H. & Berlin, V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl Acad. Sci. USA91, 12574–12578 (1994). References 91–93 identify mammalian TOR as a target of the FKBP12–rapamycin complex. ArticleCASPubMedPubMed Central Google Scholar
Chen, J., Zheng, X. F., Brown, E. J. & Schreiber, S. L. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc. Natl Acad. Sci. USA92, 4947–4951 (1995). ArticleCASPubMedPubMed Central Google Scholar
Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science273, 239–242 (1996). ArticleCASPubMed Google Scholar
Oshiro, N. et al. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells9, 359–366 (2004). ArticleCASPubMed Google Scholar
Thomas, G., Sabatini, D. M. & Hall, N. M. (Eds.) TOR — Target of Rapamycin (Springer-Verlag, Berlin, 2004). A comprehensive compilation of literature on TOR. Book Google Scholar
Mayer, C., Zhao, J., Yuan, X. & Grummt, I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev.18, 423–434 (2004). Shows that TOR regulates Pol I activity through reciprocal phosphorylation of TIF-IA. ArticleCASPubMedPubMed Central Google Scholar
Martin, D. E., Soulard, A. & Hall, M. N. TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1. Cell119, 969–979 (2004). ArticleCASPubMed Google Scholar
Hannan, K. M. et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol.23, 8862–8877 (2003). ArticleCASPubMedPubMed Central Google Scholar
Mahajan, P. B. Modulation of transcription of rRNA genes by rapamycin. Int. J. Immunopharmacol.16, 711–721 (1994). ArticleCASPubMed Google Scholar
Zaragoza, D., Ghavidel, A., Heitman, J. & Schultz, M. C. Rapamycin induces the G0 program of transcriptional repression in yeast by interfering with the TOR signaling pathway. Mol. Cell. Biol.18, 4463–4470 (1998). ArticleCASPubMedPubMed Central Google Scholar
Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev.18, 1926–1945 (2004). An excellent review of the signalling network that surrounds TOR. ArticleCASPubMed Google Scholar
Montagne, J. et al. Drosophila S6 kinase: a regulator of cell size. Science285, 2126–2129 (1999). ArticleCASPubMed Google Scholar
Radimerski, T. et al. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nature Cell Biol.4, 251–255 (2002). ArticleCASPubMed Google Scholar
Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev.16, 1472–1487 (2002). ArticleCASPubMedPubMed Central Google Scholar
Pende, M. et al. S6K1−/−/S6K2−/− mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol.24, 3112–3124 (2004). ArticleCASPubMedPubMed Central Google Scholar
Stolovich, M. et al. Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol. Cell. Biol.22, 8101–8113 (2002). ArticleCASPubMedPubMed Central Google Scholar
Lin, T. A. et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science266, 653–656 (1994). ArticleCASPubMed Google Scholar
Brunn, G. J. et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science277, 99–101 (1997). ArticleCASPubMed Google Scholar
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H. & Sabatini, D. M. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA95, 1432–1437 (1998). ArticleCASPubMedPubMed Central Google Scholar
Gingras, A. C., Kennedy, S. G., O'Leary, M. A., Sonenberg, N. & Hay, N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev.12, 502–513 (1998). ArticleCASPubMedPubMed Central Google Scholar
Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell110, 163–175 (2002). ArticleCASPubMed Google Scholar
Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell110, 177–189 (2002). References 114 and 115 report the identification of Raptor as a TOR-interacting protein necessary for the phosphorylation of TOR targets. ArticleCASPubMed Google Scholar
Nojima, H. et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem.278, 15461–15464 (2003). ArticleCASPubMed Google Scholar
Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol.13, 797–806 (2003). ArticleCASPubMed Google Scholar
Schalm, S. S. & Blenis, J. Identification of a conserved motif required for mTOR signaling. Curr. Biol.12, 632–639 (2002). ArticleCASPubMed Google Scholar
Aoki, M., Blazek, E. & Vogt, P. K. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc. Natl Acad. Sci. USA98, 136–141. (2001). ArticleCASPubMed Google Scholar
Penuel, E. & Martin, G. S. Transformation by v-Src: Ras–MAPK and PI3K–mTOR mediate parallel pathways. Mol. Biol. Cell10, 1693–1703 (1999). ArticleCASPubMedPubMed Central Google Scholar
Neshat, M. S. et al. Enhanced sensitivity of _PTEN_-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA98, 10314–10319 (2001). ArticleCASPubMedPubMed Central Google Scholar
Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA98, 10320–10325 (2001). References 121 and 122 demonstrate that inhibition of TOR by the rapamycin derivative CCI-779 blocks tumour growth in aPTEN-deficient setting. ArticleCASPubMedPubMed Central Google Scholar
Minich, W. B. & Ovchinnikov, L. P. Role of cytoplasmic mRNP proteins in translation. Biochimie74, 477–483 (1992). ArticleCASPubMed Google Scholar
Davydova, E. K., Evdokimova, V. M., Ovchinnikov, L. P. & Hershey, J. W. Overexpression in COS cells of p50, the major core protein associated with mRNA, results in translation inhibition. Nucleic Acids Res.25, 2911–2916 (1997). ArticleCASPubMedPubMed Central Google Scholar
Evdokimova, V. M. & Ovchinnikov, L. P. Translational regulation by Y-box transcription factor: involvement of the major mRNA-associated protein, p50. Int. J. Biochem. Cell Biol.31, 139–149 (1999). ArticleCASPubMed Google Scholar
Nekrasov, M. P. et al. The mRNA-binding protein YB-1 (p50) prevents association of the eukaryotic initiation factor eIF4G with mRNA and inhibits protein synthesis at the initiation stage. J. Biol. Chem.278, 13936–13943 (2003). ArticleCASPubMed Google Scholar
Bader, A. G., Felts, K. A., Jiang, N., Chang, H. W. & Vogt, P. K. Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway. Proc. Natl Acad. Sci. USA100, 12384–12389 (2003). ArticleCASPubMedPubMed Central Google Scholar
Bader, A. G. & Vogt, P. K. Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation. Mol. Cell. Biol.25, 2095–2106 (2005). ArticleCASPubMedPubMed Central Google Scholar
Preiss, T., Baron-Benhamou, J., Ansorge, W. & Hentze, M. W. Homodirectional changes in transcriptome composition and mRNA translation induced by rapamycin and heat shock. Nature Struct. Biol.10, 1039–1047 (2003). ArticleCASPubMed Google Scholar
Grolleau, A. et al. Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J. Biol. Chem.277, 22175–22184 (2002). ArticleCASPubMed Google Scholar
Rajasekhar, V. K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell12, 889–901 (2003). Reports that existing mRNAs are differentially associated with polysomes in cells that have been transformed by AKT and SRC. ArticleCASPubMed Google Scholar
Graff, J. R. & Zimmer, S. G. Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin. Exp. Metastasis20, 265–273 (2003). ArticleCASPubMed Google Scholar
Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell91, 231–241 (1997). ArticleCASPubMed Google Scholar
del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R. & Nunez, G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science278, 687–689 (1997). ArticleCASPubMed Google Scholar
Cardone, M. H. et al. Regulation of cell death protease caspase-9 by phosphorylation. Science282, 1318–1321 (1998). ArticleCASPubMed Google Scholar
Fujita, N., Sato, S., Katayama, K. & Tsuruo, T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem.277, 28706–28713 (2002). ArticleCASPubMed Google Scholar
Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nature Med.8, 1145–1152 (2002). ArticleCASPubMed Google Scholar
Liang, J. et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature Med.8, 1153–1160 (2002). ArticleCASPubMed Google Scholar
Viglietto, G. et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nature Med.8, 1136–1144 (2002). ArticleCASPubMed Google Scholar
Zhou, B. P. et al. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in _HER-2/neu_-overexpressing cells. Nature Cell Biol.3, 245–252 (2001). ArticleCASPubMed Google Scholar
Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA102, 802–807 (2005). ArticleCASPubMedPubMed Central Google Scholar
Ikenoue, T. et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res.65, 4562–4567 (2005). References 141 and 142 report that high-frequency mutations in p110α that are associated with human tumours are oncogenic in cultured cells. ArticleCASPubMed Google Scholar
Shayesteh, L. et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genet.21, 99–102 (1999). ArticleCASPubMed Google Scholar
Byun, D. S. et al. Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int. J. Cancer104, 318–327 (2003). ArticleCASPubMed Google Scholar
Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature402, 313–320 (1999). ArticleCASPubMed Google Scholar
Kang, S., Bader, A. G., Zhao, L. & Vogt, P. K. Mutated PI 3-kinases: cancer targets on a silver platter. Cell Cycle4, 578–581 (2005). ArticleCASPubMed Google Scholar
Yu, J. et al. Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol. Cell. Biol.18, 1379–1387 (1998). ArticleCASPubMedPubMed Central Google Scholar
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med.350, 2129–2139 (2004). ArticleCASPubMed Google Scholar
Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science304, 1497–1500 (2004). ArticleCASPubMed Google Scholar
Pao, W. et al. EGF receptor gene mutations are common in lung cancers from 'never smokers' and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA101, 13306–13311 (2004). ArticleCASPubMedPubMed Central Google Scholar
Tsao, M. S. et al. Erlotinib in lung cancer — molecular and clinical predictors of outcome. N. Engl. J. Med.353, 133–144 (2005). ArticleCASPubMed Google Scholar
Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl.40, 2004–2021 (2001). ArticleCASPubMed Google Scholar
Manetsch, R. et al. In situ click chemistry: enzyme inhibitors made to their own specifications. J. Am. Chem. Soc.126, 12809–12818 (2004). ArticleCASPubMed Google Scholar
Mocharla, V. P. et al. In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II. Angew. Chem. Int. Ed. Engl.44, 116–120 (2004). ArticlePubMedCAS Google Scholar
Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev.17, 1829–1834 (2003). ArticleCASPubMedPubMed Central Google Scholar
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol.13, 1259–1268 (2003). ArticleCASPubMed Google Scholar
Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol.5, 566–571 (2003). ArticleCASPubMed Google Scholar
Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell11, 1457–1466 (2003). ArticleCASPubMed Google Scholar
Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol.5, 578–581 (2003). ArticleCASPubMed Google Scholar
Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol.4, 648–657 (2002). ArticleCASPubMed Google Scholar
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol.15, 702–713 (2005). ArticleCASPubMed Google Scholar
Treins, C., Giorgetti-Peraldi, S., Murdaca, J., Semenza, G. L. & Van Obberghen, E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem.277, 27975–27981 (2002). ArticleCASPubMed Google Scholar
Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol.22, 7004–7014 (2002). ArticleCASPubMedPubMed Central Google Scholar
Massion, P. P. et al. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am. J. Respir. Crit. Care Med.170, 1088–1094 (2004). ArticlePubMed Google Scholar
Pedrero, J. M. et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int. J. Cancer114, 242–248 (2005). ArticleCASPubMed Google Scholar
Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer2, 489–501 (2002). ArticleCAS Google Scholar
Cheng, J. Q. et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA93, 3636–3641 (1996). ArticleCASPubMedPubMed Central Google Scholar
Balsara, B. R. et al. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis25, 2053–2059 (2004). ArticleCASPubMed Google Scholar
Min, Y. H. et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia17, 995–997 (2003). ArticleCASPubMed Google Scholar