The phosphatidylinositol 3-kinase-AKT pathway in humancancer

Nature Reviews Cancer

Volumn 2, Issue 7, 2002, Pages 489-501

  Vivanco, Igor ^a   Sawyers, Charles L ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; BCR ABL PROTEIN; CYCLIN D1; CYCLIN DEPENDENT KINASE; CYCLINE; EPHRIN; G PROTEIN COUPLED RECEPTOR; IMATINIB; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN RECEPTOR; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE; PHOSPHOLIPID; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN CDC42; PROTEIN KINASE B; PROTEIN P85; PROTEIN TYROSINE KINASE; RAC1 PROTEIN; S6 KINASE; SOS PROTEIN; TEMSIROLIMUS; TRASTUZUMAB; UBIQUITIN PROTEIN LIGASE; WORTMANNIN; AKT1 PROTEIN, HUMAN; LIPID; ONCOPROTEIN; PHOSPHATIDYLINOSITOL 3,4,5-TRIPHOSPHATE; POLYPHOSPHOINOSITIDE; PROTEIN SERINE THREONINE KINASE;

ANTINEOPLASTIC ACTIVITY; CAENORHABDITIS ELEGANS; CELL GROWTH; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC MYELOID LEUKEMIA; COWDEN SYNDROME; DROSOPHILA; ENZYME ACTIVATION; GASTROINTESTINAL STROMAL TUMOR; HUMAN; NONHUMAN; PHENOTYPE; POLYOMA VIRUS; PRIORITY JOURNAL; REVIEW; RNA TRANSLATION; SIGNAL TRANSDUCTION; SRC HOMOLOGY DOMAIN; TUMOR GROWTH; ANIMAL; BIOLOGICAL MODEL; CELL DIVISION; DISEASE MODEL; ENZYMOLOGY; GENE DELETION; METABOLISM; MOUSE; NEOPLASM; PHYSIOLOGY; PROTEIN SYNTHESIS;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; CELL DIVISION; DISEASE MODELS, ANIMAL; GENE DELETION; HUMANS; LIPIDS; MICE; MODELS, BIOLOGICAL; NEOPLASMS; PHENOTYPE; PHOSPHATIDYLINOSITOL PHOSPHATES; PROTEIN BIOSYNTHESIS; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 0036632368     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc839     Document Type: Article

References (176)

1. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinaseactivity with polyoma middle-T competent for transformation. Nature315, 239-242 (1985).
2. White, M. F. The IRS-signalling system: a network of docking proteins that mediate insulin action.Mol. Cell. Biochem.182, 3-11 (1998).
3. Inukai, K.:p85a gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase p50a, p55a, and p85a, with different PI 3-kinase activity elevatingresponses to insulin.J. Biol. Chem.272, 7873-7882 (1997).
4. Kaliman, P:Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis:dominant negative p85 expression blocks differentiationof L6E9 muscle cells.Mol. Endocrinol.12, 66-77 (1998).
5. Ueki, K., Algenstaedt, P, Mauvais-Jarvis, F. & Kahn, C. R.: Positive and negative regulation of phosphoinositide3-kinase-dependent signaling pathways by three differentgene products of the p85 a regulatory subunit.Mol. Cell. Biol.20, 8035-8046 (2000).
6. Yu, J.:Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110a catalyticsubunit by the p85 regulatory subunit.Mol. Cell. Biol.18, 1379-1387 (1998).
7. Rodriguez-Viciana, P:Phosphatidylinositol-3-OH kinase as a direct target of Ras.Nature370, 527-532 (1994).
8. Kodaki, T., et allThe activation of phosphatidylinositol 3-kinase by Ras.Curr. Biol.4, 798-806 (1994).
9. Cuevas, B. D.:AllTyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase.Jl BiollChem.276, 27455-27461 (2001).
10. Steck, P. A.: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that ismutated in multiple advanced cancers.Nature Genet.15, 356-362 (1997).
11. Li, J.:PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.Science275, 1943-1947 (1997).
12. Myers, M. P. The lipid phosphatase activity of PTEN is critical for its tumor supressor function.Proc. Natl Acad. Sci.USA95, 13513-13518 (1998).
13. Haas-Kogan, D.: Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumorsuppressor PTEN/MMAC.Curr. Biol.8, 1195-1198(1998).
14. Stambolic, V. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.Cell95, 29-39 (1998).
15. Stambolic, V. Shows that PTEN is a negative regulator of AKT and can reduce intracellular levels of PIP3anddephosphorylate PIP3in vitro.
16. Wu, X., Senechal, K., Neshat, M. S., Whang, Y. E. & Sawyers, C. L. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of thephosphoinositide 3-kinase/Akt pathway.Procl Natl AcadlSci. USA95, 15587-15591 (1998).
17. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid secondmessenger, phosphatidylinositol 3, 4, 5-trisphosphate.J. Biol.Chem.273, 13375-13378 (1998).
18. Gu, J.:Shc and FAK differentially regulate cell motility and directionality modulated by PTEN.J. Cell Biol.146, 389-403 (1999).
19. Tamura, M.:Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.Science280, 1614-1617 (1998).
20. Scheid, M. et allPhosphatidylinositol(3, 4, 5)P3is essential but not sufficient for PKB activation:phosphatidylinositol(3, 4)P2is required for PKBphosphorylation at Ser473. Studies using cells fromShipr--knockout mice.Jl Bioll Cheml7, 7 (2002).
21. Helgason, C. et allA dual role for Src homology 2 domain-containing inositol-5-phosphatase (SHIP) in immunity: aberrant development and enhanced function ofB lymphocytes in SHIP-mice.J. Exp. Med.191, 781-794(2000).
22. Liu, Q.:SHIP is a negative regulator of growth factor receptor-mediated PKB/AKT activation and myeloid cellsurvival.Genes Dev.13, 786-791 (1999).
23. Liu, Q.:Shows that Ship-deficient mice have hyperproliferation of myeloid cells, increased survivalof neutrophils, and enhanced PIP3accumulation.Akt activation upon engagement of certain cytokinereceptors.
24. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts.Genes Dev.13, 2905-2927 (1999).
25. Scheid, M. P & Woodgett, J. R. PKB/AKT: functional insights from genetic models.Nature Rev. Mol. Cell Biol.2, 760-768(2001).
26. Andjelkovic, M.:Role of translocation in the activation and function of protein kinase B.J. Biol. Chem.272, 31515-31524 (1997).
27. Bellacosa, A.:Akt activation by growth factors is a multiple-step process: the role of the PH domain.Oncogene17, 313-325 (1998).
28. Vanhaesebroeck, B. & Alessi, D. R. The PI3K-PDK1 connection: more than just a road to PKB.Biochem. J.346, 561-576 (2000).
29. Stokoe, D.:Dual role of phosphatidylinositol-3, 4, 5-trisphosphate in the activation of protein kinase B.Science277, 567-570 (1997).
30. Stokoe, D.:Shows that PIP3is necessary for AKT recruitment to the membrane and phosphorylation of AKT on thePDK1 site (Thr308).
31. Alessi, D. R.:Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase-Ba.Curr. Biol.7, 261-269 (1997).
32. Toker, A. & Newton, A. C. Akt/protein kinase B is regulatedby autophosphorylation at the hypothetical PDK-2 site. J. Biol. Chem.275, 8271-8274 (2000).
33. Laine, J., Kunstle, G., Obata, T, Sha, M. & Noguchi, M.: The protooncogene TCL1 is an Akt kinase coactivator.Mol. Cell6, 395-407 (2000).
34. Andjelkovic, M.:Activation and phosphorylation of a pleckstrin homology domain containing protein kinase(RAC-PK/PKB) promoted by serum and proteinphosphatase inhibitors.Proc. Natl Acad. Sci. USA93, 5699-5704 (1996).
35. Maira, S. M.:Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at theplasma membrane.Science294, 374-380 (2001).
36. Sato, S., Fujita, N. & Tsuruo, T.: Modulation of Akt kinase activity by binding to Hsp90.Proc. Natl Acad. Sci. USA97, 10832-10837 (2000).
37. Dudek, H.:Regulation of neuronal survival by the serine-threonine protein kinase Akt.Science275, 661-665 (1997).
38. Li, J.:The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene.Cancer Res.58, 5667-5672 (1998).
39. Datta, S. R.:Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.Cell91, 231-241 (1997).
40. Datta, S. R.:Shows that growth-factor-induced activation of AKT phosphorylates BAD and inhibits BAD-inducedapoptosis in primary neurons.
41. Cardone, M. H.:Regulation of cell death protease caspase-9 by phosphorylation.Science282, 1318-1321 (1998).
42. Brunet, A.:Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell96, 857-868 (1999).
43. Romashkova, J. A. & Makarov, S. S.: NF-kB is a target of AKT in anti-apoptotic PDGF signalling.Nature401, 86-90 (1999).
44. Romashkova, J. A. & Makarov, S. S.: Shows that PDGF stimulation of fibroblasts causes phosphorylation and activation of IKK by AKT andsubsequent activation of NF-kB. This finding links thePI3K-AKT pathway to anti-apoptotic transcription.
45. Kane, L. P, Shapiro, V. S., Stokoe, D. & Weiss, A.: Induction of NF-kB by the Akt/PKB kinase.Curr. Biol.9, 601-604(1999).
46. Mayo, L. D. & Donner, D. B.: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2from the cytoplasm to the nucleus.Proc. Natl Acad. Sci. USA98, 11598-11603 (2001).
47. Mayo, L. D. & Donner, D. B.: Shows that phosphorylation of MDM2 by AKT enhances its nuclear translocation, Resulting indestabilization of the p53 protein.
48. Zhou, B. P:HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.Nature Cell Biol.3, 973-982 (2001).
49. Stambolic, V.:Regulation ofPTENtranscription by p53.Mol. Cell. 8, 317-325 (2001).
50. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J.: Glycogen synthase kinase-3p regulates cyclin D1 proteolysis and subcellular localization.Genes Dev.12, 3499-3511(1998).
51. Graff, J. R.:Increased AKT activity contributes to prostate cancer progression by dramatically acceleratingprostate tumor growth and diminishing p27Kip1 expression.J. Biol. Chem.275, 24500-24505 (2000).
52. Dijkers, P F.:Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation ofp27(KIP1).Mol. Cell. Biol.20, 9138-9148 (2000).
53. Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycleregulation by Ras and PKB through p27kip1.Nature404, 782-787 (2000).
54. Lawlor, M. A. & Rotwein, P.: Insulin-like growth factor-mediated muscle cell survival: central roles for Akt and cyclin-dependent kinase inhibitor p21.Mol. Cell. Biol.20, 8983-8995 (2000).
55. Rossig, L.:Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells.Mol. Cell. Biol.21, 5644-5657 (2001).
56. Vemuri, G. S. & Rittenhouse, S. E.: Wortmannin inhibits serum-induced activation of phosphoinositide 3-kinase andproliferation of CHRF-288 cells.Biochem. Biophys. Res.Commun.202, 1619-1623 (1994).
57. Castoria, G.:PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells.EMBO J.20, 6050-6059 (2001).
58. Castoria, G.:Shows that the induction of PI3K triggers oestrogen-dependent S-phase entry in breast cancer cells.
59. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth.Cell103, 253-262 (2000).
60. Nave, B. T, Ouwens, M., Withers, D. J., Alessi, D. R. & Shepherd, P R. Mammalian target of rapamycin is a directtarget for protein kinase Identification of a convergencepoint for opposing effects of insulin and amino-aciddeficiency on protein translation.Blochem. J.344, 427-431(1999).
61. Brunn, G. J.:Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide3-kinase inhibitors, wortmannin and LY294002.EMBO J.15, 5256-5267 (1996).
62. Bodine, S. C.:Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscleatrophyin vivo. Nature Cell Biol.3, 1014-1019 (2001).
63. Rommel, C.:Mediation of IGF-1-induced skeletalmyotube hypertrophy by PI(3)K/Akt/mTOR andPI(3)K/Akt/GSK3 pathways.Nature Cell Biol.3, 1009-1013(2001).
64. Dennis, P B.: Mammalian TOR: a homeostatic ATP sensor.Science294, 1102-1105 (2001).
65. Radimerski, T:DS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1.Nature CellBiol.4, 251-255 (2002).
66. Pullen, N.: Phosphorylation and activation of p70s6k by PDK1.Science279, 707-710 (1998).
67. Liliental, J.:Genetic deletion of thePtentumor suppressor gene promotes cell motility by activation of Rac1and Cdc42 GTPases.Curr. Biol.10, 401-404 (2000).
68. Jiang, K.:Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells.NatureImmunol.1, 419-425 (2000).
69. Welch, H., Eguinoa, A., Stephens, L. R. & Hawkins, P. T. Protein kinase, B: Rac are activated in parallel within aphosphatidylinositide 3OH-kinase-controlled signalingpathway.J. Biol. Chem.273, 11248-11256 (1998).
70. Han, J.:Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosinetriphosphatases by Vav.Science279, 558-560 (1998).
71. Han, J.:Shows that phosphorylation of the RAC-specificguanine nucleotide exchange factor (GEF) VAV1 isenhanced by PIP3and inhibited by PIP2. These findingslink a GEF to PI3K-mediated RAC activation.
72. Welch, H. C.:P-Rex1, a PtdIns(3, 4, 5)P(3)- and Gpy-regulated guanine-nucleotide exchange factor for Rac.Cell108, 809-821 (2002).
73. Krugmann, S.:Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selectivecapture on phosphoinositide affinity matrices.Mol. Cell, 9, 95-108 (2002).
74. Jimenez, C.:Role of the PI3K regulatory subunit in the control of actin organization and cell migration.J. Cell Biol.151, 249-261 (2000).
75. Brunet, A.:Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1(FOXO3a).Mol. Cell. Biol.21, 952-965 (2001).
76. Park, J.:Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signalingpathway.EMBO J.18, 3024-3033 (1999).
77. Stocker, H.: AllLiving with lethal PIP3levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB.Science28, 28 (2002).
78. Stocker, H.: Uses fly genetics to argue that Akt might be the sole effector of PIP3action.
79. Shayesteh, L.et allPIK3CA is implicated as an oncogene in ovarian cancer.Nature Genet.21, 99-102 (1999).
80. Bellacosa, A.:Molecular alterations of theAKT2oncogene in ovarian and breast carcinomas.Int J. Cancer64, 280-285 (1995).
81. Cheng, J. Q.:Amplification ofAKT2in human pancreatic cells and inhibition ofAKT2expression and tumorigenicity byantisense RNA.Proc. Natl Acad. Sci. USA93, 3636-3641 (1996).
82. Ruggeri, B. A., Huang, L., Wood, M., Cheng, J. Q. & Testa, J. R.: Amplification and overexpression of theAKT2oncogene in asubset of human pancreatic ductal adenocarcinomas.Mol.Carcinog.21, 81-86 (1998).
83. Philp, A. J.:The phosphatidylinositol 3'-kinase p85a gene is an oncogene in human ovarian and colon tumors.Cancer Res.61, 7426-7429 (2001).
84. Jimenez, C.:Identification and characterization of a new oncogene derived from the regulatory subunit ofphosphoinositide 3-kinase.EMBO J.17, 743-753(1998).
85. Moscatello, D. K., Holgado-Madruga, M., Emlet, D. R., Montgomery, R. B. & Wong, A. J. Constitutive activation ofphosphatidylinositol 3-kinase by a naturally occurring mutantepidermal growth factor receptor.J. Biol. Chem.273, 200-206 (1998).
86. Watanabe, T.:A novel amplification at 17q21-23 in ovarian cancer cell lines detected by comparative genomichybridization.Gynecol. Oncol.81, 172-177 (2001).
87. Barlund, M.:Multiple genes at 17q23 undergo amplification and overexpression in breast cancer.CancerRes.60, 5340-5344 (2000).
88. Barlund, M.:Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarrayanalysis.J. Natl Cancer Inst.92, 1252-1259 (2000).
89. Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra ofPTEN/MMAC1gene: a tumor suppressor with lipidphosphatase activity.J. Natl Cancer Inst.91, 1922-1932 (1999).
90. Ali, I. U., Schriml, L. M. & Dean, M. A thorough review of the frequency ofPTENmutationin various cancers.
91. Georgescu, M. M., Kirsch, K. H., Akagi, T, Shishido, T. & Hanafusa, H. The tumor-suppressor activity of PTEN isregulated by its carboxyl-terminal region.Proc. Natl Acad. Sci. USA96, 10182-10187 (1999).
92. Whang, Y.:Frequent transcriptional silencing of the tumor suppressorPTEN/MMAC1gene in prostate cancerxenografts.Proc. Natl Acad. Sci. USA95, 5246 (1998).
93. Pekarsky, Y:Tcl1 enhances Akt kinase activity andmediates its nuclear translocation.Proc. Natl Acad. Sci. USA97, 3028-3033 (2000).
94. Shioi, T:The conserved phosphoinositide 3-kinase pathway determines heart size in mice.EMBO J.19, 2537-2548 (2000).
95. Shioi, T:Shows that cardiac-specific expression of constitutively active p110causes an enlargement ofthe heart and that dominant-negative p110causes areduction in heart size.
96. Shioi, T.:Akt/protein kinase B promotes organ growth in transgenic mice.Mol. Cell. Biol.22, 2799-2809 (2002).
97. Borlado, L. R.:Increased phosphoinositide 3-kinaseactivity induces a lymphoproliferative disorder andcontributes to tumor generationin vivo. FASEB J.14, 895-903 (2000).
98. Jones, R. G.:Protein kinase B regulates T lymphocyte survival, nuclear factorkB activation, and BcI-xl levelsin vivo.J. Exp. Med.191, 1721-1734 (2000).
99. Tuttle, R. L.:Regulation of pancreatic 3-cell growth and survival by the serine/threonine protein kinase Akt1/PKBa.Nature Med.7, 1133-1137 (2001).
100. Bernal-Mizrachi, E., Wen, W., Stahlhut, S., Welling, C. M. & Permutt, M. A. Islet p-cell expression of constitutively activeAkt1/PKBa induces striking hypertrophy, hyperplasia, andhyperinsulinemia.J. Clin. Invest.108, 1631-1638 (2001).
101. Hutchinson, J., Jin, J., Cardiff, R. D., Woodgett, J. R. & Muller, W. J.: Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required fortumor progression.Mol. Cell. Biol.21, 2203-2212 (2001).
102. Holland, E. C.:Combined activation of Ras and Akt inneural progenitors induces glioblastoma formation in mice.Nature Genet.25, 55-57 (2000).
103. Holland, E. C.:Shows that co-expression of activated Ras and Akt in neural progenitor cells in the mouse brain inducesglioblastoma.
104. Stambolic, V:High incidence of breast and endometrial neoplasia resembling human Cowden syndrome inPtertmice.Cancer Res.60, 3605-3611 (2000).
105. Suzuki, A.:High cancer susceptibility and embryonic lethality associated with mutation of thePTENtumorsuppressor gene in mice.Curr. Biol.8, 1169-1178 (1998).
106. Podsypanina, K.:Mutation ofPten/Mmac1in micecauses neoplasia in multiple organ systems.Proc. Natl Acad.Sci. USA96, 1563-1568 (1999).
107. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P.: Pten is essential for embryonic development and tumoursuppression.Nature Genet.19, 348-355 (1998).
108. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P.: The first report of a Pten-knockout mouse phenotype. Homozygous deletion causes embryonic lethality, whereas heterozygous animals are viable but developvarious tumors.
109. Goldman, J. M. & Melo, J. V.: Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N. Engl. J. Med.344, 1084-1086 (2001).
110. Druker, B. J.:Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronicmyeloid leukemia and acute lymphoblastic leukemia with thePhiladelphia chromosome.N. Engl. J. Med.344, 1038-1042(2001).
111. van Oosterom, A. T.:Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: aphase I study.Lancet358, 1421-1423 (2001).
112. Baselga, J.:In2001AACR-NCI-EORTC International Conference128(American Association for Cancer Research, Fontainebleau Hilton Hotel. Miami Beach, Florida, 2001).
113. Hu, L., Hofmann, J., Lu, Y, Mills, G. B. & Jaffe, R. B.: Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel inin vitroandin vivoovarian cancer models.Cancer Res.62, 1087-1092 (2002).
114. Hu, L., Hofmann, J., Lu, Y, Mills, G. B. & Jaffe, R. B.: Shows that non-toxic doses of LY294002 can increase the efficacy of the chemotherapeutic. paclitaxel in anovarian cancer xenograft model.
115. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. & Nussbaum, R. L.: Proliferative defect and embryonic lethalityin mice homozygous for a deletion in the p110a subunit ofphosphoinositide 3-kinase.J. Biol. Chem.274, 10963-10968 (1999).
116. Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in micewith a homozygous disruption of the c-Abl proto-oncogene.Cell65, 1153-1163 (1991).
117. Reith, A. D.:W mutant mice with mild or severe developmental defects contain distinct point mutations in thekinase domain of the c-Kit receptor.Genes Dev.4, 390-400(1990).
118. Soriano, P The PDGFa receptor is required for neural crest cell development and for normal patterning of the somites.Development124, 2691-2700 (1997).
119. Neshat, M. S.:Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR.Proc. Natl Acad. Sci.USA98, 10314-10319 (2001).
120. Neshat, M. S.:Shows that loss ofPTENor stable expression of constitutively activeAKT.sensitizes tumours toinhibition.
121. Podsypanina, K.:An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity inPtert-mice.Proc. Natl Acad. Sci. USA98, 10320-10325 (2001).
122. Podsypanina, K.:Shows that pre-neoplastic uterine lesions fail todevelop or regress inPteni.mice that are treated withan inhibito.
123. Guba, M.:Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascularendothelial growth factor.Nature Med.8, 128-135 (2002).
124. Chan, J.:Dissection of angiogenic signaling in zebrafish using a chemical genetic approach.Cancer Cell1, 257-267(2002).
125. Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B.: PTEN protects p53 from Mdm2 and sensitizescancer cells to chemotherapyJ. Biol. Chem.277, 5484-5489 (2002).
126. Li, D. M. & Sun, H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in humanglioblastoma cells.Proc. Natl Acad. Sci. USA 95, 15406-15411 (1998).
127. Heymont, J.: TEP1, the yeast homolog of the human tumor suppressor genePTEN/MMAC1/TEP1, is linked to thephosphatidylinositol pathway and plays a role in thedevelopmental process of sporulation.Proc. Natl Acad. Sci.USA97, 12672-12677 (2000).
128. Casamayor, A., Torrance, P. D., Kobayashi, T, Thorner, J. & Alessi, D. R.: Functional counterparts of mammalian proteinkinases PDK1 and SGK in budding yeast.Curr. Biol. 9, 186-197 (1999).
129. Cardenas, M. E., Cutler, N. S., Lorenz, M. C., Di Como, C. J. & Heitman, J.: The TOR signaling cascade regulates geneexpression in response to nutrients.Genes Dev.13, 3271-3279 (1999).
130. Fabrizio, P, Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D.: Regulation of longevity and stress resistance bySch9 in yeast.Science292, 288-290 (2001).
131. Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G.: A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause inCaenorhabdltls elegans. Nature382, 536-539 (1996).
132. Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G.: Shows that mutations inAge1, theC. elegansPi3k homologue, causes dauer formation and an extensionof lifespan.
133. Kimura, K. D., Tissenbaum, H. A., Liu, Y & Ruvkun, G.:Daf2, an insulin receptor-like gene that regulates longevity and diapauseinCaenorhabditis elegans. Science277, 942-946 (1997).
134. Paradis, S., Ailion, M., Toker, A., Thomas, J. H. & Ruvkun, G. A PDK1 homolog is necessary and sufficient to transduceAGE-1 PI3 kinase signals that regulate diapause inCaenorhabdltls elegans. Genes Dev.13, 1438-1452 (1999).
135. Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of theCaenorhabdltls eleganslongevity protein DAF16 byinsulin/IGF1 and germline signaling.Nature Genet.28, 139-145 (2001).
136. Mihaylova, V. T., Borland, C. Z., Manjarrez, L., Stern, M. J. & Sun, H.: ThePTENtumor suppressor homolog inCaenorhabditis elegansregulates longevity and dauerformation in an insulin receptor-like signaling pathway.Proc.Natl Acad. Sci. USA96, 7427-7432 (1999).
137. Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. Cell-autonomous regulation of cell and organ growth inDrosophilaby Akt/PKB.Nature Cell Biol.1, 500-506 (1999).
138. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P.Regulation of cellular growth by theDrosophilatarget ofrapamycin dTOR.Genes Dev.14, 2712-2724 (2000).
139. Montagne, J.: DrosophilaS6 kinase: a regulator of cell size.Science285, 2126-2129 (1999).
140. Miron, M.:The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth inDrosophila. NatureCell Biol.3, 596-601 (2001).
141. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C.:Drosophilatumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinasesignaling pathway.Genes Dev.13, 3244-3258 (1999).
142. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C.:Shows that inDrosophila, Pten is a negative regulator of Pi3k and mutations inPtenresult in increased cellsize and cell number.
143. Gao, X., Neufeld, T. P & Pan, D.:DrosophilaPTEN regulates cell growth and proliferation through PI3K-dependent and-independent pathways.Dev. Biol.221, 404-418 (2000).
144. Sasaki, T.:Colorectal carcinomas in mice lacking thecatalytic subunit of PI(3)Ky.Nature406, 897-902 (2000).
145. Barbier, M.:Tumour biology. Weakening link to colorectalcancer.Nature413, 796 (2001).
146. Fruman, D. A.:Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms ofphosphoinositide 3-kinase p85a.Nature Genet.26, 379-382 (2000).
147. Fruman, D. A.:Shows that targeted deletion of all isoforms of Pi3k regulatory subunits results in lethality, unlike deletionsof individual isoforms.
148. Suzuki, H.:Xid-like immunodeficiency in mice with disruption of the p85a subunit of phosphoinositide 3-kinase.Science283, 390-392 (1999).
149. Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. & Birnbaum, M. J.: Akt1/PKBa is required for normal growth but dispensable formaintenance of glucose homeostasis in mice.J. Biol Chem.276, 38349-38352 (2001).
150. Chen, W. S.:Growth retardation and increased apoptosis in mice with homozygous disruption of theAkt1gene.Genes Dev.15, 2203-2208 (2001).
151. Chen, W. S.:Shows thatAkt7-deficient mice are smaller than wild-type littermates, have a shorter lifespan after exposure. Genotoxic stress and show more susceptibility toapoptosis in the testes and thymus.
152. Cho, H.:Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBp).Science292, 1728-1731 (2001).
153. Wang, S. I.:Somatic mutations ofPTENin glioblastoma multiforme.Cancer Res.57, 4183-4186 (1997).
154. Saito, M.:Allelic imbalance and mutations of thePTENgene in ovarian cancer.Int. J. Cancer85, 160-165 (2000).
155. Sun, M.:AKT1/PKBa kinase is frequently elevated in human cancers and its constitutive activation is required foroncogenic transformation in NIH3T3 cells.Am. J. Pathol. 159, 431-437 (2001).
156. Teng, D. H.: MMAC1/PTENmutations in primary tumor specimens and tumor cell lines.Cancer Res.57, 5221-5225 (1997).
157. Sun, M.:Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced byestrogen receptor-a (ERa) via interaction between ERa andPI3K.Cancer Res.61, 5985-5991 (2001).
158. Yokoyama, Y.:Expression ofPTENand PTEN pseudogene in endometrial carcinoma.Int. J. Mol. Med. 6, 47-50 (2000).
159. Salvesen, H. B.:PTEN methylation is associated with advanced stage and microsatellite instability in endometrialcarcinoma.Int. J. Cancer91, 22-26 (2001).
160. Kawamura, N.: PTEN/MMAC1mutations in hepatocellular carcinomas: somatic inactivation of bothalleles in tumors.Jpn. J. Cancer Res.90, 413-418 (1999).
161. Celebi, J. T., Shendrik, I., Silvers, D. N. & Peacocke, M.:Identification ofPTENmutations in metastatic melanomaspecimens.J. Med. Genet.37, 653-657 (2000).
162. Zhou, X. P.:EpigeneticPTENsilencing in malignant melanomas withoutPTENmutation.Am. J. Pathol.157, 1123-1128 (2000).
163. Chang, J. G.:Mutation analysis of thePTEN/MMAC1gene in cancers of the digestive tract.Eur. J. Cancer35, 647-651 (1999).
164. Forgacs, E.:Mutation analysis of thePTEN/MMAC1gene in lung cancer.Oncogene17, 1557-1565 (1998).
165. Alimov, A.:Somatic mutation and homozygous deletionofPTEN/MMAC1gene of 10q23 in renal cell carcinoma.Anticancer Res.19, 3841-3846 (1999).
166. Dahia, P. L.:Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors.Cancer Res.57, 4710-4713 (1997).
167. Halachmi, N.:Somatic mutations of thePTENtumor suppressor gene in sporadic follicular thyroid tumors.GenesChromosom. Cancer23, 239-243 (1998).
168. Hsieh, M. C.:Mutation analysis ofPTEN/MMAC1in sporadic thyroid tumors.Kaohsiung J. Med. Sci.16, 9-12 (2000).
169. Ringel, M. D.:Overexpression and overactivation of Akt in thyroid carcinoma.Cancer Res.61, 6105-6111 (2001).
170. Nakahara, Y.:Mutational analysis of thePTEN/MMAC1gene in non-Hodgkin's lymphoma.Leukemia12, 1277-1280 (1998).
171. Sakai, A., Thieblemont, C., Wellmann, A., Jaffe, E. S. & Raffeld, M.PTENgene alterations in lymphoid neoplasms.Blood92, 3410-3415 (1998).
172. Fruman, D. A.:Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85a.Science283, 393-397 (1999).
173. Terauchi, Y.:Increased insulin sensitivity and hypoglycaemia in mice lacking the p85a subunit ofphosphoinositide 3-kinase.Nature Genet.21, 230-235(1999).
174. Hirsch, E.:Central role for G protein-coupled phosphoinositide 3-kinase-y in inflammation.Science287, 1049-1053 (2000).
175. Li, Z.:Roles of PLC-p2 and -p3 and PI3Ky in chemoattractant-mediated signal transduction.Science 287, 1046-1049 (2000).
176. Sasaki, T.:Function of PI3Ky in thymocyte development, T cell activation, and neutrophil migration.Science 287, 1040-1046 (2000).