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Journal of Oncology
Volume 2012 (2012), Article ID 951724, 15 pages
http://dx.doi.org/10.1155/2012/951724
Review Article

Akt: A Double-Edged Sword in Cell Proliferation and Genome Stability

1Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
2School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Cai Lun Lu 1200, Shanghai 201203, China
3The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
4College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK

Received 26 October 2011; Accepted 29 December 2011

Academic Editor: Richard T. Penson

Copyright © 2012 Naihan Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. P. F. Jones, T. Jakubowicz, and B. A. Hemmings, “Molecular cloning of a second form of rac protein kinase,” Cell Regulation, vol. 2, no. 12, pp. 1001–1009, 1991. View at Google Scholar · View at Scopus
  2. J. Q. Cheng, A. K. Godwin, A. Bellacosa et al., “AKT2, a putative oncogene encoding a member of a subfamily of protein- serine/threonine kinases, is amplified in human ovarian carcinomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 19, pp. 9267–9271, 1992. View at Publisher · View at Google Scholar · View at Scopus
  3. D. Brodbeck, P. Cron, and B. A. Hemmings, “A human protein kinase Bγ with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain,” Journal of Biological Chemistry, vol. 274, no. 14, pp. 9133–9136, 1999. View at Publisher · View at Google Scholar · View at Scopus
  4. B. Vanhaesebroeck and D. R. Alessi, “The PI3K-PBK1 connection: more than just a road to PKB,” Biochemical Journal, vol. 346, no. 3, pp. 561–576, 2000. View at Publisher · View at Google Scholar · View at Scopus
  5. P. J. Coffer and J. R. Woodgett, “Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families,” European Journal of Biochemistry, vol. 201, no. 2, pp. 475–481, 1991. View at Google Scholar · View at Scopus
  6. D. A. Altomare, K. Guo, J. Q. Cheng, G. Sonoda, K. Walsh, and J. R. Testa, “Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene,” Oncogene, vol. 11, no. 6, pp. 1055–1060, 1995. View at Google Scholar · View at Scopus
  7. D. A. Altomare, G. E. Lyons, Y. Mitsuuchi, J. Q. Cheng, and J. R. Testa, “Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin,” Oncogene, vol. 16, no. 18, pp. 2407–2411, 1998. View at Google Scholar · View at Scopus
  8. W. S. Chen, P. Z. Xu, K. Gottlob et al., “Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene,” Genes and Development, vol. 15, no. 17, pp. 2203–2208, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. H. Cho, J. L. Thorvaldsen, Q. Chu, F. Feng, and M. J. Birnbaum, “Akt1/PKBα Is Required for Normal Growth but Dispensable for Maintenance of Glucose Homeostasis in Mice,” Journal of Biological Chemistry, vol. 276, no. 42, pp. 38349–38352, 2001. View at Publisher · View at Google Scholar · View at Scopus
  10. R. S. Garofalo, S. J. Orena, K. Rafidi et al., “Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ,” Journal of Clinical Investigation, vol. 112, no. 2, pp. 197–208, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. H. Cho, J. Mu, J. K. Kim et al., “Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ),” Science, vol. 292, no. 5522, pp. 1728–1731, 2001. View at Publisher · View at Google Scholar · View at Scopus
  12. Z. Z. Yang, O. Tschopp, A. Baudry, B. Dümmler, D. Hynx, and B. A. Hemmings, “Physiological functions of protein kinase B/Akt,” Biochemical Society Transactions, vol. 32, no. 2, pp. 350–354, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. G. Song, G. Ouyang, and S. Bao, “The activation of Akt/PKB signaling pathway and cell survival,” Journal of Cellular and Molecular Medicine, vol. 9, no. 1, pp. 59–71, 2005. View at Google Scholar · View at Scopus
  14. K. M. Ferguson, J. M. Kavran, V. G. Sankaran et al., “Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains,” Molecular Cell, vol. 6, no. 2, pp. 373–384, 2000. View at Google Scholar · View at Scopus
  15. T. F. Franke, D. R. Kaplan, L. C. Cantley, and A. Toker, “Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate,” Science, vol. 275, no. 5300, pp. 665–668, 1997. View at Publisher · View at Google Scholar · View at Scopus
  16. D. Stokoe, L. R. Stephens, T. Copeland et al., “Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B,” Science, vol. 277, no. 5325, pp. 567–570, 1997. View at Publisher · View at Google Scholar · View at Scopus
  17. S. E. Lietzke, S. Bose, T. Cronin et al., “Structural basis of 3-phosphoinositide recognition by Pleckstrin homology domains,” Molecular Cell, vol. 6, no. 2, pp. 385–394, 2000. View at Google Scholar · View at Scopus
  18. D. R. Alessi, M. Andjelkovic, B. Caudwell et al., “Mechanism of activation of protein kinase B by insulin and IGF-1,” EMBO Journal, vol. 15, no. 23, pp. 6541–6551, 1996. View at Google Scholar · View at Scopus
  19. D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, “Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex,” Science, vol. 307, no. 5712, pp. 1098–1101, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. M. Delcommenne, C. Tan, V. Gray, L. Rue, J. Woodgett, and S. Dedhar, “Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 19, pp. 11211–11216, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Balendran, A. Casamayor, M. Deak et al., “PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2,” Current Biology, vol. 9, no. 8, pp. 393–404, 1999. View at Publisher · View at Google Scholar · View at Scopus
  22. C. L. Sable, N. Filippa, B. Hemmings, and E. Van Obberghen, “cAMP stimulates protein kinase B in a Wortmannin-insensitive manner,” FEBS Letters, vol. 409, no. 2, pp. 253–257, 1997. View at Publisher · View at Google Scholar · View at Scopus
  23. N. Filippa, C. L. Sable, C. Filloux, B. Hemmings, and E. Van Obberghen, “Mechanism of protein kinase B activation by cyclic AMP-dependent protein kinase,” Molecular and Cellular Biology, vol. 19, no. 7, pp. 4989–5000, 1999. View at Google Scholar · View at Scopus
  24. S. Yano, H. Tokumitsu, and T. R. Soderling, “Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway,” Nature, vol. 396, no. 6711, pp. 584–587, 1998. View at Publisher · View at Google Scholar · View at Scopus
  25. M. J. Pérez-García, V. Ceña, Y. De Pablo, M. Llovera, J. X. Comella, and R. M. Soler, “Glial cell line-derived neurotrophic factor increases intracellular calcium concentration: role of calcium/calmodulin in the activation of the phosphatidylinositol 3-kinase pathway,” Journal of Biological Chemistry, vol. 279, no. 7, pp. 6132–6142, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. M. P. Myers and N. K. Tonks, “PTEN: sometimes taking it off can be better than putting it on,” American Journal of Human Genetics, vol. 61, no. 6, pp. 1234–1238, 1997. View at Publisher · View at Google Scholar · View at Scopus
  27. L. C. Cantley and B. G. Neel, “New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4240–4245, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Osaki, M. Oshimura, and H. Ito, “PI3K-Akt pathway: its functions and alterations in human cancer,” Apoptosis, vol. 9, no. 6, pp. 667–676, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. N. R. Leslie and C. P. Downes, “PTEN function: how normal cells control it and tumour cells lose it,” Biochemical Journal, vol. 382, no. 1, pp. 1–11, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. I. Sansal and W. R. Sellers, “The biology and clinical relevance of the PTEN tumor suppressor pathway,” Journal of Clinical Oncology, vol. 22, no. 14, pp. 2954–2963, 2004. View at Publisher · View at Google Scholar · View at Scopus
  31. M. L. Sulis and R. Parsons, “PTEN: from pathology to biology,” Trends in Cell Biology, vol. 13, no. 9, pp. 478–483, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Maehama and J. E. Dixon, “The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate,” Journal of Biological Chemistry, vol. 273, no. 22, pp. 13375–13378, 1998. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Brognard and A. C. Newton, “PHLiPPing the switch on Akt and protein kinase C signaling,” Trends in Endocrinology and Metabolism, vol. 19, no. 6, pp. 223–230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Gao, F. Furnari, and A. C. Newton, “PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth,” Molecular Cell, vol. 18, no. 1, pp. 13–24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Brognard, E. Sierecki, T. Gao, and A. C. Newton, “PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms,” Molecular Cell, vol. 25, no. 6, pp. 917–931, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Liu, H. L. Weiss, P. Rychahou, L. N. Jackson, B. M. Evers, and T. Gao, “Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis,” Oncogene, vol. 28, no. 7, pp. 994–1004, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. M. Chen, C. Pratt, M. Zeeman et al., “Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression,” Cancer Cell, vol. 20, no. 2, pp. 173–186, 2011. View at Publisher · View at Google Scholar
  38. M. Qiao, J. D. Iglehart, and A. B. Pardee, “Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation,” Cancer Research, vol. 67, no. 11, pp. 5293–5299, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. D. C. Fingar, S. Salama, C. Tsou, E. Harlow, and J. Blenis, “Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E,” Genes and Development, vol. 16, no. 12, pp. 1472–1487, 2002. View at Publisher · View at Google Scholar · View at Scopus
  40. D. D. Sarbassov, S. M. Ali, and D. M. Sabatini, “Growing roles for the mTOR pathway,” Current Opinion in Cell Biology, vol. 17, no. 6, pp. 596–603, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. L. J. Saucedo and B. A. Edgar, “Why size matters: altering cell size,” Current Opinion in Genetics and Development, vol. 12, no. 5, pp. 565–571, 2002. View at Publisher · View at Google Scholar · View at Scopus
  42. N. Tapon, K. H. Moberg, and I. K. Hariharan, “The coupling of cell growth to the cell cycle,” Current Opinion in Cell Biology, vol. 13, no. 6, pp. 731–737, 2001. View at Publisher · View at Google Scholar · View at Scopus
  43. A. L. Gartel and K. Shchors, “Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes,” Experimental Cell Research, vol. 283, no. 1, pp. 17–21, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. N. N. Ahmed, H. L. Grimes, A. Bellacosa, T. O. Chan, and P. N. Tsichlis, “Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 8, pp. 3627–3632, 1997. View at Publisher · View at Google Scholar · View at Scopus
  45. R. Sears, F. Nuckolls, E. Haura, Y. Taya, K. Tamai, and J. R. Nevins, “Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability,” Genes and Development, vol. 14, no. 19, pp. 2501–2514, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Pelengaris, M. Khan, and G. Evan, “c-MYC: more than just a matter of life and death,” Nature Reviews Cancer, vol. 2, no. 10, pp. 764–776, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. J. A. Diehl, M. Cheng, M. F. Roussel, and C. J. Sherr, “Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization,” Genes and Development, vol. 12, no. 22, pp. 3499–3511, 1998. View at Google Scholar · View at Scopus
  48. J. R. Alt, J. L. Cleveland, M. Hannink, and J. A. Diehl, “Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation,” Genes and Development, vol. 14, no. 24, pp. 3102–3114, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. P. Brennan, J. W. Babbage, B. M. T. Burgering, B. Groner, K. Reif, and D. A. Cantrell, “Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F,” Immunity, vol. 7, no. 5, pp. 679–689, 1997. View at Publisher · View at Google Scholar · View at Scopus
  50. B. P. Zhou, Y. Liao, W. Xia, B. Spohn, M. H. Lee, and M. C. Hung, “Cytoplasmic localization of p21 CIP1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells,” Nature Cell Biology, vol. 3, no. 3, pp. 245–252, 2001. View at Publisher · View at Google Scholar · View at Scopus
  51. L. Rössig, A. S. Jadidi, C. Urbich, C. Badorff, A. M. Zeiher, and S. Dimmeler, “Akt-dependent phosphorylation of p21Cip1 regulates PCNA binding and proliferation of endothelial cells,” Molecular and Cellular Biology, vol. 21, no. 16, pp. 5644–5657, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. Y. Li, D. Dowbenko, and L. A. Lasky, “AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival,” Journal of Biological Chemistry, vol. 277, no. 13, pp. 11352–11361, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. J. M. Jung, J. M. Bruner, S. Ruan et al., “Increased levels of p21(WAF1)/(Cip1) in human brain tumors,” Oncogene, vol. 11, no. 10, pp. 2021–2028, 1995. View at Google Scholar · View at Scopus
  54. R. H. Medema, G. J. P. L. Kops, J. L. Bos, and B. M. T. Burgering, “AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27(kip1),” Nature, vol. 404, no. 6779, pp. 782–787, 2000. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Viglietto, M. L. Motti, P. Bruni et al., “Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27kip1 by PKB/Akt-mediated phosphorylation in breast cancer,” Nature Medicine, vol. 8, no. 10, pp. 1136–1144, 2002. View at Publisher · View at Google Scholar · View at Scopus
  56. I. Shin, F. M. Yakes, F. Rojo et al., “PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization,” Nature Medicine, vol. 8, no. 10, pp. 1145–1152, 2002. View at Publisher · View at Google Scholar · View at Scopus
  57. J. Liang, J. Zubovitz, T. Petrocelli et al., “PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest,” Nature Medicine, vol. 8, no. 10, pp. 1153–1160, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Fujita, S. Sato, K. Katayama, and T. Tsuruo, “Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization,” Journal of Biological Chemistry, vol. 277, no. 32, pp. 28706–28713, 2002. View at Google Scholar · View at Scopus
  59. G. Rodier, A. Montagnoli, L. Di Marcotullio et al., “p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis,” EMBO Journal, vol. 20, no. 23, pp. 6672–6682, 2001. View at Publisher · View at Google Scholar · View at Scopus
  60. T. Sekimoto, M. Fukumoto, and Y. Yoneda, “14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27Kip1,” EMBO Journal, vol. 23, no. 9, pp. 1934–1942, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Ciaparrone, H. Yamamoto, Y. Yao et al., “Localization and expression of p27(KIP1) in multistage colorectal carcinogenesis,” Cancer Research, vol. 58, no. 1, pp. 114–122, 1998. View at Google Scholar · View at Scopus
  62. S. P. Singh, J. Lipman, H. Goldman et al., “Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma,” Cancer Research, vol. 58, no. 8, pp. 1730–1735, 1998. View at Google Scholar · View at Scopus
  63. H. K. Lin, G. Wang, Z. Chen et al., “Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB,” Nature Cell Biology, vol. 11, no. 4, pp. 420–432, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. D. Gao, H. Inuzuka, A. Tseng, R. Y. Chin, A. Toker, and W. Wei, “Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction,” Nature Cell Biology, vol. 11, no. 4, pp. 397–408, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. A. C. Carrano, E. Eytan, A. Hershko, and M. Pagano, “SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27,” Nature Cell Biology, vol. 1, no. 4, pp. 193–199, 1999. View at Google Scholar · View at Scopus
  66. H. Sutterlüty, E. Chatelain, A. Marti et al., “p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells,” Nature Cell Biology, vol. 1, no. 4, pp. 207–214, 1999. View at Google Scholar · View at Scopus
  67. D. Ganoth, G. Bornstein, T. K. Ko et al., “The cell-cycle regulatory protein Cks1 is required for SCFSkp2-mediated ubiquitinylation of p27,” Nature Cell Biology, vol. 3, no. 3, pp. 321–324, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Spruck, H. Strohmaier, M. Watson et al., “A CDK-independent function of mammalian Cks1: targeting of SCFSkp2 to the CDK inhibitor p27Kip1,” Molecular Cell, vol. 7, no. 3, pp. 639–650, 2001. View at Publisher · View at Google Scholar · View at Scopus
  69. A. J. Levine, “p53, the cellular gatekeeper for growth and division,” Cell, vol. 88, no. 3, pp. 323–331, 1997. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Bates and K. H. Vousden, “Mechanisms of p53-mediated apoptosis,” Cellular and Molecular Life Sciences, vol. 55, no. 1, pp. 28–37, 1999. View at Publisher · View at Google Scholar · View at Scopus
  71. M. H. G. Kubbutat, S. N. Jones, and K. H. Vousden, “Regulation of p53 stability by Mdm2,” Nature, vol. 387, no. 6630, pp. 299–303, 1997. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. Haupt, R. Maya, A. Kazaz, and M. Oren, “Mdm2 promotes the rapid degradation of p53,” Nature, vol. 387, no. 6630, pp. 296–299, 1997. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Ashcroft, R. L. Ludwig, D. B. Woods et al., “Phosphorylation of HDM2 by Akt,” Oncogene, vol. 21, no. 13, pp. 1955–1962, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. Y. Ogawara, S. Kishishita, T. Obata et al., “Akt enhances Mdm2-mediated ubiquitination and degradation of p53,” Journal of Biological Chemistry, vol. 277, no. 24, pp. 21843–21850, 2002. View at Publisher · View at Google Scholar · View at Scopus
  75. L. D. Mayo and D. B. Donner, “A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 20, pp. 11598–11603, 2001. View at Publisher · View at Google Scholar · View at Scopus
  76. H. Kawai, V. Lopez-Pajares, M. M. Kim, D. Wiederschain, and Z. M. Yuan, “RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity,” Cancer Research, vol. 67, no. 13, pp. 6026–6030, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. L. K. Linares, A. Hengstermann, A. Ciechanover, S. Müller, and M. Scheffner, “HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 21, pp. 12009–12014, 2003. View at Publisher · View at Google Scholar · View at Scopus
  78. V. Lopez-Pajares, M. M. Kim, and Z. M. Yuan, “Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding,” Journal of Biological Chemistry, vol. 283, no. 20, pp. 13707–13713, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. E. Shtivelman, J. Sussman, and D. Stokoe, “A role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle,” Current Biology, vol. 12, no. 11, pp. 919–924, 2002. View at Publisher · View at Google Scholar · View at Scopus
  80. E. S. Kandel, J. Skeen, N. Majewski et al., “Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage,” Molecular and Cellular Biology, vol. 22, no. 22, pp. 7831–7841, 2002. View at Publisher · View at Google Scholar · View at Scopus
  81. C. Karlsson, S. Katich, A. Hagting, I. Hoffmann, and J. Pines, “Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis,” Journal of Cell Biology, vol. 146, no. 3, pp. 573–583, 1999. View at Publisher · View at Google Scholar · View at Scopus
  82. V. Baldin, N. Theis-Febvre, C. Benne et al., “PKB/Akt phosphorylates the CDC25B phosphatase and regulates its intracellular localisation,” Biology of the Cell, vol. 95, no. 8, pp. 547–554, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. I. Nilsson and I. Hoffmann, “Cell cycle regulation by the Cdc25 phosphatase family,” Progress in cell cycle research, vol. 4, pp. 107–114, 2000. View at Google Scholar · View at Scopus
  84. N. Davezac, V. Baldin, B. Gabrielli et al., “Regulation of CDC25B phosphatases subcellular localization,” Oncogene, vol. 19, no. 18, pp. 2179–2185, 2000. View at Google Scholar · View at Scopus
  85. K. Katayama, N. Fujita, and T. Tsuruo, “Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition,” Molecular and Cellular Biology, vol. 25, no. 13, pp. 5725–5737, 2005. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Okumura, T. Fukuhara, H. Yoshida et al., “Akt inhibits Myt1 in the signalling pathway that leads to meiotic G2/M-phase transition,” Nature Cell Biology, vol. 4, no. 2, pp. 111–116, 2002. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Maddika, S. R. Sande, E. Wiechec, L. L. Hansen, S. Wesselborg, and M. Los, “Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis,” Journal of Cell Science, vol. 121, no. 7, pp. 979–988, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Maddika, S. Panigrahi, E. Wiechec et al., “Unscheduled Akt-triggered activation of cyclin-dependent kinase 2 as a key effector mechanism of apoptin's anticancer toxicity,” Molecular and Cellular Biology, vol. 29, no. 5, pp. 1235–1248, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Brognard, A. S. Clark, Y. Ni, and P. A. Dennis, “Akt/pbotein kinace B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation,” Cancer Research, vol. 61, no. 10, pp. 3986–3997, 2001. View at Google Scholar · View at Scopus
  90. D. Lu, J. Huang, and A. Basu, “Protein kinase Cε activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-α-induced cell death,” Journal of Biological Chemistry, vol. 281, no. 32, pp. 22799–22807, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. J. Guinea Viniegra, N. Martínez, P. Modirassari et al., “Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM,” Journal of Biological Chemistry, vol. 280, no. 6, pp. 4029–4036, 2005. View at Publisher · View at Google Scholar · View at Scopus
  92. L. Bozulic, B. Surucu, D. Hynx, and B. A. Hemmings, “PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival,” Molecular Cell, vol. 30, no. 2, pp. 203–213, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Caporali, L. Levati, G. Starace et al., “AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition,” Molecular Pharmacology, vol. 74, no. 1, pp. 173–183, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. S. D. Spacey, R. A. Gatti, and G. Bebb, “The molecular basis and clinical management of ataxia telangiectasia,” Canadian Journal of Neurological Sciences, vol. 27, no. 3, pp. 184–191, 2000. View at Google Scholar · View at Scopus
  95. C. Barlow, S. Hirotsune, R. Paylor et al., “Atm-deficient mice: a paradigm of ataxia telangiectasia,” Cell, vol. 86, no. 1, pp. 159–171, 1996. View at Publisher · View at Google Scholar · View at Scopus
  96. K. A. Boehme, R. Kulikov, and C. Blattner, “p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 22, pp. 7785–7790, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. S. P. Lees-Miller, “PIKK-ing a new partner: a new role for PKB in the DNA damage response,” Cancer Cell, vol. 13, no. 5, pp. 379–380, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. A. Toker, “Akt signaling: a damaging interaction makes good,” Trends in Biochemical Sciences, vol. 33, no. 8, pp. 356–359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. F. W. King, J. Skeen, N. Hay, and E. Shtivelman, “Inhibition of Chk1 by activated PKB/Akt,” Cell Cycle, vol. 3, no. 5, pp. 634–637, 2004. View at Google Scholar
  100. I. Tonic, W. N. Yu, Y. Park, C. C. Chen, and N. Hay, “Akt activation emulates Chk1 inhibition and Bcl2 overexpression and abrogates G2 cell cycle checkpoint by inhibiting BRCA1 foci,” Journal of Biological Chemistry, vol. 285, no. 31, pp. 23790–23798, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Puc, M. Keniry, H. S. Li et al., “Lack of PTEN sequesters CHK1 and initiates genetic instability,” Cancer Cell, vol. 7, no. 2, pp. 193–204, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. M. K. Henry, J. T. Lynch, A. K. Eapen, and F. W. Quelle, “DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway,” Blood, vol. 98, no. 3, pp. 834–841, 2001. View at Publisher · View at Google Scholar · View at Scopus
  103. Y. Hirose, M. Katayama, O. K. Mirzoeva, M. S. Berger, and R. O. Pieper, “Akt activation suppresses Chk2-mediated, methylating agent-induced G 2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence,” Cancer Research, vol. 65, no. 11, pp. 4861–4869, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Sancar, L. A. Lindsey-Boltz, K. Ünsal-Kaçmaz, and S. Linn, “Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints,” Annual Review of Biochemistry, vol. 73, pp. 39–85, 2004. View at Publisher · View at Google Scholar · View at Scopus
  105. T. Helleday, J. Lo, D. C. van Gent, and B. P. Engelward, “DNA double-strand break repair: from mechanistic understanding to cancer treatment,” DNA Repair, vol. 6, no. 7, pp. 923–935, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. J. Guirouilh-Barbat, S. Huck, P. Bertrand et al., “Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells,” Molecular Cell, vol. 14, no. 5, pp. 611–623, 2004. View at Publisher · View at Google Scholar · View at Scopus
  107. J. M. Daley, P. L. Palmbos, D. Wu, and T. E. Wilson, “Nonhomologous end joining in yeast,” Annual Review of Genetics, vol. 39, pp. 431–451, 2005. View at Publisher · View at Google Scholar · View at Scopus
  108. M. R. Lieber, Y. Ma, U. Pannicke, and K. Schwarz, “Mechanism and regulation of human non-homologous DNA end-joining,” Nature Reviews Molecular Cell Biology, vol. 4, no. 9, pp. 712–720, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. E. Sonoda, H. Hochegger, A. Saberi, Y. Taniguchi, and S. Takeda, “Differential usage of non-homologous end-joining and homologous recombination in double strand break repair,” DNA Repair, vol. 5, no. 9-10, pp. 1021–1029, 2006. View at Publisher · View at Google Scholar · View at Scopus
  110. L. Wohlbold and R. P. Fisher, “Behind the wheel and under the hood: functions of cyclin-dependent kinases in response to DNA damage,” DNA Repair, vol. 8, no. 9, pp. 1018–1024, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Toulany, U. Kasten-Pisula, I. Brammer et al., “Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair,” Clinical Cancer Research, vol. 12, no. 13, pp. 4119–4126, 2006. View at Publisher · View at Google Scholar · View at Scopus
  112. G. D. Kao, Z. Jiang, A. M. Fernandes, A. K. Gupta, and A. Maity, “Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation,” Journal of Biological Chemistry, vol. 282, no. 29, pp. 21206–21212, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. M. Toulany, R. Kehlbach, U. Florczak et al., “Targeting of AKT1 enhances radiation toxicity of human tumor cells by inhibiting DNA-PKcs-dependent DNA double-strand break repair,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 1772–1781, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. M. Toulany, R. Kehlbach, H. P. Rodemann, and H. Mozdarani, “Radiocontrast media affect radiation-induced DNA damage repair in vitro and in vivo by affecting Akt signalling,” Radiotherapy and Oncology, vol. 94, no. 1, pp. 110–116, 2010. View at Publisher · View at Google Scholar
  115. S. E. Golding, R. N. Morgan, B. R. Adams, A. J. Hawkins, L. F. Povirk, and K. Valerie, “Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells,” Cancer Biology and Therapy, vol. 8, no. 8, pp. 730–738, 2009. View at Google Scholar · View at Scopus
  116. B. P. C. Chen, N. Uematsu, J. Kobayashi et al., “Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break,” Journal of Biological Chemistry, vol. 282, no. 9, pp. 6582–6587, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. M. F. Lavin and S. Kozlov, “DNA damage-induced signalling in ataxia-telangiectasia and related syndromes,” Radiotherapy and Oncology, vol. 83, no. 3, pp. 231–237, 2007. View at Publisher · View at Google Scholar
  118. J. Feng, J. Park, P. Cron, D. Hess, and B. A. Hemmings, “Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase,” Journal of Biological Chemistry, vol. 279, no. 39, pp. 41189–41196, 2004. View at Publisher · View at Google Scholar · View at Scopus
  119. C. Richardson, J. M. Stark, M. Ommundsen, and M. Jasin, “Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability,” Oncogene, vol. 23, no. 2, pp. 546–553, 2004. View at Publisher · View at Google Scholar · View at Scopus
  120. A. J. R. Bishop and R. H. Schiestl, “Homologous recombination and its role in carcinogenesis,” Journal of Biomedicine and Biotechnology, vol. 2002, no. 2, pp. 75–85, 2002. View at Publisher · View at Google Scholar
  121. I. Plo, C. Laulier, L. Gauthier, F. Lebrun, F. Calvo, and B. S. Lopez, “AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD5,” Cancer Research, vol. 68, no. 22, pp. 9404–9412, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. N. Xu, N. Hegarat, E. J. Black, M. T. Scott, H. Hochegger, and D. A. Gillespie, “Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2,” Journal of Cell Biology, vol. 190, no. 3, pp. 297–306, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. B. Barré and N. D. Perkins, “A cell cycle regulatory network controlling NF-κB subunit activity and function,” EMBO Journal, vol. 26, no. 23, pp. 4841–4855, 2007. View at Publisher · View at Google Scholar · View at Scopus
  124. A. Pedram, M. Razandi, A. J. Evinger, E. Lee, and E. R. Levin, “Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair,” Molecular Biology of the Cell, vol. 20, no. 14, pp. 3374–3389, 2009. View at Publisher · View at Google Scholar · View at Scopus
  125. S. B. Lee, I. S. Kwon, J. Park et al., “Ribosomal protein S3, a new substrate of Akt, serves as a signal mediator between neuronal apoptosis and DNA repair,” Journal of Biological Chemistry, vol. 285, no. 38, pp. 29457–29468, 2010. View at Publisher · View at Google Scholar · View at Scopus
  126. I. Plo and B. Lopez, “AKT1 represses gene conversion induced by different genotoxic stresses and induces supernumerary centrosomes and aneuploidy in hamster ovary cells,” Oncogene, vol. 28, no. 22, pp. 2231–2237, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. M. Walker, E. J. Black, V. Oehler, D. A. Gillespie, and M. T. Scott, “Chk1 C-terminal regulatory phosphorylation mediates checkpoint activation by de-repression of Chk1 catalytic activity,” Oncogene, vol. 28, no. 24, pp. 2314–2323, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. G. Zachos, M. D. Rainey, and D. A. F. Gillespie, “Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects,” EMBO Journal, vol. 22, no. 3, pp. 713–723, 2003. View at Publisher · View at Google Scholar · View at Scopus
  129. G. Zachos, M. D. Rainey, and D. A. F. Gillespie, “Chk1-dependent S-M checkpoint delay in vertebrate cells is linked to maintenance of viable replication structures,” Molecular and Cellular Biology, vol. 25, no. 2, pp. 563–574, 2005. View at Publisher · View at Google Scholar · View at Scopus
  130. J. Smith, L. Mun Tho, N. Xu, and D. A. Gillespie, “The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer,” Advances in Cancer Research, vol. 108, no. C, pp. 73–112, 2010. View at Publisher · View at Google Scholar · View at Scopus
  131. V. Garcia, K. Furuya, and A. M. Carr, “Identification and functional analysis of TopBP1 and its homologs,” DNA Repair, vol. 4, no. 11, pp. 1227–1239, 2005. View at Publisher · View at Google Scholar · View at Scopus
  132. A. Kumagai, J. Lee, H. Y. Yoo, and W. G. Dunphy, “TopBP1 activates the ATR-ATRIP complex,” Cell, vol. 124, no. 5, pp. 943–955, 2006. View at Publisher · View at Google Scholar · View at Scopus
  133. L. I. Toledo, M. Murga, P. Gutierrez-Martinez, R. Soria, and O. Fernandez-Capetillo, “ATR signaling can drive cells into senescence in the absence of DNA breaks,” Genes and Development, vol. 22, no. 3, pp. 297–302, 2008. View at Publisher · View at Google Scholar · View at Scopus
  134. K. Liu, J. C. Paik, B. Wang, F. T. Lin, and W. C. Lin, “Regulation of TopBP1 oligomerization by Akt/PKB for cell survival,” EMBO Journal, vol. 25, no. 20, pp. 4795–4807, 2006. View at Publisher · View at Google Scholar · View at Scopus
  135. S. Altiok, D. Batt, N. Altiokl et al., “Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-kinase/AKT in breast cancer cells,” Journal of Biological Chemistry, vol. 274, no. 45, pp. 32274–32278, 1999. View at Publisher · View at Google Scholar · View at Scopus
  136. C. V. Hinton, L. D. Fitzgerald, and M. E. Thompson, “Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1,” Experimental Cell Research, vol. 313, no. 9, pp. 1735–1744, 2007. View at Publisher · View at Google Scholar · View at Scopus
  137. T. Miralem and H. K. Avraham, “Extracellular matrix enhances heregulin-dependent BRCA1 phosphorylation and suppresses BRCA1 expression through its C terminus,” Molecular and Cellular Biology, vol. 23, no. 2, pp. 579–593, 2003. View at Publisher · View at Google Scholar · View at Scopus
  138. T. Xiang, A. Ohashi, Y. Huang et al., “Negative regulation of AKT activation by BRCA1,” Cancer Research, vol. 68, no. 24, pp. 10040–10044, 2008. View at Publisher · View at Google Scholar · View at Scopus
  139. T. Schäfer, B. Maco, E. Petfalski et al., “Hrr25-dependent phosphorylation state regulates organization of the pre-40S subunit,” Nature, vol. 441, no. 7093, pp. 651–655, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. D. T. Grabowski, W. A. Deutsch, D. Derda, and M. R. Kelley, “Drosophila AP3, a presumptive DNA repair protein, is homologous to human ribosomal associated protein PO,” Nucleic Acids Research, vol. 19, no. 15, p. 4297, 1991. View at Google Scholar · View at Scopus
  141. J. Kim, L. S. Chubatsu, A. Admon, J. Stahl, R. Fellous, and S. Linn, “Implication of mammalian ribosomal protein S3 in the processing of DNA damage,” Journal of Biological Chemistry, vol. 270, no. 23, pp. 13620–13629, 1995. View at Publisher · View at Google Scholar · View at Scopus
  142. S. H. Kim, J. Y. Lee, and J. Kim, “Characterization of a wide range base-damage-endonuclease activity of mammalian rpS3,” Biochemical and Biophysical Research Communications, vol. 328, no. 4, pp. 962–967, 2005. View at Publisher · View at Google Scholar
  143. V. Hegde, S. Yadavilli, and W. A. Deutsch, “Knockdown of ribosomal protein S3 protects human cells from genotoxic stress,” DNA Repair, vol. 6, no. 1, pp. 94–99, 2007. View at Publisher · View at Google Scholar · View at Scopus
  144. S. N. Radyuk, K. Michalak, I. Rebrin, R. S. Sohal, and W. C. Orr, “Effects of ectopic expression of Drosophila DNA glycosylases dOgg1 and RpS3 in mitochondria,” Free Radical Biology and Medicine, vol. 41, no. 5, pp. 757–764, 2006. View at Publisher · View at Google Scholar · View at Scopus
  145. R. Deng, J. Tang, J. G. Ma et al., “PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation,” Oncogene, vol. 30, pp. 944–955, 2011. View at Publisher · View at Google Scholar · View at Scopus
  146. M. S. Tsai, Y. H. Kuo, Y. F. Chiu, Y. C. Su, and Y. W. Lin, “Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells,” Journal of Pharmacology and Experimental Therapeutics, vol. 335, no. 3, pp. 830–840, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. J. C. Ko, S. C. Ciou, J. Y. Jhan et al., “Roles of MKK1/2-ERK1/2 and phosphoinositide 3-kinase-AKT signaling pathways in erlotinib-induced Rad51 suppression and cytotoxicity in human non-small cell lung cancer cells,” Molecular Cancer Research, vol. 7, no. 8, pp. 1378–1389, 2009. View at Publisher · View at Google Scholar · View at Scopus
  148. B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, and G. B. Mills, “Exploiting the PI3K/AKT pathway for cancer drug discovery,” Nature Reviews Drug Discovery, vol. 4, no. 12, pp. 988–1004, 2005. View at Publisher · View at Google Scholar · View at Scopus
  149. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at Google Scholar · View at Scopus
  150. E. Calvo, M. V. Bolós, and E. Grande, “Multiple roles and therapeutic implications of Akt signaling in cancer,” OncoTargets and Therapy, vol. 2, pp. 135–150, 2009. View at Google Scholar · View at Scopus
  151. D. Haas-Kogan, N. Shalev, M. Wong, G. Mills, G. Yount, and D. Stokoe, “Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC,” Current Biology, vol. 8, no. 21, pp. 1195–1198, 1998. View at Google Scholar · View at Scopus
  152. H. K. Roy, B. F. Olusola, D. L. Clemens et al., “AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis,” Carcinogenesis, vol. 23, no. 1, pp. 201–205, 2002. View at Google Scholar · View at Scopus
  153. I. U. Ali, L. M. Schriml, and M. Dean, “Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity,” Journal of the National Cancer Institute, vol. 91, no. 22, pp. 1922–1932, 1999. View at Google Scholar · View at Scopus
  154. I. Vivanco and C. L. Sawyers, “The phosphatidylinositol 3-kinase-AKT pathway in human cancer,” Nature Reviews Cancer, vol. 2, no. 7, pp. 489–501, 2002. View at Google Scholar · View at Scopus
  155. D. W. Parsons, T. L. Wang, Y. Samuels et al., “Colorectal cancer: mutations in a signalling pathway,” Nature, vol. 436, no. 7052, p. 792, 2005. View at Publisher · View at Google Scholar · View at Scopus
  156. A. Carnero, “The PKB/AKT pathway in cancer,” Current Pharmaceutical Design, vol. 16, no. 1, pp. 34–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  157. J. Woenckhaus, K. Steger, E. Werner et al., “Genomic gain of PIK3CA and increased expression of pI I 0alpha are associated with progression of dysplasia into invasive squamous cell carcinoma,” Journal of Pathology, vol. 198, no. 3, pp. 335–342, 2002. View at Publisher · View at Google Scholar · View at Scopus
  158. Y. Samuels, Z. Wang, A. Bardelli et al., “High frequency of mutations of the PIK3CA gene in human cancers,” Science, vol. 304, no. 5670, p. 554, 2004. View at Publisher · View at Google Scholar · View at Scopus
  159. L. Shayesteh, Y. Lu, W. L. Kuo et al., “PlK3CA is implicated as an oncogene in ovarian cancer,” Nature Genetics, vol. 21, no. 1, pp. 99–102, 1999. View at Publisher · View at Google Scholar · View at Scopus
  160. Y. Y. Ma, S. J. Wei, Y. C. Lin et al., “PIK3CA as an oncogene in cervical cancer,” Oncogene, vol. 19, no. 23, pp. 2739–2744, 2000. View at Google Scholar · View at Scopus
  161. D. S. Byun, K. Cho, B. K. Ryu et al., “Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma,” International Journal of Cancer, vol. 104, no. 3, pp. 318–327, 2003. View at Publisher · View at Google Scholar · View at Scopus
  162. C. B. Knobbe and G. Reifenberger, “Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′ kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas,” Brain Pathology, vol. 13, no. 4, pp. 507–518, 2003. View at Google Scholar · View at Scopus
  163. G. Giannini, E. Ristori, F. Cerignoli et al., “Human MRE11 is inactivated in mismatch repair-deficient cancers,” EMBO Reports, vol. 3, no. 3, pp. 248–254, 2002. View at Publisher · View at Google Scholar · View at Scopus
  164. A. K. C. Wong, P. A. Ormonde, R. Pero et al., “Characterization of a carboxy-terminal BRCA1 interacting protein,” Oncogene, vol. 17, no. 18, pp. 2279–2285, 1998. View at Google Scholar · View at Scopus
  165. J. H. J. Hoeijmakers, “DNA damage, aging, and cancer,” New England Journal of Medicine, vol. 361, no. 15, pp. 1475–1485, 2009. View at Publisher · View at Google Scholar · View at Scopus
  166. T. Helleday, E. Petermann, C. Lundin, B. Hodgson, and R. A. Sharma, “DNA repair pathways as targets for cancer therapy,” Nature Reviews Cancer, vol. 8, no. 3, pp. 193–204, 2008. View at Publisher · View at Google Scholar · View at Scopus
  167. A. K. Gupta, V. J. Bakanauskas, G. J. Cerniglia et al., “The Ras radiation resistance pathway,” Cancer Research, vol. 61, no. 10, pp. 4278–4282, 2001. View at Google Scholar · View at Scopus
  168. T. M. Grana, E. V. Rusyn, H. Zhou, C. I. Sartor, and A. D. Cox, “Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways,” Cancer Research, vol. 62, no. 14, pp. 4142–4150, 2002. View at Google Scholar · View at Scopus
  169. E. Edwards, L. Geng, J. Tan, H. Onishko, E. Donnelly, and D. E. Hallahan, “Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation,” Cancer Research, vol. 62, no. 16, pp. 4671–4677, 2002. View at Google Scholar · View at Scopus
  170. A. R. Gottschalk, A. Doan, J. L. Nakamura, D. Stokoe, and D. A. Haas-Kogan, “Inhibition of phosphatidylinositol-3-kinase causes increased sensitivity to radiation through a PKB-dependent mechanism,” International Journal of Radiation Oncology Biology Physics, vol. 63, no. 4, pp. 1221–1227, 2005. View at Publisher · View at Google Scholar · View at Scopus
  171. A. K. Gupta, G. J. Cerniglia, R. Mick et al., “Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002,” International Journal of Radiation Oncology Biology Physics, vol. 56, no. 3, pp. 846–853, 2003. View at Publisher · View at Google Scholar · View at Scopus
  172. A. K. Gupta, W. G. McKenna, C. N. Weber et al., “Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction,” Clinical Cancer Research, vol. 8, no. 3, pp. 885–892, 2002. View at Google Scholar · View at Scopus
  173. I. A. Kim, S. S. Bae, A. Fernandes et al., “Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines,” Cancer Research, vol. 65, no. 17, pp. 7902–7910, 2005. View at Publisher · View at Google Scholar · View at Scopus
  174. C. M. Lee, C. B. Fuhrman, V. Planelles et al., “Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines,” Clinical Cancer Research, vol. 12, no. 1, pp. 250–256, 2006. View at Publisher · View at Google Scholar · View at Scopus
  175. B. Li, M. Yuan, I. A. Kim, C. M. Chang, E. J. Bernhard, and H. K. G. Shu, “Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin,” Oncogene, vol. 23, no. 26, pp. 4594–4602, 2004. View at Publisher · View at Google Scholar · View at Scopus
  176. A. S. Clark, K. West, S. Streicher, and P. A. Dennis, “Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells,” Molecular cancer therapeutics, vol. 1, no. 9, pp. 707–717, 2002. View at Google Scholar · View at Scopus
  177. J. J. Wallin, J. Guan, W. W. Prior et al., “Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer,” Science Translational Medicine, vol. 2, no. 48, Article ID 48ra66, 2010. View at Publisher · View at Google Scholar
  178. J. M. Tang, Q. Y. He, R. X. Guo, and X. J. Chang, “Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis,” Lung Cancer, vol. 51, no. 2, pp. 181–191, 2006. View at Publisher · View at Google Scholar · View at Scopus
  179. S. K. Pal, K. Reckamp, H. Yu, and R. A. Figlin, “Akt inhibitors in clinical development for the treatment of cancer,” Expert Opinion on Investigational Drugs, vol. 19, no. 11, pp. 1355–1366, 2010. View at Publisher · View at Google Scholar · View at Scopus
  180. J. LoPiccolo, C. A. Granville, J. J. Gills, and P. A. Dennis, “Targeting Akt in cancer therapy,” Anti-Cancer Drugs, vol. 18, no. 8, pp. 861–874, 2007. View at Publisher · View at Google Scholar · View at Scopus
  181. C. W. Lindsley, “The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update,” Current Topics in Medicinal Chemistry, vol. 10, no. 4, pp. 458–477, 2010. View at Publisher · View at Google Scholar · View at Scopus
  182. S. B. Kondapaka, S. S. Singh, G. P. Dasmahapatra, E. A. Sausville, and K. K. Roy, “Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation,” Molecular Cancer Therapeutics, vol. 2, no. 11, pp. 1093–1103, 2003. View at Google Scholar · View at Scopus
  183. L. van Ummersen, K. Binger, J. Volkman et al., “A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer,” Clinical Cancer Research, vol. 10, no. 22, pp. 7450–7456, 2004. View at Publisher · View at Google Scholar · View at Scopus
  184. N. Komai, Y. Morita, T. Sakuta, A. Kuwabara, and N. Kashihara, “Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis,” Modern Rheumatology, vol. 17, no. 5, pp. 385–390, 2007. View at Publisher · View at Google Scholar · View at Scopus
  185. S. F. Barnett, M. T. Bilodeau, and C. W. Lindsley, “The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation,” Current Topics in Medicinal Chemistry, vol. 5, no. 2, pp. 109–125, 2005. View at Publisher · View at Google Scholar · View at Scopus
  186. C. W. Lindsley, S. F. Barnett, M. Yaroschak, M. T. Bilodeau, and M. E. Layton, “Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors,” Current Topics in Medicinal Chemistry, vol. 7, no. 14, pp. 1349–1363, 2007. View at Publisher · View at Google Scholar · View at Scopus
  187. H. Hirai, H. Sootome, Y. Nakatsuru et al., “MK-2206, an allosteric akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo,” Molecular Cancer Therapeutics, vol. 9, no. 7, pp. 1956–1967, 2010. View at Publisher · View at Google Scholar · View at Scopus
  188. T. A. Yap et al., “First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 29, no. 35, pp. 4688–4695, 2011. View at Google Scholar
  189. B. Markman, R. Dienstmann, and J. Tabernero, “Targeting the PI3K/Akt/mTOR pathway—beyond rapalogs,” Oncotarget, vol. 1, no. 7, pp. 530–543, 2010. View at Google Scholar
  190. NCT00460278, “A Safety and Efficacy Study of RX-0201 Plus Gemcitabine in Metastatic Pancreatic Cancer,” US National Institute of Health, Bethesda, Md, USA, 2009, http://clinicaltrials.gov/ct2/show/NCT01028495.
  191. P. Wu and Y. Z. Hu, “PI3K/Akt/mTOR pathway inhibitors in cancer: a perspective on clinical progress,” Current Medicinal Chemistry, vol. 17, no. 35, pp. 4326–4341, 2010. View at Publisher · View at Google Scholar · View at Scopus