Novel Approaches for Chemosensitization of Breast Cancer Cells: The E1A Story

  • Yong Liao
  • Dihua Yu
  • Mien-Chie Hung
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 608)


The adenoviral E1A-mediated sensitization to a variety of anti-cancer drug-induced apoptosis is a well-established phenomenon on different types of cell systems. However, the mechanisms underlying E1A-mediated chemosensitization are still not fully understood. Recent studies demonstrate that E1A-mediated sensitization to drug-induced apoptosis can occur via multiple pathways; some of which depend on the expression of functional p53 and/or p19ARF proteins, while some are not. In human breast cancer cells with Her-2/neu overexpression, which usually are more resistance to anti-cancer drugs than cells without Her-2/neu overexpression, may be sensitized through E1A-mediated downregulation of Her-2/neu. Alternatively, E1A can induce sensitization to anticancer drugs in cancer cells or normal diploid fibroblast cells through upregulating the expression of caspase proenzymes, or downregulating the activity of a critical survival factor Akt and/or upregulating the activities of a pro-apoptotic kinase p38 and a protein phosphatase PP2A, etc. This review summarizes these progresses and proposes a plausible feed-forward model for E1A-mediated chemosensitization in human breast cancer cells.


Breast Cancer Cell Epithelial Growth Factor Receptor PP2A Activity Mouse Embryo Fibroblast Cell Increase PP2A Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    American Cancer Society. cancer statistics. Atlanta: 2005.Google Scholar
  2. 2.
    Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer 2002; 2:48–58.PubMedGoogle Scholar
  3. 3.
    Yan D, Shao RP, Hung MC. E1A cancer gene therapy. In: Lattime EC, Gerson SL, eds. Gene Therapy of Cancer. 2nd ed. San Diego: Academic Press, 2002:465–477.Google Scholar
  4. 4.
    Pozzatti R, McCormick M, Thompson MA et al. The E1a gene of adenovirus type 2 reduces the metastastic potential of ras-transformed rat embryo cells. Mol Cell Biol 1988; 8:2984–2988.PubMedGoogle Scholar
  5. 5.
    Steeg P, Bevilacqua G, Pozzatti R et al. Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 E1a inhibition of experimental metastasis. Cancer Res 1988; 48:6550–6554.PubMedGoogle Scholar
  6. 6.
    Pozzatti R, McCormick M, Thompson MA et al. Regulation of the metastatic phenotype by the E1A gene of adenovirus-2. Adv Exp Med 1988; 233:293–301.Google Scholar
  7. 7.
    Yu D, Suen TC, Yan DH et la. Transcriptional repression of the neu protooncogene by the adenovirus 5 E1A gene products. Proc Natl Acad Sci USA 1990; 87:4499–4503.PubMedGoogle Scholar
  8. 8.
    Yu DH, Scorsone K, Hung MC. Adenovirus type 5 E1A gene products act as transformation suppressors of the neu oncogene. Mol Cell Biol 1991; 11:1745–1750.PubMedGoogle Scholar
  9. 9.
    Yu D, Hamada J, Zhang H et al. Mechanisms of c-erbB2/neu oncogene-induced metastasis and repression of metastatic properties by adenovirus 5 E1A gene products. Oncogene 1992; 7:2263–2270.PubMedGoogle Scholar
  10. 10.
    Frisch SM, Reich R, Collier IE et al. Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 1990; 5:75–83.PubMedGoogle Scholar
  11. 11.
    Yan D, Rau KM, Hung MC. E1A and p202 as anti-metastasis genes. In: Curiel D, Douglas J, eds. Cancer Gene Therapy. 2nd ed. Totowa: Humana Press, 2004:87–98.Google Scholar
  12. 12.
    Frisch SM. Antioncogenic effect of adenovirus E1A in human tumor cells. Proc Natl Acad Sci USA 1991; 88:9077–9081.PubMedGoogle Scholar
  13. 13.
    Chinnadurai G. Adenovirus E1a as a tumor-suppressor gene. Oncogene 1992; 7:1255–1258.PubMedGoogle Scholar
  14. 14.
    Firsch SM. E1A—oncogene or tumor suppressor. Bioessays 1995; 17:1002.Google Scholar
  15. 15.
    Frisch SM. Reversal of malignancy by the adenovirus E1a gene. Mutat Res 1996; 350:261–266.PubMedGoogle Scholar
  16. 16.
    Frisch SM. The epithelial cell default-phenotype hypothesis and its implications for cancer. Bioessays 1997; 19:705–709.PubMedGoogle Scholar
  17. 17.
    Yu DH, Hung MC. The erbB2 gene as a cancer therapeutic target and the tumor-and metastasis-suppressing function of E1A. Cancer Metast Rev 1998; 17:195–202.Google Scholar
  18. 18.
    Frisch SM. Tumor suppression activity of adenovirus E1a protein: Anoikis and the epithelial phenotype. Adv Cancer Res 2001; 80:39–49.PubMedGoogle Scholar
  19. 19.
    Frisch SM, Mymuryk JS. Adenovirus-5 E1A: paradox and paradigm. Nat Rev Mol cell Biol 2002; 3:441–452.PubMedGoogle Scholar
  20. 20.
    Frisch SM. E1A as a tumor suppressor gene: Commentary re S. Madhusudan et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene. Clin Cancer Res 2004; 10:2905–2907.PubMedGoogle Scholar
  21. 21.
    Hortobagyi GN, Hung MC, Lopez-Berestein G. A Phase I multicenter study of E1A gene therapy for patients with metastatic breast cancer and epithelial ovarian cancer that overexpresses HER-2/neu or epithelial ovarian cancer. Hum Gene Ther 1998; 9:1775–1798.PubMedGoogle Scholar
  22. 22.
    Hung MC, Hortobagyi GN, Ueno NT. Development of clinical trial of E1A gene therapy targeting HER-2/neu-overexpressing breast and ovarian cancer. Adv Exp Med Biol 2000; 465.Google Scholar
  23. 23.
    Yoo GH, Hung MC, Lopez-Berestein G et al. Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent breast and head and neck cancer. Clin Cancer Res 2001; 7:1237–1245.PubMedGoogle Scholar
  24. 24.
    Hortobagyi GN, Ueno NT, Xia W et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: A phase I clinical trial. J Clin Oncol 2001; 19:3422–3433.PubMedGoogle Scholar
  25. 25.
    Benjamin R, Helman L, Meyers P et al. A phase I/II dose escalation and activity study of intravenous injections of OCaP1 for subjects with refractory osteosarcoma metastatic to lung. Hum Gene Ther 2001; 12:1591–1593.PubMedGoogle Scholar
  26. 26.
    Villaret D, Glisson B, Kenady D et al. A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma. Head Neck 2002; 24:661–669.PubMedGoogle Scholar
  27. 27.
    Madhusudan S, Tamir A, Bates N et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene. Clin Cancer Res 2004; 10:2986–2996.PubMedGoogle Scholar
  28. 28.
    Lowe SW, Ruley HE, Jacks T et al. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74:957–967.PubMedGoogle Scholar
  29. 29.
    Sanchez-Prieto R, Carnero A, Marchetti E et al. Modulation of cellular chemoresistance in keratinocytes by activation of different oncogenes. Int J Cancer 1995; 60:235–243.PubMedGoogle Scholar
  30. 30.
    Frisch SM, Dolter KE. Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. Cancer Res 1995; 55:5551–5555.PubMedGoogle Scholar
  31. 31.
    Sanchez-Prieto R, Lleonart M, Ramon Y et al. Lack of correlation between p53 protein level and sensitivity of NDA-damaging agents in keratinocytes carrying adenovirus E1a mutants. Oncogene 1995; 11:675–682.PubMedGoogle Scholar
  32. 32.
    Ueno N, Yu D, Hung MC. Chemosensitization of Her-2/neu-overexpressing human breast cancer cells to paclitaxel (Taxol) by adenovirus type 5 E1A. Oncogene 1997; 15:953–960.PubMedGoogle Scholar
  33. 33.
    Brader KR, Wolf JK, Hung MC et al. Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism. Clin Cancer Res 1997; 3:2017–2024.PubMedGoogle Scholar
  34. 34.
    Ueno NT, Bartholomeusz C, Herrmann JL et al. E1A-mediated paclitaxel sensitization in Her-2/neu-overexpressing ovarian cancer SKOV2.ip1 through apoptosis involving the caspase-3 pathway. Clin Cancer Res 2000; 6:250–259.PubMedGoogle Scholar
  35. 35.
    Zhou Z, Jia SF, Hung MC et al. E1A sensitizes HER2/neu-overexpressing Ewing’s sarcoma cells to topoisomerase II-targeting anticancer drugs. Cancer Res 2001; 61:3394–3398.PubMedGoogle Scholar
  36. 36.
    Viniegra JG, Losa JH, Sanchez-Arevalio VJ at al. Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin. Oncogene 2002; 21:7131–7136.PubMedGoogle Scholar
  37. 37.
    Liao Y, Hung MC. Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis. Mol Cell Biol 2003; 23:6836–6848.PubMedGoogle Scholar
  38. 38.
    Lee W, Tai DI, Tsai SL et al. Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine. Cancer Res 2003; 63:6229–6236.PubMedGoogle Scholar
  39. 39.
    Liao Y, Zou YY, Xia WY et al. Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral mediated systemic delivery of E1A gene in orthotopic xonograft human breast cancer. Cancer Gene Ther 2004; 11:594–602.PubMedGoogle Scholar
  40. 40.
    Lowe SW, Ruley HE. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes and Development 1993; 7:535–545.PubMedGoogle Scholar
  41. 41.
    White E. Regulation of p53-dependent apoptosis by E1A and E1B. Curr Top Microbiol Immunol 1995; 199:34–58.PubMedGoogle Scholar
  42. 42.
    Teodoro J, Shore GC, Branton PE. Adenovirus E1A proteins induce apoptosis by both p53-dependent and p53-independent mechanisms. Oncogene 1995; 11:467–474.PubMedGoogle Scholar
  43. 43.
    Attardi LD, Lowe SW, Brugarolas J et al. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. EMBO J 1996; 15:3693–3701.PubMedGoogle Scholar
  44. 44.
    de Stanchina E, McCurrach ME, Zindy F et al. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev 1998; 12:2434–2442.PubMedGoogle Scholar
  45. 45.
    Putzer BM, Stiewe T, Parssanedjad K et al. E1A is sufficient by itself to induce apoptosis independent of p53 and othe radenoviral gene products. Cell Death Differ 2000; 7:177–188.PubMedGoogle Scholar
  46. 46.
    Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999; 187:127–137.PubMedGoogle Scholar
  47. 47.
    Houghton JA. Apoptosis and drug response. Curr Opin Oncol 1999; 11:475–481.PubMedGoogle Scholar
  48. 48.
    Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999; 59:1391–1399.PubMedGoogle Scholar
  49. 49.
    Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000; 256:42–49.PubMedGoogle Scholar
  50. 50.
    Bamford M, Walkinshaw G, B rown R. Therapeutic applications of apoptosis research. Exp Cell Res 2000; 256:1–11.PubMedGoogle Scholar
  51. 51.
    Makin G, Dive C. Apoptosis and cancer chemotherapy. Trends Cell Biol 2001; 11:S22–S26.PubMedGoogle Scholar
  52. 52.
    Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: A link between cancer genetics and chemotherapy. Cell 2002; 108:153–164.PubMedGoogle Scholar
  53. 53.
    Reed JC. Mechanisms of apoptosis avoidance in cancer. Curr Opin Oncol 1999; 11:68–75.PubMedGoogle Scholar
  54. 54.
    Igney FI, Krammer PH. Death and anti-death: Tumor resistance to apoptosis. Nature Rev Cancer 2002; 2:277–288.Google Scholar
  55. 55.
    Cryns V, Yuan J. Proteases to die for. Genes Dev 1998; 12:1551–1570.PubMedGoogle Scholar
  56. 56.
    Earnshaw WC, martins LM, Kaufmann SH. Mammalian caspases: Structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999; 68:383–424.PubMedGoogle Scholar
  57. 57.
    Strasser A, O’Conner L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000; 69:217–245.PubMedGoogle Scholar
  58. 58.
    Deveraux QL, Reed JC. IAP family proteins—supressors of apoptosis. Genes Dev 1999; 13:239–252.PubMedGoogle Scholar
  59. 59.
    Goyal L. Cell death inhibition: Keeping caspases in check. Cell 2001; 104:805–808.PubMedGoogle Scholar
  60. 60.
    Salvesen GS, Duckett CS. IAP proteins: Blocking the road to death’s door. Nat Rev Mol Cell Biol 2002; 3:401–410.PubMedGoogle Scholar
  61. 61.
    Budihardjo I, Oliver H, Lutter M et al. Biochemical pathway of caspase activation during apoptosis. Annu Rev Cell Dev 1999; 15:269–290.Google Scholar
  62. 62.
    Adrain C, Martin SJ. The mitchondrial apoptosome: A killer unleashed by the cytochrome seas. Trends in Biochem Sci 2001; 26:390–397.Google Scholar
  63. 63.
    Danial NN, Korsmeyer SJ. Cell death: Critical control points. Cell 2004; 116:205–219.PubMedGoogle Scholar
  64. 64.
    Heiden MG, Thompson CB. Bcl-2 proteins: Regulators of apoptosis or of mitochondrial homeostasis? Nat Cell Biol 1999; 1:E209–E216.Google Scholar
  65. 65.
    Huang DCS, Strasser A. BH3-only proteins—essential initiators of apoptotic cell death. Cell 2000; 103:839–842.PubMedGoogle Scholar
  66. 66.
    Fesik SW. Insights into programmed cell death through structural biology. Cell 2000; 103:273–282.PubMedGoogle Scholar
  67. 67.
    Alaoui-Jamali MA, Paterson J, Al Moustafa AE et al. The role of ErbB2 tyrosine kinase receptor in cellular intrinsic chemoresistance: Mechanisms and implications. Biochem Cell Biol 1997; 75:315–325.PubMedGoogle Scholar
  68. 68.
    Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000; 19:6115–6121.PubMedGoogle Scholar
  69. 69.
    Yu D, Hung MC. Role of erbB2 in breast cancer chemosensitivity. Bioessays 2000; 22:673–680.PubMedGoogle Scholar
  70. 70.
    Weller M. Predicting response to cancer chemotherapy: The role of p53. Cell Tissue Res 1998; 292:435–445.PubMedGoogle Scholar
  71. 71.
    Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trands biology Sci 2002; 27:462–467.Google Scholar
  72. 72.
    Oren M, Damals A, Gottlieb T et al. Regulation of p53: Intricate loops and delicate balances. Biochem Pharm 2002; 64:865–871.PubMedGoogle Scholar
  73. 73.
    Fojo T, Bates S. Strategies for reversing drug resistance. Oncogene 2003; 22:7512–7523.PubMedGoogle Scholar
  74. 74.
    Sax JK, El-Deiry WS. p53 downstream targets and chemosensitivity. Cell Death Differ 2003; 10:413–417.PubMedGoogle Scholar
  75. 75.
    Haldar S, Basu A, Croce CM. Bcl-2 is the Gardian of Microtubule integrity. Cancer Res 1997; 57:229–233.PubMedGoogle Scholar
  76. 76.
    Krajewski S, Krajewska M, Turner BC et al. Prognostic significance of apoptosis regulators in breast cancer. Endocrine-Related Cancer 1999; 6:29–40.PubMedGoogle Scholar
  77. 77.
    Schorr K, Li M, Krajewski S et al. Bcl-2 gene family and related proteins in mammary gland involution and breast cancer. J Mammary Gland Biol Neoplasia 1999; 4:153–164.PubMedGoogle Scholar
  78. 78.
    Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends in Molecular Medicine 2001; 7:314–319.PubMedGoogle Scholar
  79. 79.
    Simstein R, Burow M, Parker A et al. Apoptosis, chemoresistance, and breast cancer: Insights from the MCF-7 cell model system. Exp Biol Med 2003; 228:995–1003.Google Scholar
  80. 80.
    Debatin K. Apoptosis pathways in cancer and cancer therapy. Cancer Immmunol Immunother 2004; 53:153–159.Google Scholar
  81. 81.
    Giai M, Biglia N, Sismondi P. Chemoresistance in breast tumors. Eur J Gynaecol Oncol 1991; 12:359–373.PubMedGoogle Scholar
  82. 82.
    Dicato M, Duhem C, Pauly M et al. Multidrug resistance: Molecular and clinical aspects. Cytokines Cell Mol Ther 1997; 3:91–99.PubMedGoogle Scholar
  83. 83.
    Ruvolo PP. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 2001; 15:1153–1160.PubMedGoogle Scholar
  84. 84.
    Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim biophys Acta 2004; 1697:3–16.PubMedGoogle Scholar
  85. 85.
    Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathways in human cancer: Rationale and promise. Cancer Cell 2003; 4:257–262.PubMedGoogle Scholar
  86. 86.
    Fresno Vara JA, Casado E, de Castro J et al. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30:193–204.PubMedGoogle Scholar
  87. 87.
    Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004; 15:177–182.PubMedGoogle Scholar
  88. 88.
    Zhou BP, Liao Y, Xia W et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001; 3:973–982.PubMedGoogle Scholar
  89. 89.
    Mayo L, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001; 98:11598–11603.PubMedGoogle Scholar
  90. 90.
    Zhou BP, Liao Y, Xia W et al. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 2001; 3:245–252.PubMedGoogle Scholar
  91. 91.
    Kim AH, Khursigara G, Sun X et al. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 2001; 21:893–901.PubMedGoogle Scholar
  92. 92.
    Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4:658–665.PubMedGoogle Scholar
  93. 93.
    Inoki K, Li Y, Zhu T et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648–657.PubMedGoogle Scholar
  94. 94.
    Clark AS, West K, Streicher S et al. Constitutive and inducible Akt activity promotes resistance to chemotherapy, Trastuzumab, or Tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1:707–717.PubMedGoogle Scholar
  95. 95.
    West KA, Castillo SS, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 2002; 5:234–248.PubMedGoogle Scholar
  96. 96.
    Hill MM, Hemmings BA. Inhibition of protein kinase B/Akt: Implications for cancer therapy. Pharmacol Ther 2002; 93:243–251.PubMedGoogle Scholar
  97. 97.
    Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 2003; 73:689–701.PubMedGoogle Scholar
  98. 98.
    Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway: Molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 2004; 4:235–256.PubMedGoogle Scholar
  99. 99.
    Piette J, Piret B, Bonizzi G et al. Multiple redox regulation in NF-kappaB transcription factor activation. Biol Chem 1997; 378:1237–1245.PubMedGoogle Scholar
  100. 100.
    Arlt A, Schafer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther 2002; 40:336–347.PubMedGoogle Scholar
  101. 101.
    Branton PE. Early gene expression. In: Seth P, ed. Adenoviruses: Basic biology to gene therapy. Georgetown, TX: R.G. Landes Company, 1999.Google Scholar
  102. 102.
    Fuchs M, Gerber J, Drapkin R et al. The p400 complex is an essential E1A transformation target. Cell 2001; 106:297–307.PubMedGoogle Scholar
  103. 103.
    Moran E, Mathews MB. Multiple functional domains in the adenovirus E1A gene. Cell 1987; 48:177–178.PubMedGoogle Scholar
  104. 104.
    Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes and Devel 2000; 14:1553–1577.Google Scholar
  105. 105.
    Chakravarti D, Ogryzko V, Kao HY et al. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Cell 1999; 96:393–403.PubMedGoogle Scholar
  106. 106.
    Zhang Q, Yao H, Vo N et al. Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP. Proc Natl Acad Sci USA 2000; 97:14323–14328.PubMedGoogle Scholar
  107. 107.
    Chinnadurai G. CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol Cell 2002; 9:213–224.PubMedGoogle Scholar
  108. 108.
    Flint J, Shenk T. Viral transactivating proteins. Annu Rev Genet 1997; 31:177–212.PubMedGoogle Scholar
  109. 109.
    Ginsberg D. E2F1 pathways to apoptosis. FEBS Lett 2002; 529:122–125.PubMedGoogle Scholar
  110. 110.
    Kaelin Jr WG. E2F1 as a target: Promoter-driven suicide and small molecule modulators. Cancer Biol Ther 2003; 2:S48–54.Google Scholar
  111. 111.
    Classon M, Harlow E. The retinoblastoma tumor suppressor in development and cancer. Nat Rev Cancer 2002; 2:910–917.PubMedGoogle Scholar
  112. 112.
    Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 1993; 7:546–554.PubMedGoogle Scholar
  113. 113.
    Chiou SK, Rao L, White E. Bcl-2 blocks p53-dependent apoptosis. Mol Cell Biol 1994; 14:2556–2563.PubMedGoogle Scholar
  114. 114.
    Pan H, Griep AE. Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development. Genes Dev 1995; 9:2157–2169.PubMedGoogle Scholar
  115. 115.
    Querido E, Teodoro JG, Branton PE. Accumulation of p53 induced by the adenovirus E1A protein requires regions involved in the stimulation of DNA synthesis. J Virol 1997; 71:3526–3533.PubMedGoogle Scholar
  116. 116.
    Ding HF, McGill G, Rowan S et al. Oncogene-dependent regulation of caspase activation by p53 protein in a cell-free system. J Biol Chem 1998; 273:28378–28383.PubMedGoogle Scholar
  117. 117.
    Lowe SW. Activation of p53 by oncogenes. Endocr Relat Cancer 1999; 6:45–48.PubMedGoogle Scholar
  118. 118.
    Breckenridge DG, Shore GC. Regulation of apoptosis by E1A and Myc oncoproteins. Crit Rev Eukary Gene Exp 2000; 10:273–280.Google Scholar
  119. 119.
    Pomerantz J, Schreiber-Agus N, Liegeois NJ et al. The Ink4a tumor suppressor gene product, p19ARF, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 1998; 92:713–723.PubMedGoogle Scholar
  120. 120.
    Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor supression pathways. Cell 1998; 92:725–734.PubMedGoogle Scholar
  121. 121.
    Chiou SK, White E. p300 binding by E1A cosegregates with p53 induction but is dispensable for apoptosis. J Virol 1997; 71:3515–3525.PubMedGoogle Scholar
  122. 122.
    Li Z, Day CP, Yang JY et al. Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53. Cancer Res 2004; 64:9080–9085.PubMedGoogle Scholar
  123. 123.
    McCurrach ME, Connor TMF, Knudson CM et al. Bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci USA 1997; 94:2345–2349.PubMedGoogle Scholar
  124. 124.
    Fearnhead H, Rodriguez J, Govek EE et al. Oncogene-dependent apoptosis is mediated by caspase-9. Proc natl Acad Sci USA 1998; 95:13664–13669.PubMedGoogle Scholar
  125. 125.
    Harbour JW, Dean DC. Rb function in cell-cycle regulation and apoptosis. Nat Cell Biol 2000; 2:E65–E67.PubMedGoogle Scholar
  126. 126.
    Harbour JW, Dean DC. The Rb/E2F pathway: Expanding roles and emerging paradigms. Genes and Devel 2000; 14:2393–2409.Google Scholar
  127. 127.
    Classon M, Salama S, Gorka C et al. Combinatorial roles for pRB, p107, and p130 in E2F-mediated cell cycle control. Proc Natl Acad Sci USA 2000; 97:10820–10825.PubMedGoogle Scholar
  128. 128.
    Nicholson S, Okby NT, Khan MA et al. Alterations of p14ARF, p53, and p73 genes involved in the E2F-1-mediated apoptotic pathways in nonsmall cell lung carcinoma. Cancer Res 2001; 61:5636–5643.PubMedGoogle Scholar
  129. 129.
    Phillips A, Vousden KH. E2F-1 induced apoptosis. Apoptosis 2001; 6:173–182.PubMedGoogle Scholar
  130. 130.
    Nahle Z, Polakoff J, Davuluri RV et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nature Cell Biology 2002; 4:859–864.PubMedGoogle Scholar
  131. 131.
    Irwin M, Marin MC, Phillips AC et al. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 2000; 407:645–648.PubMedGoogle Scholar
  132. 132.
    Furukawa Y, Nishimura N, Furukawa Y et al. Apaf-1 is a mediator of E2F-1-induced apoptosis. J Biol Chem 2002; 277:39760–39768.PubMedGoogle Scholar
  133. 133.
    Phillips A, Bates S, Ryan KM et al. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev 1997; 11:1853–1863.PubMedGoogle Scholar
  134. 134.
    Phillips A, Ernst MK, Bates S et al. E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways. Mol Cell 1999; 4:771–781.PubMedGoogle Scholar
  135. 135.
    Chattopadhyay D, Ghosh MK, Mal A et al. Inactivation of p21 by E1A leads to the induction of apoptosis in DNA-damaging cells. J Virol 2001; 75:9844–9856.PubMedGoogle Scholar
  136. 136.
    Yu D, Wolf JK, Scanlon M et al. Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res 1993; 53:891–898.PubMedGoogle Scholar
  137. 137.
    Zhang Y, Yu D, Xia W et al. HER-2/neu-targeting cancer therapy via adenovirus-mediated E1A delivery in an animal model. Oncogene 1995; 10:1947–1954.PubMedGoogle Scholar
  138. 138.
    Yu D, Matin A, Xia W et al. Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. Oncogene 1995; 11:1383–1388.PubMedGoogle Scholar
  139. 139.
    Hung MC, Matin A, Zhang Y et al. HER-2/neu-targeting gene therapy—a review. Gene Ther 1995; 159:65–71.Google Scholar
  140. 140.
    Chen H, Yu D, Chinnadurai G et al. Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu. Oncogene 1997; 14:1965–1971.PubMedGoogle Scholar
  141. 141.
    Chen H, Hung MC. Involvement of coactivator p300 in the transcriptional regulation of the HER-2/neu gene. J Biol Chem 1997; 272:6101–6104.PubMedGoogle Scholar
  142. 142.
    Yu D, Liu B, Tan M et al. Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms. Oncogene 1996; 13:1359–1365.PubMedGoogle Scholar
  143. 143.
    Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783–792.PubMedGoogle Scholar
  144. 144.
    Hayes DF, Thor AD. c-erbB-2 in breast cancer: Development of a clinically useful marker. Semin Oncol 2002; 29:231–245.PubMedGoogle Scholar
  145. 145.
    Ueno NT, Bartholomeusz C, Xia W et al. Systemic gene therapy in human xenograft tumor models by liposomal delivery of the E1A gene. Cancer Res 2002; 62:6712–6716.PubMedGoogle Scholar
  146. 146.
    Sabbatini AR, Basolo F, Valentini P et al. Induction of multidrug resistance (MDR) by transfection of MCF-10A cell line with c-Ha-ras and c-erbB-2 oncogenes. Int J Cancer 1994; 59:208–211.PubMedGoogle Scholar
  147. 147.
    Yu D, Liu B, Jing T et al. Overexpression of both p185c-erbB2 and p170mdr1 renders breast cancer cells highly resistant to taxol. Oncogene 1998; 16:2087–2094.PubMedGoogle Scholar
  148. 148.
    Lee WP, Liao Y, Robinson D et al. Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity. Mol Cell Biol 1999; 19:8075–8082.PubMedGoogle Scholar
  149. 149.
    Lee WP, Wen Y, Varnum B et al. Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis. Oncogene 2002; 21:329–336.PubMedGoogle Scholar
  150. 150.
    Deng J, Xia W, Hung MC. Adenovirus 5 E1A-mediated tumor suppression associated with E1A-mediated apoptosis in vivo. Oncogene 1998; 17.Google Scholar
  151. 151.
    Deng J, Kloosterbooer F, Xia W et al. The NH(2)-terminal and conserved region 2 domains of adenovirus E1A mediate two distinct mechanisms of tumor suppression. Cancer Res 2002; 62:346–350.PubMedGoogle Scholar
  152. 152.
    Liao Y, Hung MC. A new role of protein phosphatase 2A in adenoviral E1A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells. Cancer Res 2004; 64:5938–5942.PubMedGoogle Scholar
  153. 153.
    Meric F, Lee WP, Sahin A et al. Expression profile of tyrosine kinases in breast cancer. Clin Cancer Res 2002; 8:361–367.PubMedGoogle Scholar
  154. 154.
    Cross TG, Toellner DS, Henriquez NV et al. Serine/theonine protein kinases and apoptosis. Exp Cell Res 2000; 256:34–41.PubMedGoogle Scholar
  155. 155.
    Gratton JP, Kureishi Y, Fulton D et al. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol Chem 2001; 276:30359–30365.PubMedGoogle Scholar
  156. 156.
    Tobiume K, Matsuzawa A, Takahashi T et al. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001; 2:222–228.PubMedGoogle Scholar
  157. 157.
    Ichijo H, Nishida E, Irie K et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275:90–94.PubMedGoogle Scholar
  158. 158.
    Yuan ZQ, Feldman RI, Sussman GE et al. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: Implication of AKT2 in chemoresistance. J Biol Chem 2003; 278:23432–23440.PubMedGoogle Scholar
  159. 159.
    Brazil DP, Yang ZZ, Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 2004; 29:233–242.PubMedGoogle Scholar
  160. 160.
    Webster KA. Aktion in the nucleus. Circ Res 2004; 94:856–859.PubMedGoogle Scholar
  161. 161.
    Chang F, Lee JT, Navolanic PM et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 2003; 17:590–603.PubMedGoogle Scholar
  162. 162.
    Nicholson KM, Anderson NG. The protein kinase B/Akt signaling pathway in human malignancy. Cellular Signalling 2002; 14:381–395.PubMedGoogle Scholar
  163. 163.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2:489–501.PubMedGoogle Scholar
  164. 164.
    Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Genes Dev 1998; 12:2821–2830.PubMedGoogle Scholar
  165. 165.
    Madrid LV, Mayo MW, Reuther JY et al. Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-{kappa∼B through utilization of the I{kappa∼B kinase and activation of the mitogen activated protein kinase p38. J Biol Chem 2001; 20Google Scholar
  166. 166.
    Krueger A, Baumann S, Krammer PH et al. FLICE-inhibitory proteins: Regulators of death receptor-mediated apoptosis. Mol Cell Biol 2001; 21:8247–8254.PubMedGoogle Scholar
  167. 167.
    Shao R, Karunagaran D, Zhou BP et al. Inhibition of nuclear factor-kB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis. J Biol Chem 1997; 272:32739–32742.PubMedGoogle Scholar
  168. 168.
    Shao R, Hu MCT, Zhou BP et al. E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IkB kinases and nuclear factor kB activities. J Biol Chem 1999; 274:21495–21498.PubMedGoogle Scholar
  169. 169.
    Perez D, White E. E1A sensitizes cells to tumor necrosis factor alpha by downregulating c-FLIPs. J Virol 2003; 77:2651–2662.PubMedGoogle Scholar
  170. 170.
    Tanaka H, Matsumura I, Ezoe S et al. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 2002; 9:1017–1029.PubMedGoogle Scholar
  171. 171.
    Chen M, Capps C, Willerson JT et al. E2F-1 regulates nuclear factor-kappaB activity and cell adhesion: Potential antiinflammatory activity of the transcription factor E2F-1. Circulation 2002; 106:2707–2713.PubMedGoogle Scholar
  172. 172.
    Zhou BP, Hung MC. Novel targets of Akt, p21(Cipl/WAF1), and MDM2. Semin Oncol 2002; 29:62–70.PubMedGoogle Scholar
  173. 173.
    Duelli DM, Lazebnik YA. Primary cells suppress oncogene-dependent apoptosis. Nat Cell Biol 2000; 2:859–862.PubMedGoogle Scholar
  174. 174.
    Page C, Lin HJ, Jin Y et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res 2000; 20:407–416.PubMedGoogle Scholar
  175. 175.
    Hsu SC, Gavrilin MA, Tsai MH et al. p38 mitogen-activated protein kinase is involved in Fas ligand expression. J Biol Chem 1999; 274:25769–25776.PubMedGoogle Scholar
  176. 176.
    Van Laethem A, Van Kelst S, Lippens S et al. Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J 2004; 18:1946–1948.PubMedGoogle Scholar
  177. 177.
    Schmidt M, hovelmann S, Beckers TL. A novel form of constitutively active farnesylated Akt prevents mammary epithelial cells from anoikis and suppresses chemotherapy-induced apoptosis. Brit J Cancer 2002; 87:924–932.PubMedGoogle Scholar
  178. 178.
    Cardone MH, Salvesen GS, Widmann C et al. The regulation of Anoikis: MEKK-1 activation requires cleavage by caspases. Cell 1997; 90:315–323.PubMedGoogle Scholar
  179. 179.
    Metcalfe A, Streuli C. Epithelial apoptosis. BioEssays 1997; 19:711–720.PubMedGoogle Scholar
  180. 180.
    Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124:619–626.PubMedGoogle Scholar
  181. 181.
    Frisch SM. E1a induces the expression of epithelial characteristics. J Cell Biol 1994; 127:1085–1096.PubMedGoogle Scholar
  182. 182.
    Janes SM, Watt FM. Switch from alphavbeta5 to alphavbeta6 integrin expression prodects squanmous cell carcinomas from anoikis. J Cell Biol 2004; 166:419–431.PubMedGoogle Scholar
  183. 183.
    Lei QY, Wang LY, Dai ZY et al. The relationship between PTEN expression and anoikis in human lung carcinoma cell lines. Sheng Wu hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 2002; 34:463–468.Google Scholar
  184. 184.
    Lu Y, Lin YZ, LaPushin R et al. The PTEN/MMAC1/TEP tumor supressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 1999; 18:7034–7045.PubMedGoogle Scholar
  185. 185.
    Davies MA, Lu Y, Sano T et al. Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 1998; 58:5285–5290.PubMedGoogle Scholar
  186. 186.
    Nagata Y, Lan KH, Zhou X et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cance Cell 2004; 6:117–127.Google Scholar
  187. 187.
    Berra E, Diaz-Meco MT, Moscat J. The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J Biol Chem 1998; 273:10792–10797.PubMedGoogle Scholar
  188. 188.
    Schonthal AH. Role of PP2A in intracellular signal transduction pathways. Front Biosci 1998; 3:D1262–1273.PubMedGoogle Scholar
  189. 189.
    Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999; 96:4240–4245.PubMedGoogle Scholar
  190. 190.
    Millward TA, Zolnierowicz S, Hemmmings BA. Regulation of protien kinase cascades by protein phosphatase 2A. TIBS 1999; 24:186–191.PubMedGoogle Scholar
  191. 191.
    Sato S, Fujita N, Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA 2000; 97:10832–10837.PubMedGoogle Scholar
  192. 192.
    Virshup DM. Protein phosphatase 2A: A panoply of enzymes. Curr Opin Cell Biology 2000; 12:180–185.Google Scholar
  193. 193.
    Cristofano AD, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000.Google Scholar
  194. 194.
    Zolnierowicz S. Type 2A protein phosphatases, the complex regulator of numerous signaling pathways. Biochem Pharm 2000; 60:1225–1235.PubMedGoogle Scholar
  195. 195.
    Simpson L, Parsons R. PTEN: Life as a tumor suppressor. Exp Cell Res 2001; 264:29–41.PubMedGoogle Scholar
  196. 196.
    Janssens V, Goris J. Protein phosphatase 2A: A highly regulated family of serine/threonine phosphatases implicated in cell growth and signaling. Biochem J 2001; 353:417–439.PubMedGoogle Scholar
  197. 197.
    Schonthal AH. Role of serine/threonine protein phosphatase 2A in cancer. Cancer Lett 2001; 170:1–13.PubMedGoogle Scholar
  198. 198.
    Sontag E. Protein phosphatase 2A: The Trojan Horse of cellular signaling. Cell Signal 2001; 13:7–16.PubMedGoogle Scholar
  199. 199.
    Garcia A, Cayla X, Guergnon J et al. Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochemie 2003; 85:721–726.Google Scholar
  200. 200.
    Kowluru A, Metz SA. Ceramide-activated protein phosphatase-2A activity in insulin-secreting cells. FEBS Lett 1997; 418:179–182.PubMedGoogle Scholar
  201. 201.
    Paez J, Sellers WR. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res 2003; 115:145–167.PubMedGoogle Scholar
  202. 202.
    Barford D, Das AK, Egloff MP. The structure and mechanism of protein phosphatases: Insights into catalysis and regulation. Annu Rev Biophys Biomol Struct 1998; 27:133–164.PubMedGoogle Scholar
  203. 203.
    Gotz J, Probst A, Ehler E et al. Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Calpha. Proc Natl Acad Sci USA 1998; 95:12370–12375.PubMedGoogle Scholar
  204. 204.
    Mills JC, Lee VM, Pittman RN. Activation of a PP2A-like phosphatase and dephosphorylation of tau protein characterize onset of the execution phase of apoptosis. J Cell Sci 1998; 111:625–636.PubMedGoogle Scholar
  205. 205.
    Chiang CW, Harris G, Ellig C et al. Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 2001; 97:1289–1297.PubMedGoogle Scholar
  206. 206.
    Liu W, Akhand AA, Takeda K et al. Protein phosphatase 2A-linked and-unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal. Cell Death Differ 2003; 10:772–781.PubMedGoogle Scholar
  207. 207.
    Nakashima I, Liu W, Akhand AA et al. 4-hydroxynonenal triggers multistep signal transduction cascades for suppression of cellular functions. Mol Aspects Med 2003; 24:231–238.PubMedGoogle Scholar
  208. 208.
    Choi SH, Lyu SY, Park WB. Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res 2004; 27:68–76.PubMedGoogle Scholar
  209. 209.
    Ruvolo PP, Deng X, Ito T et al. Ceramide induces Bcl-2 dephosphorylation via a mechanism involving mitochondria PP2A. J Biol Chem 1999; 274:20296–20300.PubMedGoogle Scholar
  210. 210.
    Deng X, Ito T, Carr B et al. Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 1998; 273:34157–34163.PubMedGoogle Scholar
  211. 211.
    Westermarck J, Li SP, Kallunki T et al. p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2 A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression. Mol Cell Biol 2001; 21:2373–2383.PubMedGoogle Scholar
  212. 212.
    De Zutter GS, Davis RJ. Pro-apoptotic gene expression mediated by the p38 mitogen-activated protien kinase signal transduction pathway. Proc Natl Acad Sci USA 2001; 98:6168–6173.PubMedGoogle Scholar
  213. 213.
    Assefa Z, Vantieghem A, Garmyn M et al. p38 mitogen-activated protein kinase regulates a novel, caspase-independent pathway for the mitochondrial cytochrome c release in ultraviolet B radiation-induced apoptosis. J Biol Chem 2000; 275:21416–21421.PubMedGoogle Scholar
  214. 214.
    Kennedy SG, Kandel ES, Cross TK et al. Akt/protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 1999; 19:5800–5810.PubMedGoogle Scholar
  215. 215.
    Kops GJ, Burgering BM. Forkhead transcription factors: New insights into protein kinase B (c-akt) signaling. J Mol Med 1999; 77:656–665.PubMedGoogle Scholar
  216. 216.
    Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell 2002; 111:293–303.PubMedGoogle Scholar
  217. 217.
    Chen D, Fucini RV, Olson AL et al. Osmotic shock inhibits insulin signaling by maintaining Akt/protein kinase B in an inactive dephosphorylated state. Mol Cell Biol 1999; 19:4684–4694.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  1. 1.Department of Molecular and Cellular OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

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