Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Molecular signals in anti-apoptotic survival pathways

Abstract

Drug resistance, to date, has primarily been attributed to increased drug export or detoxification mechanisms. Despite correlations between drug export and drug resistance, it is increasingly apparent that such mechanisms cannot fully account for chemoresistance in neoplasia. It is now widely accepted that chemotherapeutic drugs kill tumour cells by inducing apoptosis, a genetically regulated cell death programme. Evidence is emerging that the exploitation of survival pathways, which may have contributed to disease development in the first instance, may also be important in the development of the chemoresistance. This review discusses the components of and associations between multiple signalling cascades and their possible contribution to the development of neoplasia and the chemoresistant phenotype.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ashkenazi A, Dixit VM . Death receptors: signaling and modulation Science 1998 281: 1305–1308

    CAS  PubMed  Google Scholar 

  2. O'Connor R . Survival factors and apoptosis. In: Scheper T (ed) Advances in Biochemical Engineering/Biotechnology vol. 62: Springer-Verlag: Heidelberg 1998 pp 137–166

    Google Scholar 

  3. Zaman GJ, Flens MJ, van Leusden MR, de Haas M, Mulder HS, Lankelma J, Pinedo HM, Scheper RJ, Baas F, Broxterman HJ, Borst P . The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump Proc Natl Acad Sci USA 1994 91: 8822–8826

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Gottesman MM, Pastan I . Biochemistry of multidrug resistance mediated by the multidrug transporter Annu Rev Biochem 1993 62: 385–427

    CAS  PubMed  Google Scholar 

  5. Higgins CF . ABC transporters: from microorganisms to man Annu Rev Cell Biol 1992 8: 67–113

    CAS  PubMed  Google Scholar 

  6. Zaman GJ, Lankelma J, van Tellingen O, Beijnen J, Dekker H, Paulusma C, Oude Elferink RP, Baas F, Borst P . Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein Proc Natl Acad Sci USA 1995 92: 7690–7694

    CAS  PubMed  PubMed Central  Google Scholar 

  7. McKenna SL, Padua RA . Multidrug resistance in leukaemia Br J Haematol 1997 96: 659–674

    CAS  PubMed  Google Scholar 

  8. McCormick F . Signal transduction. How receptors turn Ras on Nature 1993 363: 15–16

    CAS  PubMed  Google Scholar 

  9. Joneson T, Bar-Sagi D . Ras effectors and their role in mitogenesis and oncogenesis J Mol Med 1997 75: 587–593

    CAS  PubMed  Google Scholar 

  10. Downward J . Ras signalling and apoptosis Curr Opin Genet Dev 1998 8: 49–54

    CAS  PubMed  Google Scholar 

  11. Weijzen S, Velders MP, Kast WM . Modulation of the immune response and tumor growth by activated Ras Leukemia 1999 13: 502–513

    CAS  PubMed  Google Scholar 

  12. Quilliam LA, Huff SY, Rabun KM, Wei W, Park W, Broek D, Der CJ . Membrane-targeting potentiates guanine nucleotide exchange factor CDC25 and SOS1 activation of Ras transforming activity Proc Natl Acad Sci USA 1994 91: 8512–8516

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wittinghofer A, Scheffzek K, Ahmadian MR . The interaction of Ras with GTPase-activating proteins FEBS Lett 1997 410: 63–67

    CAS  PubMed  Google Scholar 

  14. Bos JL . Ras oncogenes in human cancer: a review Cancer Res 1989 49: 4682–4689

    CAS  PubMed  Google Scholar 

  15. Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler MW . Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors J Mol Med 1996 74: 35–42

    CAS  PubMed  Google Scholar 

  16. Castelli C, Sensi M, Lupetti R, Mortarini R, Panceri P, Anichini A, Parmiani G . Expression of interleukin 1 alpha, interleukin 6, and tumor necrosis factor alpha genes in human melanoma clones is associated with that of mutated N-RAS oncogene Cancer Res 1994 54: 4785–4790

    CAS  PubMed  Google Scholar 

  17. Demetri GD, Ernst TJ, Pratt ESd, Zenzie BW, Rheinwald JG, Griffin JD . Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes J Clin Invest 1990 86: 1261–1269

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Thorn J, Molloy P, Iland H . SSCP detection of N-ras promoter mutations in AML patients Exp Hematol 1995 23: 1098–1103

    CAS  PubMed  Google Scholar 

  19. Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON . Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene Cell 1995 82: 981–988

    CAS  PubMed  Google Scholar 

  20. Padua RA . Molecular genetics of leukaemia. In: Whittaker JA (ed) Leukaemia 2nd edn: Blackwell Scientific Publications: Oxford 1992 pp 123–150

    Google Scholar 

  21. Byrne JL, Marshall CJ . The molecular pathophysiology of myeloid leukaemias: Ras revisited Br J Haematol 1998 100: 256–264

    CAS  PubMed  Google Scholar 

  22. Price CM, Marshall CJ, Bashey A . Sequential acquisition of trisomy 8 and N-ras mutation in acute myeloid leukaemia demonstrated by analysis of isolated leukaemic colonies Br J Haematol 1994 88: 338–342

    CAS  PubMed  Google Scholar 

  23. Gougopoulou DM, Kiaris H, Ergazaki M, Anagnostopoulos NI, Grigoraki V, Spandidos DA . Mutations and expression of the ras family genes in leukemias Stem Cells 1996 14: 725–729

    CAS  PubMed  Google Scholar 

  24. Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O'Hagan R, Pantginis J, Zhou H, Horner JWN, Cordon-Cardo C, Yancopoulos GD, DePinho RA . Essential role for oncogenic Ras in tumour maintenance Nature 1999 400: 468–472

    CAS  PubMed  Google Scholar 

  25. Lee YY, Kim WS, Bang YJ, Jung CW, Park S, Yoon WJ, Cho KS, Kim IS, Jung TJ, Cho IY, Kim BK, Kim NK, Koeffler HP . Analysis of mutations of neurofibromatosis type 1 gene and N-ras gene in acute myelogenous leukemia Stem Cells 1995 13: 556–563

    CAS  PubMed  Google Scholar 

  26. Kinoshita T, Yokota T, Arai K, Miyajima A . Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells Oncogene 1995 10: 2207–2212

    CAS  PubMed  Google Scholar 

  27. Adams JM, Cory S . The Bcl-2 protein family: arbiters of cell survival Science 1998 281: 1322–1326

    CAS  PubMed  Google Scholar 

  28. Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud JP, Guyotat D . High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy Blood 1993 81: 3091–3096

    CAS  PubMed  Google Scholar 

  29. Delia D, Aiello A, Soligo D, Fontanella E, Melani C, Pezzella F, Pierotti MA, Della Porta G . bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells Blood 1992 79: 1291–1298

    CAS  PubMed  Google Scholar 

  30. Osarogiagbon UR, McGlave PB . Chronic myelogenous leukemia Curr Opin Hematol 1999 6: 241–246

    CAS  PubMed  Google Scholar 

  31. Sattler M, Salgia R . Activation of hematopoietic growth factor signal transduction pathways by the human oncogene BCR/ABL Cytokine Growth Factor Rev 1997 8: 63–79

    CAS  PubMed  Google Scholar 

  32. Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG . BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner Oncogene 1998 16: 335–348

    CAS  PubMed  Google Scholar 

  33. Ahuja H, Bar-Eli M, Arlin Z, Advani S, Allen SL, Goldman J, Snyder D, Foti A, Cline M . The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia J Clin Invest 1991 87: 2042–2047

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B . Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway EMBO J 1997 16: 6151–6161

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Oliff A . Farnesyltransferase inhibitors: targeting the molecular basis of cancer Biochim Biophys Acta 1999 1423: C19–30

    CAS  PubMed  Google Scholar 

  36. Cox AD, Der CJ . Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1997 1333: F51–71

    CAS  PubMed  Google Scholar 

  37. Beaupre DM, Kurzrock R . RAS inhibitors in hematologic cancers: biologic considerations and clinical applications Invest New Drugs 1999 17: 137–143

    CAS  PubMed  Google Scholar 

  38. Cochet O, Kenigsberg M, Delumeau I, Virone-Oddos A, Multon MC, Fridman WH, Schweighoffer F, Teillaud JL, Tocque B . Intracellular expression of an antibody fragment-neutralizing p21 ras promotes tumor regression Cancer Res 1998 58: 1170–1176

    CAS  PubMed  Google Scholar 

  39. Coffey MC, Strong JE, Forsyth PA, Lee PW . Reovirus therapy of tumors with activated Ras pathway Science 1998 282: 1332–1334

    CAS  PubMed  Google Scholar 

  40. Avruch J, Zhang XF, Kyriakis JM . Raf meets Ras: completing the framework of a signal transduction pathway Trends Biochem Sci 1994 19: 279–283

    CAS  PubMed  Google Scholar 

  41. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis Science 1995 270: 1326–1331

    CAS  PubMed  Google Scholar 

  42. O'Gorman DM, McKenna SL, McGahon AJ, Knox KA, Cotter TG . Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals Leukemia 2000 14: 602–611

    CAS  PubMed  Google Scholar 

  43. Cleveland JL, Troppmair J, Packham G, Askew DS, Lloyd P, Gonzalez-Garcia M, Nunez G, Ihle JN, Rapp UR . v-raf suppresses apoptosis and promotes growth of interleukin-3- dependent myeloid cells Oncogene 1994 9: 2217–2226

    CAS  PubMed  Google Scholar 

  44. Wang HG, Rapp UR, Reed JC . Bcl-2 targets the protein kinase Raf-1 to mitochondria Cell 1996 87: 629–638

    CAS  PubMed  Google Scholar 

  45. Zimmermann S, Moelling K . Phosphorylation and regulation of Raf by Akt (protein kinase B) Science 1999 286: 1741–1744

    CAS  PubMed  Google Scholar 

  46. Majewski M, Nieborowska-Skorska M, Salomoni P, Slupianek A, Reiss K, Trotta R, Calabretta B, Skorski T . Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt Cancer Res 1999 59: 2815–2819

    CAS  PubMed  Google Scholar 

  47. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR . Protein kinase C alpha activates RAF-1 by direct phosphorylation Nature 1993 364: 249–252

    CAS  PubMed  Google Scholar 

  48. Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN, Hay N . The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal Genes Dev 1997 11: 701–713

    CAS  PubMed  Google Scholar 

  49. Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway EMBO J 1997 16: 2783–2793

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kodaki T, Woscholski R, Hallberg B, Rodriguez-Viciana P, Downward J, Parker PJ . The activation of phosphatidylinositol 3-kinase by Ras Curr Biol 1994 4: 798–806

    CAS  PubMed  Google Scholar 

  51. Hu P, Margolis B, Skolnik EY, Lammers R, Ullrich A, Schlessinger J . Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors Mol Cell Biol 1992 12: 981–990

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Carpenter CL, Cantley LC . Phosphoinositide 3-kinase and the regulation of cell growth Biochim Biophys Acta 1996 1288: M11–6

    PubMed  Google Scholar 

  53. Downward J . Mechanisms and consequences of activation of protein kinase B/Akt Curr Opin Cell Biol 1998 10: 262–267

    CAS  PubMed  Google Scholar 

  54. Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR . Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha Biochem J 1998 331: 299–308

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Franke TF, Cantley LC . Apoptosis. A Bad kinase makes good Nature 1997 390: 116–117

    CAS  PubMed  Google Scholar 

  56. Scheid MP, Duronio V . Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation Proc Natl Acad Sci USA 1998 95: 7439–7444

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD, Korsmeyer SJ . Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A Mol Cell 1999 3: 413–422

    CAS  PubMed  Google Scholar 

  58. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC . Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD Science 1999 284: 339–343

    CAS  PubMed  Google Scholar 

  59. Plo I, Bettaieb A, Payrastre B, Mansat-De Mas V, Bordier C, Rousse A, Kowalski-Chauvel A, Laurent G, Lautier D . The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines FEBS Lett 1999 452: 150–154

    CAS  PubMed  Google Scholar 

  60. Maehama T, Dixon JE . PTEN: a tumour suppressor that functions as a phospholipid phosphatase Trends Cell Biol 1999 9: 125–128

    CAS  PubMed  Google Scholar 

  61. Kitada S, Krajewska M, Zhang X, Scudiero D, Zapata JM, Wang HG, Shabaik A, Tudor G, Krajewski S, Myers TG, Johnson GS, Sausville EA, Reed JC . Expression and location of pro-apoptotic Bcl-2 family protein BAD in normal human tissues and tumor cell lines Am J Pathol 1998 152: 51–61

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hinton HJ, Welham MJ . Cytokine-induced protein kinase B activation and bad phosphorylation do not correlate with cell survival of hemopoietic cells J Immunol 1999 162: 7002–7009

    CAS  PubMed  Google Scholar 

  63. Mercurio F, Manning AM . Multiple signals converging on NF-kappaB Curr Opin Cell Biol 1999 11: 226–232

    CAS  PubMed  Google Scholar 

  64. Foo SY, Nolan GP . NF-kappaB to the rescue: RELs, apoptosis and cellular transformation Trends Genet 1999 15: 229–235

    CAS  PubMed  Google Scholar 

  65. Ghosh S, May MJ, Kopp EB . NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses Annu Rev Immunol 1998 16: 225–260

    CAS  PubMed  Google Scholar 

  66. Romashkova JA, Makarov SS . NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling Nature 1999 401: 86–90

    CAS  PubMed  Google Scholar 

  67. Wang CY, Guttridge DC, Mayo MW, Baldwin AS Jr . NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis Mol Cell Biol 1999 19: 5923–5929

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G . NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes Proc Natl Acad Sci USA 1999 96: 9136–9141

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW . Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control Proc Natl Acad Sci USA 1997 94: 10057–10062

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . Suppression of TNF-alpha-induced apoptosis by NF-kappaB Science 1996 274: 787–789

    CAS  PubMed  Google Scholar 

  71. Wang CY, Mayo MW, Baldwin AS Jr . TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB Science 1996 274: 784–787

    Article  CAS  PubMed  Google Scholar 

  72. Grimm S, Bauer MK, Baeuerle PA, Schulze-Osthoff K . Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis J Cell Biol 1996 134: 13–23

    CAS  PubMed  Google Scholar 

  73. Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR . DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1 Mol Cell 1998 1: 543–551

    CAS  PubMed  Google Scholar 

  74. Hellin AC, Calmant P, Gielen J, Bours V, Merville MP . Nuclear factor–kappaB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug Oncogene 1998 16: 1187–1195

    CAS  PubMed  Google Scholar 

  75. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB . NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase Nature 1999 401: 82–85

    CAS  PubMed  Google Scholar 

  76. Cryns V, Yuan J . Proteases to die for Genes Dev 1998 12: 1551–1570

    CAS  PubMed  Google Scholar 

  77. Meinhardt G, Roth J, Totok G, Auner H, Emmerich B, Hass R . Signaling defect in the activation of caspase-3 and PKCdelta in human TUR leukemia cells is associated with resistance to apoptosis Exp Cell Res 1999 247: 534–542

    CAS  PubMed  Google Scholar 

  78. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC . The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases EMBO J 1997 16: 6914–6925

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE . Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer J Clin Invest 1997 100: 2952–2960

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Daniel PB, Walker WH, Habener JF . Cyclic AMP signaling and gene regulation Annu Rev Nutr 1998 18: 353–383

    CAS  PubMed  Google Scholar 

  81. Montminy M . Transcriptional regulation by cyclic AMP Annu Rev Biochem 1997 66: 807–822

    CAS  PubMed  Google Scholar 

  82. Goldman PS, Tran VK, Goodman RH . The multifunctional role of the co-activator CBP in transcriptional regulation Recent Prog Horm Res 1997 52: 103–119

    CAS  PubMed  Google Scholar 

  83. Du K, Montminy M . CREB is a regulatory target for the protein kinase Akt/PKB J Biol Chem 1998 273: 32377–32379

    CAS  PubMed  Google Scholar 

  84. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF . The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB Mol Cell Biol 1999 19: 6195–6206

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou P, Qian L, Kozopas KM, Craig RW . Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions Blood 1997 89: 630–643

    CAS  PubMed  Google Scholar 

  86. Chao JR, Wang JM, Lee SF, Peng HW, Lin YH, Chou CH, Li JC, Huang HM, Chou CK, Kuo ML, Yen JJ, Yang-Yen HF . mcl-1 is an immediate–early gene activated by the granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response Mol Cell Biol 1998 18: 4883–4898

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Paradis S, Ruvkun G . Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor Genes Dev 1998 12: 2488–2498

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Cell 1999 96: 857–868

    CAS  PubMed  Google Scholar 

  89. Tang ED, Nunez G, Barr FG, Guan KL . Negative regulation of the forkhead transcription factor FKHR by Akt J Biol Chem 1999 274: 16741–16746

    CAS  PubMed  Google Scholar 

  90. Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM . Direct control of the Forkhead transcription factor AFX by protein kinase B Nature 1999 398: 630–634

    CAS  PubMed  Google Scholar 

  91. Widmann C, Gibson S, Johnson GL . Caspase-dependent cleavage of signaling proteins during apoptosis. A turn-off mechanism for anti-apoptotic signals J Biol Chem 1998 273: 7141–7147

    CAS  PubMed  Google Scholar 

  92. Carmody RJ, Cotter TG . Molecular events and mechanisms of apoptosis Sepsis 1998 2: 9–19

    Google Scholar 

  93. Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM . Conversion of Bcl-2 to a Bax-like death effector by caspases Science 1997 278: 1966–1968

    CAS  PubMed  Google Scholar 

  94. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . Regulation of cell death protease caspase-9 by phosphorylation Science 1998 282: 1318–1321

    CAS  PubMed  Google Scholar 

  95. Fujita E, Kouroku Y, Miho Y, Tsukahara T, Ishiura S, Momoi T . Wortmannin enhances activation of CPP32 (Caspase-3) induced by TNF or anti-Fas Cell Death Differ 1998 5: 289–297

    CAS  PubMed  Google Scholar 

  96. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR . Glycogen synthase kinase-3: functions in oncogenesis and development Biochim Biophys Acta 1992 1114: 147–162

    CAS  PubMed  Google Scholar 

  97. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B Nature 1995 378: 785–789

    CAS  PubMed  Google Scholar 

  98. Fiol CJ, Williams JS, Chou CH, Wang QM, Roach PJ, Andrisani OM . A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression J Biol Chem 1994 269: 32187–32193

    CAS  PubMed  Google Scholar 

  99. Welsh GI, Proud CG . Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B Biochem J 1993 294: 625–629

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC . Regulation of endothelium-derived nitric oxide production by the protein kinase Akt Nature 1999 399: 597–601

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM . Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation Nature 1999 399: 601–605

    CAS  PubMed  Google Scholar 

  102. Kanashiro CA, Khalil RA . Signal transduction by protein kinase C in mammalian cells Clin Exp Pharmacol Physiol 1998 25: 974–985

    CAS  PubMed  Google Scholar 

  103. Toker A . Signaling through protein kinase C Front Biosci 1998 3: D1134–1147

    CAS  PubMed  Google Scholar 

  104. Blobe GC, Obeid LM, Hannun YA . Regulation of protein kinase C and role in cancer biology Cancer Metastasis Rev 1994 13: 411–431

    CAS  PubMed  Google Scholar 

  105. Blobe GC, Stribling S, Obeid LM, Hannun YA . Protein kinase C isoenzymes: regulation and function Cancer Surv 1996 27: 213–248

    CAS  PubMed  Google Scholar 

  106. Cornford P, Evans J, Dodson A, Parsons K, Woolfenden A, Neoptolemos J, Foster CS . Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer Am J Pathol 1999 154: 137–144

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Manni A, Buckwalter E, Etindi R, Kunselman S, Rossini A, Mauger D, Dabbs D, Demers L . Induction of a less aggressive breast cancer phenotype by protein kinase C-alpha and -beta overexpression Cell Growth Differ 1996 7: 1187–1198

    CAS  PubMed  Google Scholar 

  108. Choi PM, Tchou-Wong KM, Weinstein IB . Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression Mol Cell Biol 1990 10: 4650–4657

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cacace AM, Guadagno SN, Krauss RS, Fabbro D, Weinstein IB . The epsilon isoform of protein kinase C is an oncogene when overexpressed in rat fibroblasts Oncogene 1993 8: 2095–2104

    CAS  PubMed  Google Scholar 

  110. Housey GM, Johnson MD, Hsiao WL, O'Brian CA, Murphy JP, Kirschmeier P, Weinstein IB . Overproduction of protein kinase C causes disordered growth control in rat fibroblasts Cell 1988 52: 343–354

    CAS  PubMed  Google Scholar 

  111. Megidish T, Mazurek N . A mutant protein kinase C that can transform fibroblasts Nature 1989 342: 807–811

    CAS  PubMed  Google Scholar 

  112. Borner C, Filipuzzi I, Weinstein IB, Imber R . Failure of wild-type or a mutant form of protein kinase C-alpha to transform fibroblasts Nature 1991 353: 78–80

    CAS  PubMed  Google Scholar 

  113. Perletti GP, Folini M, Lin HC, Mischak H, Piccinini F, Tashjian A . Overexpression of protein kinase C epsilon is oncogenic in rat colonic epithelial cells Oncogene 1996 12: 847–854

    CAS  PubMed  Google Scholar 

  114. Perletti G, Tessitore L, Sesca E, Pani P, Dianzani MU, Piccinini F . Epsilon PKC acts like a marker of progressive malignancy in rat liver, but fails to enhance tumorigenesis in rat hepatoma cells in culture Biochem Biophys Res Commun 1996 221: 688–691

    CAS  PubMed  Google Scholar 

  115. Wang XY, Repasky E, Liu HT . Antisense inhibition of protein kinase C alpha reverses the transformed phenotype in human lung carcinoma cells Exp Cell Res 1999 250: 253–263

    CAS  PubMed  Google Scholar 

  116. Fine RL, Chambers TC, Sachs CW . P-glycoprotein, multidrug resistance and protein kinase C Stem Cells 1996 14: 47–55

    CAS  PubMed  Google Scholar 

  117. Blobe GC, Sachs CW, Khan WA, Fabbro D, Stabel S, Wetsel WC, Obeid LM, Fine RL, Hannun YA . Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha J Biol Chem 1993 268: 658–664

    CAS  PubMed  Google Scholar 

  118. Beck J, Handgretinger R, Klingebiel T, Dopfer R, Schaich M, Ehninger G, Niethammer D, Gekeler V . Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML Leukemia 1996 10: 426–433

    CAS  PubMed  Google Scholar 

  119. Wang S, Vrana JA, Bartimole TM, Freemerman AJ, Jarvis WD, Kramer LB, Krystal G, Dent P, Grant S . Agents that down-regulate or inhibit protein kinase C circumvent resistance to 1-beta-D-arabinofuranosylcytosine-induced apoptosis in human leukemia cells that overexpress Bcl-2 Mol Pharmacol 1997 52: 1000–1009

    CAS  PubMed  Google Scholar 

  120. Murata M, Nagai M, Fujita M, Ohmori M, Takahara J . Calphostin C synergistically induces apoptosis with VP-16 in lymphoma cells which express abundant phosphorylated Bcl-2 protein Cell Mol Life Sci 1997 53: 737–743

    CAS  PubMed  Google Scholar 

  121. Ruvolo PP, Deng X, Carr BK, May WS . A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis J Biol Chem 1998 273: 25436–25442

    CAS  PubMed  Google Scholar 

  122. Ito T, Deng X, Carr B, May WS . Bcl-2 phosphorylation required for anti-apoptosis function J Biol Chem 1997 272: 11671–11673

    CAS  PubMed  Google Scholar 

  123. Gubina E, Rinaudo MS, Szallasi Z, Blumberg PM, Mufson RA . Overexpression of protein kinase C isoform epsilon but not delta in human interleukin-3-dependent cells suppresses apoptosis and induces bcl-2 expression Blood 1998 91: 823–829

    CAS  PubMed  Google Scholar 

  124. Perletti GP, Concari P, Brusaferri S, Marras E, Piccinini F, Tashjian AH Jr . Protein kinase Cepsilon is oncogenic in colon epithelial cells by interaction with the ras signal transduction pathway Oncogene 1998 16: 3345–3348

    CAS  PubMed  Google Scholar 

  125. Chen CY, Faller DV . Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2 Oncogene 1995 11: 1487–1498

    CAS  PubMed  Google Scholar 

  126. Tan Y, Ruan H, Demeter MR, Comb MJ . p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway J Biol Chem 1999 274: 34859–34867

    CAS  PubMed  Google Scholar 

  127. Jamieson L, Carpenter L, Biden TJ, Fields AP . Protein kinase Ciota activity is necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis J Biol Chem 1999 274: 3927–3930

    CAS  PubMed  Google Scholar 

  128. Copeland KF, Haaksma AG, Goudsmit J, Krammer PH, Heeney JL . Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax AIDS Res Hum Retroviruses 1994 10: 1259–1268

    CAS  PubMed  Google Scholar 

  129. Lozano J, Berra E, Municio MM, Diaz-Meco MT, Dominguez I, Sanz L, Moscat J . Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase J Biol Chem 1994 269: 19200–19202

    CAS  PubMed  Google Scholar 

  130. Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ . Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1 Science 1998 281: 2042–2045

    CAS  PubMed  Google Scholar 

  131. Tibbles LA, Woodgett JR . The stress-activated protein kinase pathways Cell Mol Life Sci 1999 55: 1230–1254

    CAS  PubMed  Google Scholar 

  132. Karin M, Liu Z, Zandi E . AP-1 function and regulation Curr Opin Cell Biol 1997 9: 240–246

    CAS  PubMed  Google Scholar 

  133. Gille H, Strahl T, Shaw PE . Activation of ternary complex factor Elk-1 by stress-activated protein kinases Curr Biol 1995 5: 1191–1200

    CAS  PubMed  Google Scholar 

  134. Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE . ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation EMBO J 1995 14: 951–962

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Ham J, Babij C, Whitfield J, Pfarr CM, Lallemand D, Yaniv M, Rubin LL . A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death Neuron 1995 14: 927–939

    CAS  PubMed  Google Scholar 

  136. Colotta F, Polentarutti N, Sironi M, Mantovani A . Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines J Biol Chem 1992 267: 18278–18283

    CAS  PubMed  Google Scholar 

  137. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ . Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway Science 2000 288: 870–874

    CAS  PubMed  Google Scholar 

  138. Roffler-Tarlov S, Brown JJ, Tarlov E, Stolarov J, Chapman DL, Alexiou M, Papaioannou VE . Programmed cell death in the absence of c-Fos and c-Jun Development 1996 122: 1–9

    CAS  PubMed  Google Scholar 

  139. Nishina H, Fischer KD, Radvanyi L, Shahinian A, Hakem R, Rubie EA, Bernstein A, Mak TW, Woodgett JR, Penninger JM . Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3 Nature 1997 385: 350–353

    CAS  PubMed  Google Scholar 

  140. Faris M, Kokot N, Latinis K, Kasibhatla S, Green DR, Koretzky GA, Nel A . The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression J Immunol 1998 160: 134–144

    CAS  PubMed  Google Scholar 

  141. Le-Niculescu H, Bonfoco E, Kasuya Y, Claret FX, Green DR, Karin M . Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death Mol Cell Biol 1999 19: 751–763

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Abreu-Martin MT, Palladino AA, Faris M, Carramanzana NM, Nel AE, Targan SR . Fas activates the JNK pathway in human colonic epithelial cells: lack of a direct role in apoptosis Am J Physiol 1999 276: G599–G605

    CAS  PubMed  Google Scholar 

  143. Low W, Smith A, Ashworth A, Collins M . JNK activation is not required for Fas-mediated apoptosis Oncogene 1999 18: 3737–3741

    CAS  PubMed  Google Scholar 

  144. Lenczowski JM, Dominguez L, Eder AM, King LB, Zacharchuk CM, Ashwell JD . Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis Mol Cell Biol 1997 17: 170–181

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Iordanov MS, Magun BE . Different mechanisms of c-Jun NH(2)-terminal kinase-1 (JNK1) activation by ultraviolet-B radiation and by oxidative stressors J Biol Chem 1999 274: 25801–25806

    CAS  PubMed  Google Scholar 

  146. Terada K, Kaziro Y, Satoh T . Ras-dependent activation of c-jun N-terminal kinase/stress activated protein kinase in response to interleukin-3 stimulation in hematopoietic BaF3 cells J Biol Chem 1997 272: 4544–4548

    CAS  PubMed  Google Scholar 

  147. Johnson R, Spiegelman B, Hanahan D, Wisdom R . Cellular transformation and malignancy induced by ras require c-jun Mol Cell Biol 1996 16: 4504–4511

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Raitano AB, Halpern JR, Hambuch TM, Sawyers CL . The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation Proc Natl Acad Sci USA 1995 92: 11746–11750

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Zanke BW, Boudreau K, Rubie E, Winnett E, Tibbles LA, Zon L, Kyriakis J, Liu FF, Woodgett JR . The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat Curr Biol 1996 6: 606–613

    CAS  PubMed  Google Scholar 

  150. Seimiya H, Mashima T, Toho M, Tsuruo T . c-Jun NH2-terminal kinase-mediated activation of interleukin-1beta converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis J Biol Chem 1997 272: 4631–4636

    CAS  PubMed  Google Scholar 

  151. Birkenkamp KU, Dokter WH, Esselink MT, Jonk LJ, Kruijer W, Vellenga E . A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation Leukemia 1999 13: 1037–1045

    CAS  PubMed  Google Scholar 

  152. Okumura K, Shirasawa S, Nishioka M, Sasazuki T . Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-Jun NH2-terminal kinase pathway in human colon cancer cells Cancer Res 1999 59: 2445–2450

    CAS  PubMed  Google Scholar 

  153. Tsujimoto Y, Cossman J, Jaffe E, Croce CM . Involvement of the bcl-2 gene in human follicular lymphoma Science 1985 228: 1440–1443

    CAS  PubMed  Google Scholar 

  154. Miyashita T, Reed JC . bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs Cancer Res 1992 52: 5407–5411

    CAS  PubMed  Google Scholar 

  155. Miyashita T, Reed JC . Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line Blood 1993 81: 151–157

    CAS  PubMed  Google Scholar 

  156. Bissonnette RP, Echeverri F, Mahboubi A, Green DR . Apoptotic cell death induced by c-myc is inhibited by bcl-2 Nature 1992 359: 552–554

    CAS  PubMed  Google Scholar 

  157. Jaattela M, Benedict M, Tewari M, Shayman JA, Dixit VM . Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells Oncogene 1995 10: 2297–2305

    CAS  PubMed  Google Scholar 

  158. Robertson JD, Datta K, Kehrer JP . Bcl-xL overexpression restricts heat-induced apoptosis and influences hsp70, bcl-2, and Bax protein levels in FL5.12 cells Biochem Biophys Res Commun 1997 241: 164–168

    CAS  PubMed  Google Scholar 

  159. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME . Two CD95 (APO-1/Fas) signaling pathways EMBO J 1998 17: 1675–1687

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Minn AJ, Rudin CM, Boise LH, Thompson CB . Expression of bcl-xL can confer a multidrug resistance phenotype Blood 1995 86: 1903–1910

    CAS  PubMed  Google Scholar 

  161. Chao DT, Korsmeyer SJ . BCL-2 family: regulators of cell death Annu Rev Immunol 1998 16: 395–419

    CAS  PubMed  Google Scholar 

  162. Reed J . Bcl-2 family proteins Oncogene 1998 17: 3225–3236

    PubMed  Google Scholar 

  163. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB . bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death Cell 1993 74: 597–608

    CAS  PubMed  Google Scholar 

  164. Reed JC . Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance Curr Opin Oncol 1995 7: 541–546

    CAS  PubMed  Google Scholar 

  165. Hermine O, Haioun C, Lepage E, d'Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P . Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA) Blood 1996 87: 265–272

    CAS  PubMed  Google Scholar 

  166. Maung ZT, MacLean FR, Reid MM, Pearson AD, Proctor SJ, Hamilton PJ, Hall AG . The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia Br J Haematol 1994 88: 105–109

    CAS  PubMed  Google Scholar 

  167. Gasparini G, Barbareschi M, Doglioni C, Palma PD, Mauri FA, Boracchi P, Bevilacqua P, Caffo O, Morelli L, Verderio P, Pezzella F, Harris AL . Expression of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer Clin Cancer Res 1995 1: 189–198

    CAS  PubMed  Google Scholar 

  168. Bensi L, Longo R, Vecchi A, Messora C, Garagnani L, Bernardi S, Tamassia MG, Sacchi S . Bcl-2 oncoprotein expression in acute myeloid leukemia Haematologica 1995 80: 98–102

    CAS  PubMed  Google Scholar 

  169. Russell NH, Hunter AE, Bradbury D, Zhu YM, Keith F . Biological features of leukaemic cells associated with autonomous growth and reduced survival in acute myeloblastic leukaemia Leuk Lymphoma 1995 16: 223–229

    CAS  PubMed  Google Scholar 

  170. Karakas T, Maurer U, Weidmann E, Miething CC, Hoelzer D, Bergmann L . High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia Ann Oncol 1998 9: 159–165

    CAS  PubMed  Google Scholar 

  171. Hellemans P, van Dam PA, Weyler J, van Oosterom AT, Buytaert P, Van Marck E . Prognostic value of bcl-2 expression in invasive breast cancer Br J Cancer 1995 72: 354–360

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Joensuu H, Pylkkanen L, Toikkanen S . Bcl-2 protein expression and long-term survival in breast cancer Am J Pathol 1994 145: 1191–1198

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Furuya Y, Krajewski S, Epstein JI, Reed JC, Isaacs JT . Expression of bcl-2 and the progression of human and rodent prostatic cancers Clin Cancer Res 1996 2: 389–398

    CAS  PubMed  Google Scholar 

  174. Campos L, Sabido O, Rouault JP, Guyotat D . Effects of BCL-2 antisense oligodeoxynucleotides on in vitro proliferation and survival of normal marrow progenitors and leukemic cells Blood 1994 84: 595–600

    CAS  PubMed  Google Scholar 

  175. Kitada S, Takayama S, De Riel K, Tanaka S, Reed JC . Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression Antisense Res Dev 1994 4: 71–79

    CAS  PubMed  Google Scholar 

  176. Bargou RC, Wagener C, Bommert K, Mapara MY, Daniel PT, Arnold W, Dietel M, Guski H, Feller A, Royer HD, Dorken B . Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice J Clin Invest 1996 97: 2651–2659

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Sumantran VN, Ealovega MW, Nunez G, Clarke MF, Wicha MS . Overexpression of Bcl-XS sensitizes MCF-7 cells to chemotherapy-induced apoptosis Cancer Res 1995 55: 2507–2510

    CAS  PubMed  Google Scholar 

  178. Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, Nordling S, Reed JC . Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma Cancer Res 1995 55: 4471–4478

    CAS  PubMed  Google Scholar 

  179. Deng G, Lane C, Kornblau S, Goodacre A, Snell V, Andreeff M, Deisseroth AB . Ratio of bcl-xshort to bcl-xlong is different in good- and poor-prognosis subsets of acute myeloid leukemia Mol Med 1998 4: 158–164

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Oltvai ZN, Milliman CL, Korsmeyer SJ . Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death Cell 1993 74: 609–619

    CAS  PubMed  Google Scholar 

  181. Hsu YT, Youle RJ . Nonionic detergents induce dimerization among members of the Bcl-2 family J Biol Chem 1997 272: 13829–13834

    CAS  PubMed  Google Scholar 

  182. Otter I, Conus S, Ravn U, Rager M, Olivier R, Monney L, Fabbro D, Borner C . The binding properties and biological activities of Bcl-2 and Bax in cells exposed to apoptotic stimuli J Biol Chem 1998 273: 6110–6120

    CAS  PubMed  Google Scholar 

  183. Holmgreen SP, Huang DC, Adams JM, Cory S . Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members Cell Death Differ 1999 6: 525–532

    CAS  PubMed  Google Scholar 

  184. Minn AJ, Kettlun CS, Liang H, Kelekar A, Vander Heiden MG, Chang BS, Fesik SW, Fill M, Thompson CB . Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms EMBO J 1999 18: 632–643

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Minshall C, Arkins S, Straza J, Conners J, Dantzer R, Freund GG, Kelley KW . IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors J Immunol 1997 159: 1225–1232

    CAS  PubMed  Google Scholar 

  186. Hu Y, Benedict MA, Wu D, Inohara N, Nunez G . Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation Proc Natl Acad Sci USA 1998 95: 4386–4391

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Moriishi K, Huang DC, Cory S, Adams JM . Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1 Proc Natl Acad Sci USA 1999 96: 9683–9688

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, Kroemer G . Mitochondrial control of nuclear apoptosis J Exp Med 1996 183: 1533–1544

    CAS  PubMed  Google Scholar 

  189. Kroemer G, Zamzami N, Susin SA . Mitochondrial control of apoptosis Immunol Today 1997 18: 44–51

    CAS  PubMed  Google Scholar 

  190. Keith FJ, Russell NH . The role of p53 in malignancy Cancer Treat Res 1996 84: 113–137

    CAS  PubMed  Google Scholar 

  191. Kastan MB, Canman CE, Leonard CJ . P53, cell cycle control and apoptosis: implications for cancer Cancer Metastasis Rev 1995 14: 3–15

    CAS  PubMed  Google Scholar 

  192. Soddu S, Sacchi A . P53 role in DNA repair and tumorigenesis J Exp Clin Cancer Res 1997 16: 237–242

    CAS  PubMed  Google Scholar 

  193. Canman CE, Gilmer TM, Coutts SB, Kastan MB . Growth factor modulation of p53-mediated growth arrest versus apoptosis Genes Dev 1995 9: 600–611

    CAS  PubMed  Google Scholar 

  194. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC . Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo Oncogene 1994 9: 1799–1805

    CAS  PubMed  Google Scholar 

  195. Krammer PH . CD95(APO-1/Fas)-mediated apoptosis: live and let die Adv Immunol 1999 71: 163–210

    CAS  PubMed  Google Scholar 

  196. Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME . Differential modulation of apoptosis sensitivity in CD95 type I and type II cells J Biol Chem 1999 274: 22532–22538

    CAS  PubMed  Google Scholar 

  197. Friesen C, Herr I, Krammer PH, Debatin KM . Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells Nature Med 1996 2: 574–577

    CAS  PubMed  Google Scholar 

  198. Muller M, Strand S, Hug H, Heinemann EM, Walczak H, Hofmann WJ, Stremmel W, Krammer PH, Galle PR . Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO- 1/Fas) receptor/ligand system and involves activation of wild-type p53 J Clin Invest 1997 99: 403–413

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM . The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells Cancer Res 1997 57: 3823–3829

    CAS  PubMed  Google Scholar 

  200. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT . Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity J Natl Cancer Inst 1997 89: 783–789

    CAS  PubMed  Google Scholar 

  201. Posovszky C, Friesen C, Herr I, Debatin KM . Chemotherapeutic drugs sensitize pre-B ALL cells for CD95- and cytotoxic T-lymphocyte-mediated apoptosis Leukemia 1999 13: 400–409

    CAS  PubMed  Google Scholar 

  202. Costa-Pereira AP, McKenna SL, Cotter TG . Activation of SAPK/JNK by camptothecin sensitises androgen-independent prostate cancer cells to Fas-induced apoptosis Br J Cancer 2000 82: 1827–1834

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Villunger A, Egle A, Marschitz I, Kos M, Bock G, Ludwig H, Geley S, Kofler R, Greil R . Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance Blood 1997 90: 12–20

    CAS  PubMed  Google Scholar 

  204. Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, Mariani SM, Stremmel W, Krammer PH, Galle PR . Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells – a mechanism of immune evasion? Nature Med 1996 2: 1361–1366

    CAS  PubMed  Google Scholar 

  205. McGahon AJ, Costa Pereira AP, Daly L, Cotter TG . Chemotherapeutic drug-induced apoptosis in human leukaemic cells is independent of the Fas (APO-1/CD95) receptor/ligand system Br J Haematol 1998 101: 539–547

    CAS  PubMed  Google Scholar 

  206. Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ, Kaufmann SH . Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions Blood 1997 90: 935–943

    CAS  PubMed  Google Scholar 

  207. Villunger A, Egle A, Kos M, Hartmann BL, Geley S, Kofler R, Greil R . Drug-induced apoptosis is associated with enhanced Fas (Apo-1/CD95) ligand expression but occurs independently of Fas (Apo-1/CD95) signaling in human T-acute lymphatic leukemia cells Cancer Res 1997 57: 3331–3334

    CAS  PubMed  Google Scholar 

  208. Munker R, Lubbert M, Yonehara S, Tuchnitz A, Mertelsmann R, Wilmanns W . Expression of the Fas antigen on primary human leukemia cells Ann Hematol 1995 70: 15–17

    CAS  PubMed  Google Scholar 

  209. Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT . Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs J Biol Chem 1999 274: 7987–7992

    CAS  PubMed  Google Scholar 

  210. Hata H, Matsuzaki H, Takeya M, Yoshida M, Sonoki T, Nagasaki A, Kuribayashi N, Kawano F, Takatsuki K . Expression of Fas/Apo-1 (CD95) and apoptosis in tumor cells from patients with plasma cell disorders Blood 1995 86: 1939–1945

    CAS  PubMed  Google Scholar 

  211. Roth W, Fontana A, Trepel M, Reed JC, Dichgans J, Weller M . Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics Cancer Immunol Immunother 1997 44: 55–63

    CAS  PubMed  Google Scholar 

  212. Nakamura S, Takeshima M, Nakamura Y, Ohtake S, Matsuda T . Induction of apoptosis in HL60 leukemic cells by anticancer drugs in combination with anti-Fas monoclonal antibody Anticancer Res 1997 17: 173–179

    CAS  PubMed  Google Scholar 

  213. Mizutani Y, Okada Y, Yoshida O, Fukumoto M, Bonavida B . Doxorubicin sensitizes human bladder carcinoma cells to Fas-mediated cytotoxicity Cancer 1997 79: 1180–1189

    CAS  PubMed  Google Scholar 

  214. Peli J, Schroter M, Rudaz C, Hahne M, Meyer C, Reichmann E, Tschopp J . Oncogenic Ras inhibits Fas ligand-mediated apoptosis by downregulating the expression of Fas EMBO J 1999 18: 1824–1831

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Fenton RG, Hixon JA, Wright PW, Brooks AD, Sayers TJ . Inhibition of Fas (CD95) expression and Fas-mediated apoptosis by oncogenic Ras Cancer Res 1998 58: 3391–3400

    CAS  PubMed  Google Scholar 

  216. Hausler P, Papoff G, Eramo A, Reif K, Cantrell DA, Ruberti G . Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B Eur J Immunol 1998 28: 57–69

    CAS  PubMed  Google Scholar 

  217. Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M . PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis Oncogene 1999 18: 3936–3943

    CAS  PubMed  Google Scholar 

  218. Drew L, Kumar R, Bandyopadhyay D, Gupta S . Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells Int Immunol 1998 10: 877–889

    CAS  PubMed  Google Scholar 

  219. Lotem J, Sachs L . Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells Blood 1992 80: 1750–1757

    CAS  PubMed  Google Scholar 

  220. Kasimir-Bauer S, Ottinger H, Meusers P, Beelen DW, Brittinger G, Seeber S, Scheulen ME . In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy Exp Hematol 1998 26: 1111–1117

    CAS  PubMed  Google Scholar 

  221. Izquierdo MA, Shoemaker RH, Flens MJ, Scheffer GL, Wu L, Prather TR, Scheper RJ . Overlapping phenotypes of multidrug resistance among panels of human cancer-cell lines Int J Cancer 1996 65: 230–237

    CAS  PubMed  Google Scholar 

  222. Fanidi A, Harrington EA, Evan GI . Cooperative interaction between c-myc and bcl-2 proto-oncogenes Nature 1992 359: 554–556

    CAS  PubMed  Google Scholar 

  223. Barbacid M . ras genes Annu Rev Biochem 1987 56: 779–827

    CAS  PubMed  Google Scholar 

  224. Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG, Druker BJ . CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins Blood 1997 90: 4947–4952

    CAS  PubMed  Google Scholar 

  225. le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R, Formelli F, Gambacorti-Passerini C . In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor J Natl Cancer Inst 1999 91: 163–168

    CAS  PubMed  Google Scholar 

  226. Sausville EA, Lush RD, Headlee D, Smith AC, Figg WD, Arbuck SG, Senderowicz AM, Fuse E, Tanii H, Kuwabara T, Kobayashi S . Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models Cancer Chemother Pharmacol 1998 42: S54–59

    CAS  PubMed  Google Scholar 

  227. Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A, Campochiaro P, Wood J, O'Reilly T, Meyer T . PKC412 – a protein kinase inhibitor with a broad therapeutic potential Anticancer Drug Des 2000 15: 17–28

    CAS  PubMed  Google Scholar 

  228. Teicher BA, Alvarez E, Mendelsohn LG, Ara G, Menon K, Ways DK . Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy Adv Enzyme Regul 1999 39: 313–327

    CAS  PubMed  Google Scholar 

  229. Reed JC . Promise and problems of Bcl-2 antisense therapy J Natl Cancer Inst 1997 89: 988–990

    CAS  PubMed  Google Scholar 

  230. Bataille R, Barlogie B, Lu ZY, Rossi JF, Lavabre-Bertrand T, Beck T, Wijdenes J, Brochier J, Klein B . Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma Blood 1995 86: 685–691

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from The Irish Cancer Society, Enterprise Ireland, The Children's Leukaemia Research Project, Ireland and the Health Research Board, Ireland.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Gorman, D., Cotter, T. Molecular signals in anti-apoptotic survival pathways. Leukemia 15, 21–34 (2001). https://doi.org/10.1038/sj.leu.2401998

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401998

Keywords

This article is cited by

Search

Quick links