282
Views
35
CrossRef citations to date
0
Altmetric
Research Article

Induction of apoptosis in cancer: new therapeutic opportunities

&
Pages 451-469 | Published online: 08 Jul 2009

Reference

  • Kerr JF, Wyllie AH, Currie Alt Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–57.
  • Bursch W, Kleine L, Tenniswood M. The biochemistry of cell death by apoptosis. Biochem Cell Biol 1990; 68: 1071–4.
  • Ellis RE, Yuan J, Horvitz HR. Mechanisms and functions of cell death. Annu Rev Cell Biol 1991; 7: 663–98.
  • Jacobson MD, Weil M, Raff MC. programmed cell death in animal development. Cell 1997; 88: 347–54.
  • Kuida K, Zheng TS, Na S, Kuan C-Y, Yang D, Karasuya- ma H, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996; 384: 368–72.
  • Kuida K, Haydar TF, Kuan C-Y, Gu Y, Taya C, Kara- suyama H, et al. Reduced apoptosis and cytochrome c- mediated caspase activation in mice lacking caspase 9. Cell 1998; 94: 325–37.
  • Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998; 94: 339–52.
  • Varfolomeev EE, Schuchmann M, Luria V, Chiannilkul- chai N, Bechmann JS, Mett IL, et al. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apot, and DR3 and is lethal prenatally. Immunity 1998; 9: 267–76.
  • Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456–62.
  • Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984; 226: 1097–9.
  • Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41: 899–906.
  • Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bc1-2 and a hybrid bc1-2/immunoglo-bulin transcript resulting from the t(14;18) translocation. Cell 1986; 47: 19–28.
  • Vaux DL, Cory S, Adams JM. Bc1-2 gene promotes a haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335: 440–2.
  • McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. bc1-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lympho- proliferation. Cell 1989; 57: 79–88.
  • McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 1991; 349: 254–6.
  • Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999; 59: 1391–9.
  • Kaufmann SH. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 1989; 49: 5870–8.
  • Eastman A. Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 1990; 2: 275–80.
  • Hidcman JA. Apoptosis induced by anticancer drugs. Cancer Metastasis Rev 1992; 11: 121–39.
  • Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol 1999; 17: 2941–53.
  • Cryns V, Yuan J. Proteases to die for. Genes Dev 1998; 12: 1551–70.
  • Aravind L, Dixit VM, Koonin EV. Apoptotic molecular machinery: vastly increased complexity in vertebrates re-vealed by genome comparisons. Science 2001; 291: 1279–84.
  • Hengartner M. The biochemistry of apoptosis. Nature 2000; 407: 770–6.
  • Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281: 1305–8.
  • Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet 1999; 33: 29–55.
  • Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing sig-naling complex (DISC) with the receptor. EMBO J 1995; 14: 5579–88.
  • Yang X, Chang HY, Baltimore D. Autoproteolytic activa- tion of pro-caspases by oligomerization. Mol Cell 1998; 1: 319–25.
  • Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J Biol Chem 1998; 273: 2926–30.
  • Fesik SW. Insights into programmed cell death through structural biology. Cell 2000; 103: 273–82.
  • Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–12.
  • Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15: 2922–33.
  • Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsa- kopoulou V, Ross AJ, et at. Proapoptotic Bax and Bak: A requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727–30.
  • Liu XS, Kim CN, Yang J, Jemmerson R, Wang XD. Induction of apoptotic program in cell-free extracts - requirement for dATP and cytochrome c. Cell 1996; 86: 147–57.
  • Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, et al. Bc1-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 1996; 184: 1331–41.
  • Du C, Fang M, Li Y, Li L, Wang X. smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.
  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et at. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antag- onizing TAP proteins. Cell 2000; 102: 43–53.
  • Saleh A, Srinivasula SM, Acharya S, Fishel R, Alnemri ES. Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J Biol Chem 1999; 274: 17941–5.
  • Zou H, Li Y, Liu X, Wang X. An Apaf-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274: 11549–56.
  • Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, partici-pates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405–13.
  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–89.
  • Stinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES. Autoactivation of procaspase-9 by Apaf-l-mediated oligomerization. Mol Cell 1998; 1: 949–57.
  • Li H, Zhu H, Xu C-J, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491–501.
  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bc12 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94: 481–90.
  • Eskes R, Desagher S, Antonsson B, Martinou J. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial members. Mol Cell Biol 2000; 20: 929–35.
  • Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14: 2060–71.
  • Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 1993; 67: 2168–74.
  • Birnbaum MJ, Clem RJ, Miller LK. An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypep-tide with Cys/His sequence motifs. J V irol 1994; 68: 2521–8.
  • Verhagen AM, Coulson EJ, Vaux DI- Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol 2001; 2: 1–10.
  • Sun C, Cai M, Meadows RP, Xu N, Gunasekera AH, Herrmann J, et al. NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem 2000; 275: 33777–81.
  • Stinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apopto-sis. Nature 2001; 410: 112–6.
  • Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, et al. Structural basis for the inhibition of caspase- 3 by XIAP. Cell 2001; 104: 791–800.
  • alai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, et at. Structural basis of caspase-7 inhibition by XIAP. Cell 2001; 104: 769–80.
  • Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell 2001; 104:781–90.
  • Ashhab Y, Alian A, Polliack A, Panet A, Yehuda DB. Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett 2001; 495: 56–60.
  • Kasof GM, Gomes BC. Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 2001; 276: 3238–46.
  • Vucic D, Stennicke FIR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 2000; 10: 1359–66.
  • Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 2002; 9: 459–70.
  • Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzou-nova M, Hernandez JM, Hossfeld DK, et al. The apop- tosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999; 93: 3601–9.
  • Ambrosini G, Adida c, Alfieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917–21.
  • Alfieri DC. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med 2001; 7: 542–7.
  • Bown N, Cotterill S, Lastowska M, O'Neill S, Pearson AD, Plantaz D, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999; 340: 1954–61.
  • Plantaz D, Mohapatra G, Matthay KK, Pellarin M, Seeger RC, Feuerstein BG. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by com-parative genomic hybridization. Am J Pathol1997; 150: 81–9.
  • Islam A, Kageyama H, Takada N, Kawamato T, Takayasu H, Isogai E, et al. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Onco-gene 2000; 19: 617–23.
  • Azuhata T, Scott D, Takamizawa S, Wen J, Davidoff A, Fukuzawa M, et al. The inhibitor of apoptosis protein Survivin is associated with high-risk behavior of neuroblas-toma. J Pediatr Surg 2001; 36: 1785–91.
  • Tajiri T, Tanaka S, Shono K, Kinoshita Y, Fujii Y, Suita S, et al. Quick quantitative analysis of gene dosages associated with prognosis in neuroblastoma. Cancer Lett 2001; 166: 89–94.
  • Adams JM, Cory S. The Bc1-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–6.
  • Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13: 1899–911.
  • Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, et al. The combined functions of proapoptotic Bc1-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389–99.
  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain- only molecules preventing BAX- and BAK-mediated mito-chondrial apoptosis. Mol Cell 2001; 8: 705–11.
  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–9.
  • Meijerink JP, Mensink EJ, Wang K, Sedlak TV/, Sloetjes AW, de Witte T, et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 1998; 91: 2991–7.
  • Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, et al. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res 2000; 60: 4328–30.
  • TschopP J, limier M, Thome M. Inhibition of Fas death signals by FLIPs. Curr Opin Immunol 1998; 10: 552–8.
  • Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386: 517–21.
  • Bertin J, Armstrong RC, Ottilie S, Martin DA, Wang Y, Banks S, et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Nat! Acad Sci USA 1997; 94: 1172–6.
  • Hu S, Vincenz C, Buller M, Dixit VM. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-l-induced apoptosis. J Biol Chem 1997; 272: 9621–4.
  • Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D. CASH, a novel caspase homologue with death effector domains. J Biol Chem 1997; 272: 19641–4.
  • Han DKM, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, et al. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BcLX1. and initiates cell death. Proc Nat! Acad Sci USA 1997; 94: 11333–8.
  • Hu S, Vincenz C, Ni J, Gentz R, Dixit VM. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD- 95-induced apoptosis. J Biol Chem 1997; 272: 17255–7.
  • Inohara N, Koseki T, Hu Y, Chen S, Nunez G. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Nat! Acad Sci USA 1997; 94: 10717–22.
  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388: 190–5.
  • Rasper DM, Vaillancourt JP, Hadano S, Houtzager VM, Seiden I, Keen SL, et al. Cell death attenuation by `Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ 1998; 5: 271–88.
  • Shu HB, Halpin DR, Goeddel DV. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 1997; 6: 751–63.
  • Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J Biol Chem 1997; 272: 18542–5.
  • Yeh W-C, hie A, Elia A, Ng M, Shu H-B, Wakeham A, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 2000; 12: 633–42.
  • Yeh W-C, de la Pompa JL, McCurrach ME, Shu H-B, Elia AJ, Shahinian A, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998; 279: 1954–8.
  • Ryu BK, Lee MG, Chi SG, Kim YW, Park JR. Increased expression of cFLIP(L) in colonic adenocarcinoma. J Pathol 2001; 194: 15–9.
  • Bullani RR, Huard B, Viard-Leveugle I, Byers HR, Irmler M, Saurat JH, et al. Selective expression of FLIP in malignant melanocytic skin lesions. J Invest Dermatol 2001; 117: 360–4.
  • Djerbi M, Screpanti V, Catrina Al, Bogen B, Biberfeld P, Grandien A. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med 1999; 190: 1025–31.
  • Meclema JP, de Jong J, van Hall T, Melief CJM, Offringa R. Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 1999; 190: 1033–8.
  • Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 13: 2905–27.
  • Talapatra S, Thompson CB. Growth factor signaling in cell survival: implications for cancer treatment. J Pharmacol Exp Ther 2001; 298: 873–8.
  • Dana SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery. Cell 1997; 91: 231–41.
  • del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278: 687–9.
  • Cardone MH, Roy N, Stennicke FIR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–21.
  • Brunet A, Bonn A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–68.
  • Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF- KB by the Akt/PKB kinase. Curr Biol 1999; 9: 601–4.
  • Karin M, Cao Y, Greten FR, Li ZW. NF-KB in cancer: from innocent bystander to major culprit. Nature Rev Cancer 2002; 2: 301–10.
  • Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 2001; 98: 10983–5.
  • Simpson L, Parsons It PTEN: life as a tumor suppressor. Exp Cell Res 2001; 264: 29–41.
  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, etal. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–7.
  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15: 356–62.
  • Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 1997; 57: 2124–9.
  • Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19: 348–55.
  • Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor re in mice. Curr Biol 1998; 8: 1169–78.
  • Podsypamna K, E lenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmacl in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 1999; 96: 1563–8.
  • Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, et al. P-TEN, the tumor suppressor from human chromo-some 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 1997; 94: 9052–7.
  • Maehama T, Dixon, TF. The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem 1998; 273: 13375–8.
  • Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 1998; 95: 13513–8.
  • Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 1998; 8: 1195–8.
  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt- dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95: 29–39.
  • Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase func-tions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Nat! Acad Sci USA 1998; 95: 15587–91.
  • Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R, et aL Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 1998; 58: 5285–90.
  • Li J, Simpson L, Takahashi M, Miliaresis C, Myers MP, Tonics N, et al. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res 1998; 58: 5667–72.
  • Vousden K. p53: death star. Cell 2000; 103: 691–4.
  • Vugelstein B, Lane D, Levine A. Surfing the p53 network. Nature 2000; 408: 307–10.
  • Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–9.
  • Kubbutat MH, Jones SN, Vousden KFL Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.
  • Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001; 27: 247–54.
  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland it, Sherr CJ, et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immor-talization. Genes Dev 1998; 12: 2422–33.
  • de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, et ..4• FAA signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev 1998; 12: 2434–42.
  • Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995; 83: 993–1000.
  • Stott FJ, Bates S, James MC, McConnel BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feed-back loop with p53 and MDM2. EMBO J 1998; 17: 5001–14.
  • Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998; 92: 725–34.
  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, et al. The Ink4a tumor suppressor gene product, pl9Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998; 92: 713–23.
  • Kamijo T, Weber JD, Zambetti F, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998; 95: 8292–7.
  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–25.
  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–16.
  • Gu Y, Turck CW, Morgan DO. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 1993; 366: 707–10.
  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366: 701–4.
  • Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994; 266: 1821–8.
  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, et al. Tumor suppressor p53 is a regulator of bc1-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9: 1799–805.
  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al. Noxa, a BF13-only member of the bc1-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053–8.
  • Oda K, Aralcawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, et al. p53A1P1, a potential mediator of p53- dependent apoptosis, and its regulation by Ser-46-phos-phorylated p53. Cell 2000; 102: 849–62.
  • Yu J, Zhang L, Hwang P, Kinzler K, Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001; 7: 673–82.
  • Nakano K, Vousden K. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7: 683–94.
  • Moroni MC, Hichman ES, Denchi EL, Caprara G, Golli E, Cecconi F, et al. Apaf-1 is a transcriptional target for E2F and p53. Nature Cell Biol 2001; 3: 552–8.
  • Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995; 15: 3032–40.
  • Muller M, Strand S, Hug H, Heinemann EM, Walczak H, Hofmann WJ, et al. 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: 403–13.
  • Tamura T, Aoyama N, Saya H, Haga H, Futami S, Miyamoto M, et al. Induction of Fas-mediated apoptosis in p53-transfected human colon carcinoma cells. Oncogene 1995; 11: 1939–46.
  • Reinke V, Lozano G. The p53 targets mdm2 and Fas are not required as mediators of apoptosis in vivo. Oncogene 1997; 15: 1527–34.
  • Wu G, Burns T, McDonald E, Ill, Jiang W, Meng R, Krantz I, et al. KILLER/DRS is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997; 17: 141–3.
  • Lin Y, Ma W, Benchimol S. Pidd, a new death-domain- containing protein, is induced by p53 and promotes apopto- sis. Nat Genet 2000; 26: 124–7.
  • Caelles C, Hehnberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 1994; 370: 220–3.
  • Wagner AJ, Kokontis JM, Hay N. myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p2lwafUcipl. Genes Dev 1994; 8: 2817–30.
  • Rowan S, Ludwig RI, Haupt Y, Bates S, Lu X, Oren M, et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J 1996; 15: 827–38.
  • Aurelio ON, Cajot J-F, Hua ML-H, Khwaja Z, Stanbridge Germ-line-derived hinge domain p53 mutants have lost apoptotic but not cell cycle arrest functions. Cancer Res 1998; 58: 2190–5.
  • Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by trans-activation- deficient p53. Genes Dev 1995; 9: 2170–83.
  • Chen X, Ko L, Jayaraman L, Prives C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev 1996; 10: 2438–51.
  • Ding H-F, Lin Y-L, McGill G, Juo P, Zhu H, Blenis J, et al. Essential role for caspase-8 in transcription-independent apoptosis triggered by p53. J Biol Chem 2000; 275: 38905–11.
  • Jimenez GS, Nister M, Stommel JM, Beeche M, Barcarse EA, Zhang XQ, et al. A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat Genet 2000; 26: 37–43.
  • Fisher DE. Apoptosis in cancer therapy: crossing the thresh- old. Cell 1994; 78: 539–42.
  • Lowe SW, Ruley HE, Jacks T, Housman DE. p53_ dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74: 957–67.
  • Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R, et al. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res 1996; 24: 141–6.
  • Attardi LD, Jacks T. The role of P53 in tumour suppression: lessons from mouse models. Cell Mol Life Sci 1999; 55: 48–63.
  • Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 2002; 1: 289–98.
  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.
  • Dang CV. c-myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999; 19: 1–11.
  • Eisenman RN. Deconstructing myc. Genes Dev 2001; 15: 2023–30.
  • Sheiness D, Fanshier L, Bishop JM. Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol 1978; 28: 600–10.
  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, et al. The c-myc oncogene driven by immunoglobulin enhancers induced lymphoid malignancy in transgenic mice. Nature 1985; 318: 533–8.
  • Schoenenberger CA, Andres AC, Groner B, van der Valk M, LeMeur M, Gerlinger P. Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J 1988; 7: 169–75.
  • Skoda RC, Tsai SF, Orkin SH, Leder P. Expression of c-MYC under the control of GATA-1 regulatory sequences causes erythroleukemia in transgenic mice. J Exp Med 1995; 181: 1603–13.
  • Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999; 4: 199–207.
  • Marcu KB, Bossone SA, Patel AJ. myc function and regulation. Annu Rev Biochem 1992; 61: 809–60.
  • Armelin HA, Armelin MC, Kelly K, Stewart T, Leder P, Cochran BH, et al. Functional role for c-myc in mitogenic response to platelet-derived growth factor. Nature 1984; 310: 655–60.
  • Eilers M, Schirm S, Bishop JM. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J 1991; 10: 133–41.
  • Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 1991; 6: 1915–22.
  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69: 119–28.
  • Xiao Q, Claassen G, Shi J, Adachi S, Sedivy J, Hann SR. Transactivation-defective c-MycS retains the ability to regulate proliferation and apoptosis. Genes Dev 1998; 12: 3803–8.
  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 1999; 284: 156–9.
  • Green DR, Evan G. A matter of life and death. Cancer Cell 2002; 1: 19–30.
  • Fanidi A, Harrington E, Evan G. Cooperative interaction between c-myc and bc1-2 proto-oncogenes. Nature 1992; 359: 554–6.
  • Bissonnette RP, Echeverri F, Mahboubi A, Green DR. Apoptotic cell death induced by c-myc is inhibited by bc1-2. Nature 1992; 359: 552–4.
  • Juin P, Hueber A-O, Littlewood T, Evan G. c-Myc-induced sensitization to apotosis is mediated through cytochrome c release. Genes Dev 1999; 13: 1367–81.
  • Hueber A-O, Zomig M, Lyon D, Suda T, Nagata S, Evan G. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science 1997; 278: 1305–9.
  • Klefstrom J, Aright E, Litdewood T, Jaattel a M, Saksela E, Evan GI, et al. Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-KB activation. EMBO J 1997; 16: 7382–92.
  • Henneking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science 1994; 265: 2091–3.
  • Schmitt CA, McCurrach ME, de Stanchina E, Wallace- Brodeur RR, Lowe SW. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 1999; 13: 2670–7.
  • Lindstrom MS, Klangby U, Wiman KG. p14ARF homo- zygous deletion or MDM2 overexpression in Burkitt lym-phoma lines carrying wild type p53. Oncogene 2001; 20: 2171–7.
  • Hiebert SW, Padcham G, Strom DK, Haffner R, Oren M, Zambetti G, et al. E2f-1/dp-1 induces p53 and overrides survival factors to trigger apoptosis. Mol Cell Biol 1995; 15: 6864–74.
  • Kowalik TF, DeGregori J, Leone G, Jakoi L, Nevins JR. E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ 1998; 9: 113–8.
  • Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, et al. p14ARF links the tumour suppressors RB and p53. Nature 1998; 395: 124–5.
  • Sears RC, Nevins JR. Signaling networks that link cell proliferation and cell fate. J Biol Chem 2002; 277: 11617–20.
  • Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, et al. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell 2001; 8: 105–13.
  • Mitchell KO, Ricci MS, Miyashita T, Dicker DT, Jin Z, Reed JC, et al. Bax is a transcriptional target and mediator of c-myc-induced apoptosis. Cancer Res 2000; 60: 6318–25.
  • Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–62.
  • Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–30.
  • DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA 1997; 94: 7245–50.
  • Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Hemp K, et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992; 359: 288–94.
  • Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Nature 1992; 359: 295–300.
  • Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992; 359: 328–30.
  • Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb- deficient mouse embryos. Mol Cell 1998; 2: 293–304.
  • Field SJ, Tsai FY, Kuo F, Zubiaga AM, Kaelin WG, Livingston DM, et al. E2f-1 functions in mice to promote apoptosis and suppress proliferation. Cell 1996; 85: 549–61.
  • Qin XQ, Livingston DM, Kaelin WJ, Adams PD. Deregu- lated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci USA 1994; 91: 10918–22.
  • Shan B, Lee W-FL Dereguolated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol 1994; 14: 8166–73.
  • Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 1995; 69: 2491–500.
  • Wu X, Levine AJ. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci USA 1994; 91: 3602–6.
  • Morgenbesser SD, Williams BO, Jacks T, DePinho RA. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 1994; 371: 72–4.
  • Macleod KF, Hu Y, Jacks T. Loss of Rb activates both p53- dependent and independent cell death pathways in the developing mouse nervous system. EMBO J 1996; 15: 6178–88.
  • Jost CA, Mann MC, Kaelin WG, Jr. p73 is a human p53- related protein that can induce apoptosis. Nature 1997; 389: 191–4.
  • Irwin M, Mann MC, Phillips AC, Seelan RS, Smith DI, Liu W, et al. Role for the p53 homologue p73 in E2F-1- induced apoptosis. Nature 2000; 407: 645–8.
  • Hsieh JK, Fredersdorf S, Kouzarides T, Martin K, Lu X. E2F1-induced apoptosis requires DNA binding but not transactivation and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev 1997; 11: 1840–52.
  • Phillips AC, Bates S, Ryan KM, Helin K, Vousden KH. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev 1997; 11: 1853–63.
  • Phillips AC, Ernst MK, Bates S, Rice NR, Vousden KH. E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways. Mol Cell 1999; 4: 771–81.
  • Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49: 4682–9.
  • Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 1991; 349: 117–27.
  • Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev 1998; 8: 49–54.
  • Frame S, Bafinain A. Integration of positive and negative growth signals during ras pathway activation in vivo. Curr Opin Genet Dev 2000; 10: 106–13.
  • Ruley HE. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 1983; 304: 602–6.
  • Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperat-ing oncogenes. Nature 1983; 304: 596–602.
  • Debbas M, White E. Wild-type p53 mediates apoptosis by MA, which is inhibited by MB. Genes Dev 1993; 7: 546–54.
  • Rao L, Debbas P, Sabbatini P, Hockenberry D, Korsmeyer S, White E. The adenovirus MA proteins induces apoptosis which is inhibited by the MB 19K and Bc1-2 proteins. Proc Natl Acad Sci USA 1992; 89: 7742–6.
  • Tsuneoka M, Mekada E. Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c-myc and activated ras. Oncogene 2000; 19: 115–23.
  • Kauffinann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, et al. Suppression of c-Myc- induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 1997; 385: 544–8.
  • Jansen B, Schlagbauer-Wadl H, Eichler HG, Wolff K, van Elsas A, Schrier PI, et al. Activated N-ras contributes to the chemoresistance of human melanoma in severe combined immunodeficiency (SCID) mice by blocking apoptosis. Cancer Res 1997; 57: 362–5.
  • Bernhard EJ, Stanbridge EJ, Gupta S, Gupta AK, Soto D, Bakanauskas VJ, et al. Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines. Cancer Res 2000; 60: 6597–600.
  • Wolfinan JC, Wolfinan A. Endogenous c-N-Ras provides a steady-state anti-apoptotic signal. J Biol Chem 2000; 275: 19315–23.
  • Bergmann A, Agapite J, McCall K, Steller H. The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 1998; 95: 331–41.
  • Kurada P, White K. Ras promotes cell survival in Drosophila by downregulating hid expression. Cell 1998; 95: 319–29.
  • Gomez J, Martinez C, Fernandez B, Garcia A, Rebollo A. Ras activation leads to cell proliferation or apoptotic cell death upon interleukin-2 stimulation or lymphokine depriva-tion, respectively. Eur J Immunol 1997; 27: 1610–8.
  • Henkemeyer M, Rossi DJ, Hohnyard DP, Puri MC, Mbamalu G, Harpal K, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 1995; 377: 695–701.
  • Karim FD, Rubin GM. Ectopic expression of activated Rasl induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development 1998; 125: 1–9.
  • Tanaka N, Ishihara M, Kitagawa M, Harada H, Kimura T, Matsuyama T, et al. Cellular commitment to oncogene- induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell 1994; 77: 829–39.
  • Ma P, Magut M, Chen X, Chen CY. P53 is necessary for the apoptotic response mediated by a transient increase of Ras activity. Mol Cell Biol 2002; 22: 2928–38.
  • Palmer° I, Pantoja C, Serrano M. p19ARF links the tumour suppressor 1353 to Ras. Nature 1998; 395: 125–6.
  • Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 2000; 103: 321–30.
  • Lin AW, Lowe SW. Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci USA 1999; 98: 5025–30.
  • Mayo MW, Wang CY, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ, et al. Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 1997; 278: 1812–5.
  • Feig LA, Buchsbaum RJ. Cell signaling: life or death decisions of ras proteins. Curr Biol 2002; 12: R259–61.
  • Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J Biol Chem 2000; 275: 35669–72.
  • Fullwood P, Marchini S, Rader JS, Martinez A, Macartney D, Broggini M, et al. Detailed genetic and physical mapping of tumor suppressor loci on chromosome 3p in ovarian cancer. Cancer Res 1999; 59: 4662–7.
  • Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 2000; 25: 315–9.
  • Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001; 93: 691–9.
  • Vavvas D, Li X, Avruch J, Zhang XF. Identification of Norel as a potential Ras effector. J Biol Chem 1998; 273: 5439–42.
  • Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang X, et al. Identification of a novel ras-regulated proapoptotic pathway. Curr Biol 2002; 12: 253–65.
  • Creasy CL, Chernoff J. Cloning and characterization of a human protein kinase with homology to Ste20. J Biol Chem 1995; 270: 21695–700.
  • Lee KK, Murakawa M, Nishida E, Tsubuki S, Kawashima S, Sakamaki K, et al. Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis. Oncogene 1998; 16: 3029–37.
  • Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mstl. EMBO J 1998; 17: 2224–34.
  • Coultas L, Strasser A. The molecular control of DNA damage-induced cell death. Apoptosis 2000; 5: 491–507.
  • Rich T, Allen R, Wyllie A. Defying death after DNA damage. Nature 2000; 407: 777–83.
  • Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, et al. Thymocyte apoptosis induced by p53- dependent and independent pathways. Nature 1993; 362: 849–52.
  • Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993; 362: 847–9.
  • Lotem J, Sachs L. Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents. Blood 1993; 82: 1092–6.
  • Merritt A, Potten C, Kemp C, Hickman J, Balmain A, Lane D, et al. Role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res 1994; 54: 614–7.
  • Griffiths SD, Clarke AR, Healy LE, Ross G, Ford AM, Hooper ML, et al. Absence of p53 permits propagation of mutant cells following genotoxic damage. Oncogene 1997; 14: 523–31.
  • Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, et al. p53 status and the efficacy of cancer therapy in vivo. Science 1994; 266: 807–10.
  • Weinstein JN, Myers TG, O'Connor PM, Friend SH, Fornace AJ, Jr., Kohn KW, et al. An information-intensive approach to the molecular pharmacology of cancer. Science 1997; 275: 343–9.
  • Vogelstein B, Kinzler KW. Achilles' heel of cancer? Nature 2001; 412: 865–6.
  • Merritt JA, Roth JA, Logothetis CJ. Clinical evaluation of adenoviral-mediated p53 gene transfer: review of INGN 201 studies. Semin Oncol 2001; 28: 105–14.
  • Verma IM, Somia N. Gene therapy - promises, problems and prospects. Nature 1997; 389: 239–42.
  • Hupp TR, Lane DP, Ball K. Strategies for manipulating the p53 pathway in the treatment of human cancer. Biochem J 2000; 352: 1–17.
  • Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 1997; 3: 632–8.
  • Selivanova G, Ryabchenko L, jansson E, Iotsova V, Wiman KG. Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol 1999; 19: 3395–402.
  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low- molecular-weight com-pound. Nat Med 2002; 8: 282–8.
  • Oltvai ZN, Milliman CL, Korsmeyer SJ. Bc1-2 heterodi- merizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609–19.
  • Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80: 293–9.
  • Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, et al. 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: 4471–8.
  • Tai YT, Strobel T, Kufe D, Cannistra SA. In vivo cytotoxicity of ovarian cancer cells through tumor-selective expression of the BAX gene. Cancer Res 1999; 59: 2121–6.
  • Honda T, Gjertsen BT, Spurgers KB, Briones F, Lee SJ, Hobbs ML, et al. Restoration of bax in prostate cancer suppresses tumor growth and augments therapeutic cell death induction. Anticancer Res 2001; 21: 3141–6.
  • Soengas SM, Capodieci P, Polsky D, Mora J, EsteIler M, Opitz-Araya X, et at. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 2001; 409: 207–11.
  • Teitz T, Wei T, Valentine M, Vanin E, Grenet J, Valentine V, et al. Caspase 8 is deleted or silenced preferen-tially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000; 6: 529–35.
  • Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ho R, Ikegaki N, et al. Resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in neuroblasto-ma cells correlates with a loss of caspase-8 expression. Cancer Res 2001; 61: 1314–9.
  • Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature 2000; 407: 810–6.
  • Flaherty KT, Stevenson JP, O'Dwyer PJ. Antisense thera-peutics: lessons from early clinical trials. Curr Opin Oncol 2001; 13: 499–505.
  • Schlagbauer-Wadl H, Klosner G, Heere-Ress E, Waltering S, Moll I, Wolff K, et al. Bc1-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice. J Invest Dermatol 2000; 114: 725–30.
  • Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, et at. bc1-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 1998; 4: 232–4.
  • Waters JS, Webb A, Cunningham D, Clarke PA, Raynaud F, di Stefano F, et at. Phase I clinical and pharmacokinetic study of bc1-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J CI in Oncol 2000; 18: 1812–23.
  • Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA, et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res 2000; 60: 2805–9.
  • Chen J, Wu W, Tahir SK, Kroeger PE, Rosenberg SH, Cowsert LM, et al. Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth. Neoplasia 2000; 2: 235–41.
  • Wang J-1-, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, et al. Structure-based discovery of an organic compound that binds Bc1-2 protein and induces apoptosis of tumor cells. Proc Nat! Acad Sci USA 2000; 97: 7124–9.
  • Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108: 153–64.
  • old U. Tumor necrosis factor (TNF). Science 1985; 230: 630–2.
  • Liu Z-G, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death. Cell 1996; 87: 565–76.
  • Van Antwerp DJ, Martin SJ, Kaki T, Green DR, Verma Suppression of TNF-a-induced apoptosis by NF-kB. Science 1996; 274: 787–9.
  • Wang CY, Mayo MW, Baldwin AS, Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 1996; 274: 784–7.
  • Beg AA, Baltimore D. An essential role for NF-kB in preventing TNF-a-induced cell death. Science 1996; 274: 782–4.
  • Wang C-Y, Cusack JC, Liu R, Baldwin AS. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kB. Nat Med 1999; 5: 412–7.
  • Loelcsley RI\4, Killeen N, Lenard() MI The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487–501.
  • Griffith TS, Lynch DH. TRAIL: a molecule with multiple receptors and control mechanisms. Curr Biol 1998; 10: 559–63.
  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155–62.
  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5: 157–63.
  • French LE, Tschopp J. The TRAIL to selective tumor death. Nat Med 1999; 5: 146–7.
  • Walczak H, &Inchon A, Stahl H, Krammer PH. Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bc1-2- or Bc1-xL-overexpres-sing chemotherapy-resistant tumor cells. Cancer Res 2000; 60: 3051–7.
  • Da Costa LT, Jen J, He TC, Chan TA, Kinzler KW, Vogelstein B. converting cancer genes into killer genes. Proc Natl Acad Sci USA 1996; 93: 4192–6.
  • Bischoff JR, Kim DH, Williams A, Heise C, Horn S, Muna M, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–6.
  • Raj K, Ogston P, Beard P. Virus-mediated killing of cells that lack p53 activity. Nature 2001; 412: 914–7.
  • Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, et at. Essential role for oncogenic Ras in tumour maintenance. Nature 1999; 400: 468–72.
  • Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001; 15: 3249–62.
  • Huettner CS, Zhang P, Van Etten RA, Tenen DG. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000; 24: 57–60.
  • Cunningham CC, Holmlund JT, Geary RS, Kwoh TJ, DOLT A, Johnston JF, et at. A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer 2001; 92: 1265–71.
  • Adjei AA, Erlichman C, Davis JN, Cutler DL, Sloan JA, Marks RS, et al. A phase I trial of the farnesyl transferase inhibitor 5CH66336: evidence for biological and clinical activity. Cancer Res 2000; 60: 1871–7.
  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et at. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–6.
  • Dan S, Naito M, Tsuruo T. Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR - ABL tyrosine kinase, CGP 57148. Cell Death Differ 1998; 5: 710–5.
  • Fang G, Kim CN, Perkins CL, Ramadevi N, Winton E, Wittmann S, et al. CGP57148B (STI-571) induces differ- entiation and apoptosis and sensitizes Bcr-Abl-positive hu-man leukemia cells to apoptosis due to antileukemic drugs. Blood 2000; 96: 2246–53.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.