Skip to main content
SpringerLink
Log in

Stress-responsive signal transduction: emerging concepts and biological significance

  • Chapter
Apoptosis Genes

Abstract

In the past few years, substantial evidence has been put forth that suggests increasing complexity of the mechanism of action of cytotoxic, mutagenic or carcinogenic agents, commonly known as stress-inducers. The developing theme in a stress-induced cellular response is stimulation of a signal transduction pathway regulated by either cell growth and proliferation-related (survival) factors or programmed cell death-related (apoptotic) factors. The balance between the survival and apoptotic signals depends on the cell type, and dictates the fate of the cell. This review summarises current knowledge of the intracellular signal transduction responses elicited by ionising radiation in rodent and mammalian cells, and focuses on the involvement of Raf-1 protein serine-threonine kinase in the signalling pathways initiated by diverse stress-inducers including ionising radiation, ultraviolet radiation, growth factor-deprivation, and cytokines.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aloni-Grinstein R., Schwartz D., and Rotter, V. (1995) Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression. EMBO J. 14: 1392–1401.

    CAS  PubMed  Google Scholar 

  • Anderson, C.W. (1993) DNA damage and the DNA-activated protein kinase. Trends Biochem. Sci. 18: 433–437.

    Article  CAS  PubMed  Google Scholar 

  • Arsura M., Wu M., and Soneshein, G. (1996) TGF beta 1 inhibits NF-kappaB/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Immunity 5: 31–40.

    Article  CAS  PubMed  Google Scholar 

  • Askew, D.S., Ashmun, R.A., Simmons, B.C. et al. (1991) Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 6: 1915–1922.

    CAS  PubMed  Google Scholar 

  • Baeuerle, P.A., and Baltimore, D. (1996) NF-kappa B: ten years after. Cell 87: 13–20.

    Article  CAS  PubMed  Google Scholar 

  • Baffy G., Miyashita T., Williamson, J. et al. (1993) Apoptosis is induced by withdrawal of interleukin-3(IL-3) from an IL-3 dependent hematopoietic cell line associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J.Biol.Chem. 268: 6511–6519.

    CAS  PubMed  Google Scholar 

  • Baldwin, A.S.Jr. (1996) The NF-kappaB and I kappa B proteins: new discoveries and insights. Ann.Rev.Immunol. 14: 649–683.

    Article  CAS  Google Scholar 

  • Barth H., Hoffmann I., Klein, S. et al. (1996) Role of cdc25-C phosphatase in the immediate G2 delay induced by the exogenous factors epidermal growth factor and phorbol ester. J.Cell Physiol. 168: 589–599.

    Article  CAS  PubMed  Google Scholar 

  • Baskaran R., Wood, L.D., Whitaker, L.L. et al. (1997) Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionising radiation. Nature 387: 516–519.

    Article  CAS  PubMed  Google Scholar 

  • Beck, T.W., Huleihel M., Gunnell, M. et al. (1987) The complete coding sequence of human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nuc. Acids Res. 15: 595–609.

    Article  CAS  Google Scholar 

  • Bedford, J.S. and Mitchell, J.B. (1977) Mitotic accumulation of HeLa cells during continuous irradiation. Radiat. Res. 70: 173–180.

    Article  CAS  PubMed  Google Scholar 

  • Beg, A.A., and Baltimore, D. (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274: 782–784.

    Article  CAS  PubMed  Google Scholar 

  • Bertrand F., Philippe C., Antoine, P.J. et al. (1995) Insulin activates nuclear factor κB in mammalian cells through a Raf-1-mediated pathway. J. Biol. Chem. 270: 24435–24441.

    Article  CAS  PubMed  Google Scholar 

  • Bezzubova O., Silbergleit A., Yamaguchi-Iwai, Y. et al. (1997) Reduced X-ray resistance and homologous recombination frequencies in a Rad54-1- mutant of the chicken DT40 cell line. Cell 89: 185–193.

    Article  CAS  PubMed  Google Scholar 

  • Biedermann, K.A., Sun, J.R., Giaccia, A.J. et al. (1991) Scid mutation in mice confers hypersensitivity and a defieciency in DNA double-strand break repair. Proc.Natl.Acad.Sci. USA 88: 1394–1397.

    Article  CAS  PubMed  Google Scholar 

  • Blagoskonny, M.V., Schulte, T.W., Nguyen, P. et al. (1996) Taxol-induced apoptosis and phosphorylation of bcl-2 protein involves c-Raf-1 and represents a novel c-raf-1 signal transduction pathway. Cancer Res. 56: 1851–1854.

    Google Scholar 

  • Blagosklonny, M.V., Giannakakou P., El-Deiry, W.S. et al. (1997) Raf-1/Bcl-2 phosphorylation: A step from microtubule damage to cell death. Cancer Res. 57: 130–135.

    CAS  PubMed  Google Scholar 

  • Blunt T., Finnie, N.J., Taccioli, G.E. et al. (1995) Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine Scid mutation. Cell 80: 813–823.

    Article  CAS  PubMed  Google Scholar 

  • Bonner, T.L, Oppermann H., Seeburg, I. et al. (1986) The complete sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene. Nuc. Acids Res. 14: 1009–1015.

    Article  CAS  Google Scholar 

  • Boulakia C., Chen G., Ng, F.W.H. et al. (1996) Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly (ADP-ribose) polymerase. Oncogene 12: 29–36.

    Google Scholar 

  • Brach, M.A., Hass R., Sherman, M.L. et al. (1991) Ionising radiation induces expression and binding activity of the nuclear factor κB. J.Clin.Invest. 88: 691–695.

    Article  CAS  PubMed  Google Scholar 

  • Bruder, J.T., Heidecker G., Rapp, U.R. (1992) Serum-, TPA-, and Ras-induced expression from AP-1/Ets-driven promoters require Raf-1 kinase. Gen. Dev. 6: 545–556.

    Article  CAS  Google Scholar 

  • Brugarolas J., Chandrasekaran C., Gordon, J.I. et al. (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557.

    Article  CAS  PubMed  Google Scholar 

  • Burgering, B.M., Pronk, G.J., van Weeren, P. et al. (1993) cAMP antagonizes p21ras directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor. EMBO J. 12: 4211–4220.

    CAS  PubMed  Google Scholar 

  • Burkhardt, A.L., Bmnswick, M, Bolen, J.B. et al (1991) Anti-immunoglobulin stimulation of B lympohocytes activates src-related protein-tyrosine kinases. Proc.Natl.Acad.Sci. USA 88: 7410–7414.

    Article  CAS  PubMed  Google Scholar 

  • Buscher D., Dello Sparba P., Hipskind, R.A. et al (1993) v-Raf confers CSF-1 independent growth to a macrophage cell line and leads to immediate early gene expression without MAP-kinase activation. Oncogene 8: 3323–3332.

    CAS  PubMed  Google Scholar 

  • Canman, C.E., Wolff, A.C, Chen, C.Y. et al (1994) The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia. Cancer Res. 54: 5054–5058.

    CAS  PubMed  Google Scholar 

  • Canman, C.E., Gilmer, T.M., Coutts, S.B. et al (1995) Growth factor modulation of p53-mediated growth arrest versus apoptosis. Gen. Dev. 9: 600–611.

    Article  CAS  Google Scholar 

  • Carpenter, C.L and Cantley, L.C. (1996) Phosphoinositide kinases. Curr.Opin.Cell Biol 8: 153–158.

    Article  CAS  PubMed  Google Scholar 

  • Carson, E.B., McMahon. M., Baylin, S. et al (1995) Ret gene silencing is associated with Raf-1-induced medullary thyroid carcinoma cell differentiation. Cancer Res. 55: 2048–2052.

    CAS  PubMed  Google Scholar 

  • Chae, H.P., Jarvis, L.J. and Uckun, F.M. (1993) Role of tyrosine phosphorylation in radiation-induced activation of c-jun protooncogene in human lymphohematopoietic precursor cells. Cancer Res. 53: 447–451.

    CAS  PubMed  Google Scholar 

  • Chao, J.R., Chen, C. and Wang, T. (1996). Characterization of factor-independent variants derived from TF-1 hematopoietic progenitor cells: the role of the Raf/MAP kinase pathway in the anti-apoptopic effect of GM-CSF. Oncogene 14: 721–728.

    Article  CAS  Google Scholar 

  • Chen, I.T., Smith, M.L., O‘Connor, P.M. et al (1995) Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21waf1/Cip1 with PCNA. Oncogene 11: 1931–1937.

    CAS  PubMed  Google Scholar 

  • Chen Q., Lin, T.H., Der, C.J. et al (1996) Integrin-mediated activation of mitogen activated protein (MAP) or extracellular signal-related kinase (MEK) and kinase is independent of Ras. J.Biol Chem. 271: 18122–18127.

    Article  CAS  PubMed  Google Scholar 

  • Chen, R.-H, Sarnecki, C. and Blenis, J. (1992) Nuclear localization and regulation of erk-and rsk- encoded protein kinases. Mol.Cell.Biol. 12: 915–927.

    CAS  PubMed  Google Scholar 

  • Chen, Y.-R., Meyer, C.F. and Tan, T.-H. (1996) Persistent activation of c-Jun N-terminal kinase (JNK1) in (-radiation-induced apoptosis. J.Biol Chem. 271: 631–634.

    Article  CAS  PubMed  Google Scholar 

  • Chmura, S.J., Nodzenski E., Beckett, M.A. et al. (1997) Loss of ceramide production confers resistance to radiation-induced apoptosis. Cancer Res. 57: 1270–1275.

    CAS  PubMed  Google Scholar 

  • Cleveland, J.L., Troppmair J., Packham, G. et al (1994) v-Raf suppresses apoptosis and promotes growth of interleukin-3-dependent myeloid cells. Oncogene 9: 2217–2226.

    CAS  PubMed  Google Scholar 

  • Cook, S.J. and McCormick, F. (1993) Inhibition by cAMP of Ras-dependent activation of Raf. Science 262: 1069–1072.

    Article  CAS  PubMed  Google Scholar 

  • Corey S., Eguinoa A., Puyana-Theall, K. et al (1993) Granulocyte macrophage-colony stimulating factor stimulates both association and activation of phosphoinositide 3-OH-kinase and src-related tyrosine kinase(s) in human myeloid derived cells. EMBO J. 12: 2681–2690.

    CAS  PubMed  Google Scholar 

  • Cowley S., Paterson H., Kemp, P. et al (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and transformation of NIH 3T3 cells. Cell 77: 841–852.

    Article  CAS  PubMed  Google Scholar 

  • Cuvillier O., Pirianov G., Kleuser, B. et al. (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381: 8000–8003.

    Article  Google Scholar 

  • Datta K., Bellacosa A., Chan, T.D. et al. (1996) Akt is a direct target of the PI 3-kinase: Activation by growth factors, v-src and v-Ha-ras in Sf9 and mammalian cells. J. Biol. Chem. 271: 30835–30839.

    Article  CAS  PubMed  Google Scholar 

  • Datta, S.R., Dudek H., Tao, X. et al. (1997) Akt phosphorylation of Bad couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241.

    Article  CAS  PubMed  Google Scholar 

  • Datta R., Rubin E., Sukhatme, V. et al. (1992a) Ionising radiation activates transcription of the EGR1 genevia CArG elements. Proc.Natl.Acad.Sci. USA 89: 10149–10153.

    Article  CAS  PubMed  Google Scholar 

  • Datta R., Hallahan, D.E., Kharbanda, S.M. et al (1992b) Involvement of reactive oxygen intermediates in the induction of c-Jun gene transcription by ionising radiation. Biochemistry 31: 83000–83006.

    Google Scholar 

  • Datta R., Hass R., Gunji, H. et al (1992c) Down-Regulation of cell cycle control genes by ionising radiation. Cell Growth Diff. 3: 637–644.

    CAS  PubMed  Google Scholar 

  • Datta R., Manome Y., Taneja., N. et al (1995) Over expression of Bcl-XL by cytotoxic drug exposure confers resistance to ionising radiation-induced internucleosomal DNA fragmentation. Cell Growth Diff. 6: 363–370.

    CAS  PubMed  Google Scholar 

  • Datta R., Kojima H., Banach, D. et al (1997) Activation of a CrmA-insensitive, p35-sensitive pathway in ionising radiation-induced apoptosis. J.Biol Chem. 272: 1965–1969.

    Article  CAS  PubMed  Google Scholar 

  • Daum G., Eisenman-Tappe I., Fries, H.W. et al (1994) The ins and outs of Raf kinases. Trends Biochem.Sci. 19: 474–480.

    Article  CAS  PubMed  Google Scholar 

  • Deng, C, Zhang P., Harper, J.W. et al. (1995) Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in Gl checkpoint control. Cell 82: 675–684.

    Article  CAS  PubMed  Google Scholar 

  • Dent P., Haser W., Haystead, T.A. et al. (1992) Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science 257: 1404–1407.

    Article  CAS  PubMed  Google Scholar 

  • Devary Y., Gottlieb, R.A., Smeal, T. et al. (1992) The mammalian ultraviolet response is triggered by activation of src tyrosine kinases. Cell 71: 1081–1091.

    Article  CAS  PubMed  Google Scholar 

  • Devary Y., Rosette, C, DiDonato, J.A. et al. (1993) NF-κB activation by ultraviolet light not dependent on a nuclear signal. Science 261: 1442–1445.

    Article  CAS  PubMed  Google Scholar 

  • Diaz B., Barnard D., Filson, A. et al. (1997) Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling. Mol.Cell.Biol. 17: 4509–4516.

    CAS  PubMed  Google Scholar 

  • Donaldson, K.L., Goolsby G., Kiener, P.A. et al. (1994) Activation of p34cdc coincident with Taxol-induced apoptosis. Cell Growth Diff. 5: 1041–1050.

    CAS  PubMed  Google Scholar 

  • Dudek H., Datta, S.R., Franke, T.F. et al. (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275: 661–668.

    Article  CAS  PubMed  Google Scholar 

  • Dulic V., Kaufmann, W.K., Wilson, S.J. et al. (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76: 1013–1023.

    Article  CAS  PubMed  Google Scholar 

  • El-Deiry, W.S., Tokino T., Velculescu, V.E. et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.

    Article  CAS  PubMed  Google Scholar 

  • Elkind, M.M., Han, A. and Volz, K. (1963) Radiation response of mammalian cells grown in culture. IV. Dose dependence of division delay and post-irradiation growth of surviving and non-surviving Chinese hamster cells. J.Natl.Cancer Inst. 30: 705–711.

    Google Scholar 

  • Emoto Y., Manome Y., Meinhardt, G. et al. (1995) Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J. 14: 6148–6156.

    CAS  PubMed  Google Scholar 

  • Essers J., Hendriks, R.W., Swagemakers, S.M.A. et al. (1997) Disruption of mouse Rad54 reduces ionising radiation resistance and homologous recombination. Cell 89: 195–204.

    Article  CAS  PubMed  Google Scholar 

  • Evan, G.L, Wyllie, A.H., Gilbest, C.S. et al. (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69: 119–128.

    Article  CAS  PubMed  Google Scholar 

  • Evan, G.I. and Littlewood, T.D. (1993) The role of c-myc in cell growth. Curr. Opin. Genet. Dev. 3: 44–49.

    Article  CAS  PubMed  Google Scholar 

  • Fabian, J.R., Daar, I.O. and Morrison, D.K. (1993) Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol.Cell.Biol. 13: 7170–7179.

    CAS  PubMed  Google Scholar 

  • Farrow, S.N. and Brown, R. (1996) New members of the Bcl-2 family and their protein partners. Curr.Opin.Gen.Dev. 6: 45–49.

    Article  CAS  Google Scholar 

  • Finco, T.S. and Balwin, A.S.Jr. (1993) 6 site-dependent induction of gene expression by diverse inducers of nuclear factor κB requires Raf-1. J.Biol.Chem. 268: 17676–17679.

    CAS  PubMed  Google Scholar 

  • Finco T., Westwick, J.K., Norris, J.L. et al. (1997) Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J.Biol.Chem. 272: 24113–24116.

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald, T.J., Santucci, M.A., Das, I. et al. (1991) The v-abl, c-fms, or v-myc oncogene induces gamma radiation resistance of hematopoietic progenitor cell line 32d cl 3 at clinical low dose rate. Int.J. Radial Oncol. Biol.Phys. 21: 1203–1210.

    Article  CAS  Google Scholar 

  • Folgueira L., Algeciras, A. and MacMorran, W.S. (1996) The Ras-Raf pathway is activated in human immunodeficiency virus-infected monocytes and participates in the activation of NF-κB. J.Virology 70: 2332–2338.

    CAS  PubMed  Google Scholar 

  • Ford, J.M. and Hanawalt, P.C. (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc.Natl.Acad.Sci. USA 92: 8876–8880.

    Article  CAS  PubMed  Google Scholar 

  • Fornace, A.J, Jr., (1992) Mammalian genes induced by radiation: Activation of genes associated with growth control. Ann. Rev. Gen. 26: 507–526.

    Article  CAS  Google Scholar 

  • Franke, T.F., Yang, S.-I, Chan, T.O. et al. (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol-3-kinase. Cell 81: 727–736.

    Article  CAS  PubMed  Google Scholar 

  • Franke, T.F., Kaplan, D.R. and Cantley, L.C. (1997) P13K: Downstream AKTion blocks apoptosis. Cell 88: 435–437.

    Article  CAS  PubMed  Google Scholar 

  • Fried, L.M., Koumenis, C, Peterson, S.R. et al. (1996) The DNA damage response in DNA-dependent protein kinase-deficient SCID mouse cells: Replication protein A hyperphosphorylation and p53 induction. Proc.Natl.Acad.Sci. USA 93: 13825–13830.

    Article  CAS  PubMed  Google Scholar 

  • Fuks Z., Persaud, R.S., Alfieri, A. et al. (1994) Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res. 54: 2582–2590.

    CAS  PubMed  Google Scholar 

  • Fulop, G.M. and Phillips, R.A. (1990) The scid mutation in mice causes a general defect in DNA repair. Nature 347: 479–482.

    Article  CAS  PubMed  Google Scholar 

  • Gokhale, P.C, Soldatenkov V., Wang, F.-W et al. (1997) Antisense raf oligodeoxyribonucleotide is protected by liposomal encapsulation and inhibits raf-1 protein expression in vitro and in vivo: implication for gene therapy of radioresistant cancer. Gene Therapy 4: 1289–1299.

    Article  CAS  PubMed  Google Scholar 

  • Gokhale, P.C, McRae D., Monia, B.P. et al. (1998). Antisense raf oligonucleotide is a tumor radiosensitizer. Cambridge Healthtech Institute’s Conference on Antisense Technologies.

    Google Scholar 

  • Gottlieb, T.M. and Jackson, S.P. (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72: 131–142.

    Article  CAS  PubMed  Google Scholar 

  • Greenberger, J.S., Sakakeeny, M.A. et al. (1983) Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines. Proc.Natl.Acad.Sci.USA 80: 2931–2935.

    Article  CAS  PubMed  Google Scholar 

  • Gu Y., Jin S., Gao, Y. et al. (1997) Ku70-deficient embryonic stem cells have increased ionising radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc.Natl.Acad.Sci. USA. 94: 8076–8081.

    Article  CAS  PubMed  Google Scholar 

  • Hafner S., Adler, H.S., Mischak, H. et al. (1994) Mechanism of inhibition of Raf-1 by protein kinase A. Mol.Cell.Biol. 14: 6696–6703.

    CAS  PubMed  Google Scholar 

  • Haimovitz-Friedman A., Vlodavsky I., Chaudhuri, A. et al. (1991) Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells. Cancer Res. 51: 2552–2558.

    CAS  PubMed  Google Scholar 

  • Haimovitz-Friedman A., Balaban N., McLoughlin, M. et al. (1994a). Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis. Cancer Res. 54: 2591–2597.

    CAS  PubMed  Google Scholar 

  • Haimovitz-Friedman A., Kan, C.C, Ehleiter, D. et al. (1994b) Ionising radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp.Med. 180: 525–535.

    Article  CAS  PubMed  Google Scholar 

  • Haldar S., Negrini, M, Monne, M. et al. (1994) Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 54: 2095–2097.

    CAS  PubMed  Google Scholar 

  • Halevy O., Novitch, B.G., Spicer, D.B. et al. (1995) Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267: 1018–1021.

    Article  CAS  PubMed  Google Scholar 

  • Hall, E.J. (1988) In: Radiobiology for the radiologist (Hall, E.J., ed) pp.128–135, Lippincott, Philadelphia.

    Google Scholar 

  • Hallahan, D.E., Spriggs, D.R., Beckett, M.A. et al. (1989) Increased tumor necrosis factor-α mRNA after cellular exposure to ionising radiation. Proc.Natl.Acad.Sci. USA. 86: 10104–10107.

    Article  CAS  PubMed  Google Scholar 

  • Hallahan, D.E., Virudachalam S., Sherman, M.L. et al. (1991a) Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionising radiation. Cancer Res. 51: 4565–4569.

    CAS  PubMed  Google Scholar 

  • Hallahan, D.E., Sukhatme, V.P., Sherman, M.L. et al, (1991b) Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and Jun. Proc.Natl.Acad.Sci. USA. 88: 2156–2160.

    Article  CAS  PubMed  Google Scholar 

  • Hallahan, D.E., Gius D., Kuchibhotla, J. et al. (1993) Radiation signaling mediated by jun activation following dissociation from a cell type-specific repressor. J. Biol.Chem. 268: 4903–4907.

    CAS  PubMed  Google Scholar 

  • Hallahan, D.E., Dunphy E., Virudachalam, S. et al. (1995) c-jun and Egr-1 participate in DNA synthesis and cell survival in response to ionising radiation exposure. J.Biol.Chem. 270: 30303–30309.

    Article  CAS  PubMed  Google Scholar 

  • Harper, J.W., Adami, G.R. Wei, N. et al. (1993) The p21 Cdk-interacting protein Cip 1 is a potent inhibtor of G1 cyclin-dependent kinases. Cell 75: 805–816.

    Article  CAS  PubMed  Google Scholar 

  • Harper J.W. and Elledge, S.J. (1996) Cdk inhibitors in development and cancer. Curr. Opin. Genet. Dev. 6: 56–64.

    Article  CAS  PubMed  Google Scholar 

  • Harrington, E.A., Bennett, M.R., Fanidi, A. et al. (1994) c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 13: 3286–3295.

    CAS  PubMed  Google Scholar 

  • Hartwell, L.H. and Kastan, M.B. (1994) Cell cycle control and cancer. Science 266: 1821–1828.

    Article  CAS  PubMed  Google Scholar 

  • Heidecker G., Huleihel, M, Cleveland, J.L. et al. (1990) Mutational activation of c-raf-1 and definition of the minimal transforming sequence. Mol. Cell.Biol. 10: 2503–2512.

    CAS  PubMed  Google Scholar 

  • Hockenbery D., Nunez G., Milliman, C. et al. (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336.

    Article  CAS  PubMed  Google Scholar 

  • Hockenberry D., Oltivai Z., Yin, X. et al. (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241–251.

    Article  Google Scholar 

  • Hollander, M.C, Alamo I., Jackman, J. et al. (1993) Analysis of the mammalian gadd45 gene and its response to DNA damage. J.Biol.Chem. 268: 24385–24393.

    CAS  PubMed  Google Scholar 

  • Hollander, M.C., Zhan Q., Bae, I. et al. (1997) Mammalian GADD34, an apoptosis-and DNA damage-inducible gene. J.Biol.Chem. 272: 13731–13737.

    Article  CAS  PubMed  Google Scholar 

  • Hong, J.H., Chiang, C.-S., Campbell, I.L. et al. (1995) Induction of acute phase gene expression by brain irradiation. Int.J. Radiation Oncology Biol.Phys. 33: 619–626.

    Article  CAS  Google Scholar 

  • Horwitz, S.B. (1992) Mechanism of action of Taxol. Trends Pharmacol.Sci. 13: 134–136.

    Article  CAS  PubMed  Google Scholar 

  • Howard, A. and Pelc, S.R. (1953) Synthesis of deoxyribonucleic acid in normal and irradiated cells and its relation to chromosome breakage. Heredity 6: 261–273.

    CAS  Google Scholar 

  • Howe, L.R., Leevers, S.J., Gomez, N. et al. (1992) Activation of the MAP kinase pathway by the protein kinase Raf. Cell 71: 335–342.

    Article  CAS  PubMed  Google Scholar 

  • Huang L., Clarkin, K.C. and Wahl, G.M. (1996) p53-dependent cell cycle arrests are preserved in DNA-activated protein kinase-deficient mouse fibroblasts. Cancer Res. 56: 2940–2944.

    CAS  PubMed  Google Scholar 

  • Ikawa S., Fukui M., Ueyama, Y. et al. (1988) B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol.Cell.Biol. 8: 2651–2654.

    CAS  PubMed  Google Scholar 

  • Jeggo, P.A., Tesmer, J. and Chen, D.J. (1991) Genetic analysis of ionising radiation sensitive mutants of cultured mammalian cell lines. Mut. Res. 254: 125–133.

    Article  CAS  Google Scholar 

  • Jelinek T., Dent T., Sturgill, T.W. et al. (1996) Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation. Mol.Cell.Biol. 16: 1027–1034.

    CAS  PubMed  Google Scholar 

  • Kao, G.D., McKenna, W.G., Maity, A. et al. (1997) Cyclin B1 availability is a rate-limiting component of the radiation-induced G2 delay in HeLa cells. Cancer Res. 57: 753–758.

    CAS  PubMed  Google Scholar 

  • Kasid U., Pfeifer A., Weichselbaum, R.R. et al (1987) The raf oncogene is associated with a radiation-resistant human laryngeal cancer. Science 237: 1039–1041.

    Article  CAS  PubMed  Google Scholar 

  • Kasid U., Pfeifer A., Brennan, T. et al. (1989) Effect of antisense c-Raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma. Science 243: 1354–1356.

    Article  CAS  PubMed  Google Scholar 

  • Kasid U., Pirollo K., Dritschilo, A. et al. (1993) Oncogenic basis of radiation resistance. Advances in Cancer Res. 61: 195–233.

    Article  CAS  Google Scholar 

  • Kasid U., Suy S., Dent, P. et al. (1996) Activation of Raf by ionising radiation. Nature 382: 813–816.

    Article  CAS  PubMed  Google Scholar 

  • Kasid U., Wang, F-H. and Whiteside, T.L. (1997) Ionising radiation and TNFα stimulate gene expression of a Thr/Tyr-protein phosphatase HVH1 and inhibitory factor IκBα. Mol.Cell. Biochem. 173: 193–197.

    Article  CAS  PubMed  Google Scholar 

  • Kastan, M.B., Onyekwere, O., Sidransky, D. et al. (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51: 6304–6311.

    CAS  PubMed  Google Scholar 

  • Kastan, M.B., Zhan Q., El-Deiry, W.S. et al. (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587–597.

    Article  CAS  PubMed  Google Scholar 

  • Kato, J.Y., Matsuoka M., Polyak, K. et al. (1994) Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27kjpl) of cyclin dependent kinase 4 activation. Cell 79: 487–496.

    Article  CAS  PubMed  Google Scholar 

  • Kauffmann-Zeh A., Rodriguez-Viciana P., Ulrich, E. et al. (1997) Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3) K and PKB. Nature 386: 544–548.

    Article  Google Scholar 

  • Kennedy, S.G., Wagner, A.J., Conzen, S.D. et al. (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Gen. Dev. 11: 701–713.

    Article  CAS  Google Scholar 

  • Kerkhoff, E. and Rapp, U.R. (1997) Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol.Cell.Biol. 17: 2576–2586.

    CAS  PubMed  Google Scholar 

  • Kharbanda S., Saleem A., Sharman, T. et al. (1994a) Activation of pp90rsk and mitogen-activated serine/threonine protein kinases by ionising radiation. Proc.Natl.Acad.Sci. USA. 91: 5416–5420.

    Article  CAS  PubMed  Google Scholar 

  • Kharbanda S., Saleem A., Datta, R. et al. (1994b) Ionising radiation induces rapid tyrosine phosphorylation of p34cdc2. Cancer Res. 54: 1412–1414.

    CAS  PubMed  Google Scholar 

  • Kharbanda S., Saleem A., Shafman, T. et al. (1995a) Ionising radiation stimulates a Grb2-mediated association of the stress-activated protein kinase with phosphatidylinositol 3-kinase. J. Biol.Chem. 270: 18871–18874.

    Article  CAS  PubMed  Google Scholar 

  • Kharbanda S., Ren R., Pandley, P. et al. (1995b) Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376: 785–788.

    Article  CAS  PubMed  Google Scholar 

  • Kharbanda S., Bharti A., Pei, D. et al. (1996) The stress response to ionising radiation involves c-Abl-dependent phosphorylation of SHPTP1. Proc.NatLAcad.Sci. USA. 93: 6898–6901.

    Article  CAS  Google Scholar 

  • Kharbanda. S., Pandey P., Schofield, L. et al. (1997) Role for Bcl-XL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc.Natl.Acad.Sci. USA. 94: 6939–6942.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • King, W.G., Mattaliano, M.D., Chan, T.O. et al. (1997) Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation. Mol.Cell.Biol 17: 4406–4418.

    CAS  PubMed  Google Scholar 

  • Kinoshita T., Yokota T., Arai, K. et al. (1995) Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors. EMBO J. 14: 266–275.

    CAS  PubMed  Google Scholar 

  • Kirchgessner, C.U., Patil, C.K., Evans, J.W. et al. (1995) DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science 267: 1178–1183.

    Article  CAS  PubMed  Google Scholar 

  • Kitada S., Takayama S., DeRiel, K. et al. (1994) Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of Bcl-2 gene expression. Antisense Res.Dev. 4: 71–79.

    CAS  PubMed  Google Scholar 

  • Kitada S., Krajewski S., Miyashita, T. et al. (1996) Gamma-radiation induces upregulation of bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12: 187–192.

    CAS  PubMed  Google Scholar 

  • Kluck, R.M, Bossy-Wetzel E., Green, D.R. et al. (1996). The release of cytochrome C from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275: 1132–1136.

    Article  Google Scholar 

  • Kolch W., Cleveland, J.L. and Rapp, U. (1990) Role of oncogenes in the abrogation of growth factor requirements of hemopoietic cells. Crit.Rev.Cancer 2: 279–303.

    Google Scholar 

  • Kolch W., Heidecker G., Lloyd, P. et al. (1991) Raf-1 protein kinase is required for growth of induced NIH 3T3 cells. Nature 349: 426–428.

    Article  CAS  PubMed  Google Scholar 

  • Kolch W., Heidecker G., Kochs, G. et al. (1993) Protein kinase C alpha activates Raf-1 by direct phosphorylation. Nature 364: 249–252.

    Article  CAS  PubMed  Google Scholar 

  • Kolesnick, R. and Golde, D.W. (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77: 325–328.

    Article  CAS  PubMed  Google Scholar 

  • Koong, A.C., Chen, E.Y., Mivechi, N.F. et al. (1994) Hypoxic activation of nuclear factor-KB is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Cancer Res. 54: 5273–5279.

    CAS  PubMed  Google Scholar 

  • Krajewski S., Tanaka S., Takayama, S. et al. (1993) Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res. 53: 4701–4714.

    CAS  PubMed  Google Scholar 

  • Kuerbitz, S.J., Plunkett, B.S., Walsh, W.V. et al. (1992) Wild type p53 is a cell cycle checkpoint determinant following irradiation. Proc.Natl.Acad.Sci. USA. 89: 7491–7495.

    Article  CAS  PubMed  Google Scholar 

  • Kuo, W.L., Abe M., Rhee, J. et al. (1996) Raf, but not MEK or ERK is sufficient for differentiation of hippocampal neuronal cells. Mol.CelLBiol. 16: 1458–1470.

    CAS  Google Scholar 

  • Kwak, S.P., Hakes, D.J., Martell, K.J. et al. (1994) Isolation and characterization of a human dual protein-tyrosine phosphatase gene. J.Biol.Chem. 269: 3596–35604.

    CAS  PubMed  Google Scholar 

  • Kyriakis, J.M., App H., Zhang, X.-F. et al. (1992) Raf-1 activates MAP kinase-kinase. Nature 358: 417–421.

    Article  CAS  PubMed  Google Scholar 

  • Lavoie, J.N., L‘Allemain G., Brunet, A. et al. (1996) Cyclin D1 expression is regulated positively by the p42/p44 MAPK and negatively by the p38/HOGMAPK pathway. J.BioLChem. 271: 20608–20616.

    CAS  Google Scholar 

  • Lee, L.-F, Haskill, J.S., Mukaida, N. et al. (1997) Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter. Mol.CelLBiol. 17: 5097–5105.

    CAS  Google Scholar 

  • Leevers, S.J., Paterson, H.F. and Marshall, C.J. (1994) Requirement for ras in raf activation is overcome by targeting raf to the plasma membrane. Nature 369: 411–414.

    Article  CAS  PubMed  Google Scholar 

  • Leigh, B.R., Hancock, S.L. and Knox, S.J. (1993) The effect of stem cell factor on irradiated human bone marrow. Cancer Res. 53: 3857–3859.

    CAS  PubMed  Google Scholar 

  • Lenormand P., Sardet C., Pages, G. et al (1993) Growth factors induce nuclear translocation of MAP kinases (p42mapk/p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J.Cell Biol 122: 1079–1088.

    Article  CAS  PubMed  Google Scholar 

  • Li P., Nijhawan D., Budihardjo, I. et al. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479–489.

    Article  CAS  PubMed  Google Scholar 

  • Li, S.-F. and Sedivy, J.M. (1993) Raf-1 protein kinase activates the NF-κB transcription factor by dissociating the cytoplasmic NF-κB-IκB complex. Proc.Natl.Acad.Sci.USA. 90: 9247–9251.

    Article  CAS  PubMed  Google Scholar 

  • Littlewood, T.D., Hancock, D.C., Danielian, P.S. et al. (1995) A modified estrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nuc. Acids Res. 23: 1686–1690.

    Article  CAS  Google Scholar 

  • Liu Y., Gorospe M., Yang, C. et al. (1995) Role of mitogen-activated protein kinase phosphatase during the cellular response to genotoxic stress. Inhibition of c-Jun N-terminal kinase activity and AP-1-dependent gene activation. J. BioiChem. 270: 8377–8380.

    CAS  Google Scholar 

  • Liu, Z.-G., Baskaran R., Lea-Chou, E.T. et al (1996 a) Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature 384: 273–276.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Z-G., Hsu H., Goeddel, D.V. et al (1996b) Dissection of TNF receptor-1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87: 565–576.

    Article  CAS  PubMed  Google Scholar 

  • Ludwig S., Engel K., Hoffmeyer, A. et al (1996) 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways. MolCell.Biol. 16: 6687–6697.

    CAS  Google Scholar 

  • Macleod, K.F., Sherry N., Hannon, G. et al. (1995) p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Gen. Dev. 9: 935–944.

    Article  CAS  Google Scholar 

  • Malynn, B.A., Blackwell, T.K., Fulop, G.M. et al (1988) The Scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell 54: 453–460.

    Article  CAS  PubMed  Google Scholar 

  • Marais R., Light Y., Paterson, H.F. et al. (1995) Ras recruits raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 14: 3136–3145.

    CAS  PubMed  Google Scholar 

  • Marshall, C.J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185.

    Article  CAS  PubMed  Google Scholar 

  • Marshall, C.J. (1996 a) Cell signalling. Raf gets it together. Nature 383: 127–128.

    Article  CAS  PubMed  Google Scholar 

  • Marshall, CJ. (1996 b) Ras effectors. Curr.Opin. Cell Biol. 8: 197–204.

    Article  CAS  PubMed  Google Scholar 

  • McKenna, W.G., Iliakis G., Weiss, M.C. et al (1991) Increase G2 delay in radiation-resistant cells obtained by transformation of primary rat embryo cells with the oncogenes H-Ras and v-Myc. Radiation Res. 125: 283–287.

    Article  CAS  PubMed  Google Scholar 

  • McKenna, W.G., Bernhard, E.J., Markiewicz, D.A. et al (1996) Regulation of radiation-induced apoptosis in oncogene-transfected fibroblasts: influence of H-ras on the G2 delay. Oncogene 12: 237–245.

    CAS  PubMed  Google Scholar 

  • McLaughlin, M.M., Kumar S., McDonnell, P.C. et al. (1996) Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J.BioiChem. 271: 8488–8492.

    CAS  Google Scholar 

  • Metz T., Harris, A.W. and Adams, J.M. (1995) Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes. Cell 82: 29–36.

    Article  CAS  PubMed  Google Scholar 

  • Minn, A.J., Rudin, C.M., Boise, L.H. et al. (1995) Expression of Bcl-XL can confer a multiple resistance phenotype. Blood 86: 1903–1910

    CAS  PubMed  Google Scholar 

  • Minn, A.J., Velez P., Schendel, S.L. et al. (1997) Bcl-XL forms an ion channel in synthetic lipid membranes. Nature 385: 353–357.

    Article  CAS  PubMed  Google Scholar 

  • Miyashita T., Krajewski S., Krajewska, M. et al. (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9: 1799–1805.

    CAS  PubMed  Google Scholar 

  • Moelling K., Heimann B., Beimling, P. et al (1984) Serine and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins. Nature 312: 558–561.

    Article  CAS  PubMed  Google Scholar 

  • Monia, B.P., Johnston, J.F., Geiger, T. et al. (1996) Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against c-raf kinase. Nature Med. 2: 668–675.

    Article  CAS  PubMed  Google Scholar 

  • Moodie, S.A., Willumsen, B.M., Weber, M.J. et al (1993) Complexes of RasGTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260: 1658–1661.

    Article  CAS  PubMed  Google Scholar 

  • Morgan, S.E. and Kastan, M.B. (1997 a) p53 and ATM: Cell cycle, cell death, and cancer. Adv.Cancer Res. 71: 1–25.

    Article  CAS  PubMed  Google Scholar 

  • Morrison, D.K. (1990) The Raf-1 kinase as a transducer of mitogenic signals. Cancer Cells 2: 377–382.

    CAS  PubMed  Google Scholar 

  • Murnane, J.P. (1995) Cell cycle regulation in response to DNA damage in mammalian cells: a historical perspective. Cancer Metastasis Rev. 14: 17–29.

    Article  CAS  PubMed  Google Scholar 

  • Muschel, R.J., Zhang, H.B., Iliakis G. et al (1991) Cyclin B expression in HeLa cells during the G2 block induced by ionising radiation. Cancer Res. 51: 5113–5117.

    CAS  PubMed  Google Scholar 

  • Nakagawa T., Mabry M., DeBustros, A. et al (1987) Introduction of v-Ha-Ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells. Proc.Natl.Acad.Sci.USA. 84: 5923–5927.

    Article  CAS  PubMed  Google Scholar 

  • Nakielny S., Cohen P., Wu, J. et al (1992) MAP kinase activator from insulin-stimulated skeletal muscle is a protein threonine/tyrosine kinase. EMBO J. 11: 2123–2129.

    CAS  PubMed  Google Scholar 

  • Naumovski, L. and Cleary, M.L. (1996). The p53-binding protein 53BP2 also interacts with Bcl-2 and impedes cell cycle progression at G2/M. MolCell.Biol. 16: 3884–3892.

    CAS  Google Scholar 

  • Neta, R. and Oppenheim, J.J. (1991) Radioprotection with cytokines-learning from nature to cope with radiationdamage. Cancer Cells 3: 391–396.

    CAS  PubMed  Google Scholar 

  • Nguyen M., Millar, D.G., Yong, V.W. et al. (1993) Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J.Biol.Chem. 268: 25265–25268.

    CAS  PubMed  Google Scholar 

  • Nunez G., London L., Hockenberry, D. et al. (1990) Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J. Immunol 144: 3602–3610.

    CAS  PubMed  Google Scholar 

  • Obeid, L.M., Linardic, C.M, Karolak, L.A. et al. (1993) Programmed cell death induced by ceramide. Science 259: 1769–1771.

    Article  CAS  PubMed  Google Scholar 

  • Olivera, A and Spiegel, S. (1993) Sphingosine 1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365: 557–560.

    Article  CAS  PubMed  Google Scholar 

  • Oltvai, Z.N. and Korsmeyer, S.J. (1994) Checkpoints of dueling dimers foil death wishes. Cell 79: 189–192.

    Article  CAS  PubMed  Google Scholar 

  • Pandey P., Raingeaud J., Kaneke, M. et al. (1996) Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and-independent mechanisms. J.Biol.Chem. 271: 23775–23779.

    Article  CAS  PubMed  Google Scholar 

  • Patel, B.K.R., Ray S., Whiteside, T.L. et al. (1997) Correlation of Constitutive activation of Raf-1 with morphological transformation and abrogation of tyrosine phosphorylation of distinct sets of proteins in human squamous carcinoma cells. Mol Carcinogenesis 18: 1–6.

    Article  CAS  Google Scholar 

  • Patel S., Wang, F.-W., Whiteside, T.L. et al (1997) Constitutive modulation of Raf-1 protein kinase is associated with differential gene expression of several known and unknown genes. MolMedicine 3: 647–685.

    Google Scholar 

  • Patel S., Wang, F.-W., Whiteside, T.L. and Kasid, U. (1998) Ionizing radiation and TNF-α stimulate expression of α1-antichymotrypsin gene in human squamous carcinoma cells. Acta Oncologia In Press.

    Google Scholar 

  • Pfeifer, A.M.A., Mark, G. III, Malan-Shibley et al (1989) Cooperation of c-raf-1 and c-myc protooncogenes in the neoplastic transformation of simian virus 40 large tumor antigen-immortalized human bronchial epithelial cells. Proc.Natl.Acad.Sci. USA 86: 10075–10079.

    Article  CAS  PubMed  Google Scholar 

  • Pines, J. (1995) Cyclins, CDKs and cancer. Semin. Cancer Biol 6: 63–72.

    Article  CAS  PubMed  Google Scholar 

  • Pirollo, K.F., Garner R., Yuan, S.Y. et al. (1989) Raf involvement in the simultaneous genetic transfer of the radioresistant and transforming phenotypes. Int. J. Radiat. Biol. 55: 783–796.

    Article  CAS  PubMed  Google Scholar 

  • Pirollo, K.F., Hao Z., Rait, A. et al. (1997) Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells. Biochem. Biophys.Res.Com. 230: 196–201.

    Article  CAS  PubMed  Google Scholar 

  • Polyak K., Lee, M.H., Erdjument-Bromage, H. et al. (1994) Cloning of p27kipl, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66.

    Article  CAS  PubMed  Google Scholar 

  • Qureshi, S.A., Rim M., Bruder, J. et al (1991) An inhibitory mutant of c-raf-1 blocks v-src-induced activation of the egr-1 promoter. J.Biol.Chem. 266: 20594–20597.

    CAS  PubMed  Google Scholar 

  • Radler-Pohl A., Sachsenmaier, C, Gebel, S. et al. (1993) UV-induced activation of AP-1 involves obligatory extranuclear steps including Raf-1 kinase. EMBO J. 12: 1005–1012.

    CAS  PubMed  Google Scholar 

  • Rajan, J.V., Wang M., Marquis, S.T. et al. (1996) Brca2 is coordinately regulated with Brcal during proliferation and differentiation in mammary epithelial cells. Proc.Natl.Acad.Sci. USA. 93: 13078–13083.

    Article  CAS  PubMed  Google Scholar 

  • Rapp, U.R., Goldsborough, M.D., Mark, G.E. et al. (1983) Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc.Natl.Acad.Sci. USA. 80: 4218–4222.

    Article  CAS  PubMed  Google Scholar 

  • Rapp, U.R. (1991) Role of Raf-1 serine/threonine protein kinase in growth factor signal transduction. Oncogene 6: 495–500.

    CAS  PubMed  Google Scholar 

  • Ravi, R.K., Weber E., McMahon, M. et al. (1998) Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J.Clin. Invest. 101: 153–159.

    Article  CAS  PubMed  Google Scholar 

  • Reed, J. (1997) Double identity for proteins of the BCL-2 family. Nature 387: 773–776.

    Article  CAS  PubMed  Google Scholar 

  • Renshaw, M.W, Kipreos, E.T., Albrecht, M.R. et al (1992) Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth, depending on cell context. EMBO J. 11: 3941–3951.

    CAS  PubMed  Google Scholar 

  • Rudin, C.M. and Thompson, C.B. (1997) Apoptosis and disease: Regulation and clinical relevance of programmed cell death. Annu.Rev.Med. 48: 267–281.

    Article  CAS  PubMed  Google Scholar 

  • Sahijdak, W.M., Yang, C.-R., Zuckerman J.S. et al. (1994) Alterations in transcription factor binding in radioresistant human melanoma cells after ionising radiation. Radiation Res. 138: S47–S51.

    Article  CAS  PubMed  Google Scholar 

  • Salvesen, G.S. and Dixit, V.M. (1997) Caspases: Intracellular signaling by proteolysis. Cell 91: 443–446.

    Article  CAS  PubMed  Google Scholar 

  • Samuels, M.L., Weber, M.J., Bishop, J.M. et al. (1993) Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human Raf-1 protein kinase. Mol.Cell.Biol. 13: 6241–6252.

    CAS  PubMed  Google Scholar 

  • Santana P., Pena, L.A., Haimovitz-Friedman, A. et al. (1996) Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86: 189–199.

    Article  CAS  PubMed  Google Scholar 

  • Sato N., Sakamaki K., Terada, N. et al (1993) Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signalling. EMBO J. 12: 4181–4189.

    CAS  PubMed  Google Scholar 

  • Schieven, G.L., Kirihara, J.M, Myers, D.E. et al. (1993) Reactive oxygen intermediates activate NF-κB in a tyrosine kinase-dependent mechanism and in combination with vanadate activate the p561ck and p59fyn tyrosine kinases in human lymphocytes. Blood 82: 1212–1220.

    CAS  PubMed  Google Scholar 

  • Scully R., Chen J., Ochs, R.L. et al. (1997a) Dynamic changes of Brcal subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90: 425–435.

    Article  CAS  PubMed  Google Scholar 

  • Scully R., Chen J., Plug, A. et al (1997b) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88: 265–275.

    Article  CAS  PubMed  Google Scholar 

  • Seger, R. and Krebs, E.G. (1995) The MAPK signaling cascade. FASEB J. 9: 726–735.

    CAS  PubMed  Google Scholar 

  • Selvakumaran M., Lin H., Miyashita, T. et al (1994) Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene 9: 1791–1798.

    CAS  PubMed  Google Scholar 

  • Sentman, C.L., Shutter, J.R., Hockenbery, D. et al. (1991) Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67: 879–888.

    Article  CAS  PubMed  Google Scholar 

  • Serrano M., Lin, A.W., McCurragh, M.E. et al. (1997) Oncogenic Ras provokes premature cell senescene associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.

    Article  CAS  PubMed  Google Scholar 

  • Sewig A., Wiseman B., Lloyd, A.C. et al. (1997) High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell. Biol. 17: 5588–5597.

    Google Scholar 

  • Shafman, T. Khanna, K.K., Kedar, P. et al. (1997) Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387: 450–451.

    Article  Google Scholar 

  • Sharan, S.K., Morimatsu M., Albrecht, U. et al. (1997a) Embryonic lethality and radiation hypersensivity mediated by Rad51 in mice lacking Brca2. Nature 386: 804–810.

    Article  CAS  PubMed  Google Scholar 

  • Sharan, S.K. and Bradley, A. (1997b) Murine Brca2: Sequence, map position and expression pattern. Genomics 40: 234–241.

    Article  CAS  PubMed  Google Scholar 

  • Sherman, M.L., Datta R., Hallahan, D.E. et al (1990) Ionising radiation regulates expression of the c-jun protooncogene. Proc. Natl. Acad. Sci. USA. 87: 5663–5666.

    Article  CAS  PubMed  Google Scholar 

  • Shiina N., Goth Y., Kubomura, N. et al. (1994) Microtubule severing by elongation factor 1 alpha. Science 266: 282–285

    Article  CAS  PubMed  Google Scholar 

  • Singleton, B.K., Priestley A., Steingrimsdottir, H. et al. (1997) Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol. Cell. Biol. 17: 1264–1273.

    CAS  PubMed  Google Scholar 

  • Sipley, J.D., Menninger, J.C, Hartley, K.O. et al (1995) Gene for the catalytic subunit of the human DNA-activated protein kinase maps to the site of the XRCC7 gene on chromosome 8. Proc. Natl. Acad. Sci. USA. 92: 7515–7519.

    Article  CAS  PubMed  Google Scholar 

  • Sklar, M.D., McQuiston S., Terry, V.O. et al (1986) Radiat. Oncol. Biol. Phys. 12 (Suppl. 1), 190–191.

    Google Scholar 

  • Smith, D.M., Tran, H.M., Soo, V.W. et al. (1994) Enhanced synthesis of tumor necrosis factor-inducible proteins, plasminogen activator inhibitor-2, manganese superoxide dismutase, and protein 28/5.6, is selectively triggered by the 55kDa tumor necrosis factor receptor in human melanoma cells. J. Biol. Chem. 269: 9898–9905.

    CAS  PubMed  Google Scholar 

  • Smith, M.L., Chen, I.-T., Zhan, Q. et al. (1994) Interaction of the p53-regulated protein Gadd4 with proliferating cell nuclear antigen. Science 266: 1376–1380.

    Article  CAS  PubMed  Google Scholar 

  • Smith, M.R., Heidecker G., Rapp, U.R. et al. (1990) Induction of transformation and DNA synthesis after microinjection of Raf proteins. Mol. C ell. Biol. 10: 3828–3833.

    CAS  Google Scholar 

  • Smith, S.A., Easton, D.G., Evans, D.G.R. et al. (1992) Allele losses in the region 17q 12-21 in familial breast and ovarian cancer involve the wild type chromosome. Nature Genet. 2: 128–131.

    Article  CAS  PubMed  Google Scholar 

  • Soldatenkov, V.A., Dritschilo A., Wang, F.-W et al (1997) Inhibition of Raf-1 protein kinase by antisense phosphorothioate oligodeoxyribonucleotide is associated with sensitization of human laryngeal squamous carcinoma cells to gamma radiation. Cancer J. Sci. Am. 3: 13–20.

    CAS  PubMed  Google Scholar 

  • Solomon, M.J., Glotzer M., Lee, T.H. et al (1990) Cyclin activation of p34cdc2. Cell 63: 1013–1024.

    Article  CAS  PubMed  Google Scholar 

  • Songyang Z., Baltimore D., Cantley, L. et al. (1997). Interleukin 3-dependent survival by the Akt proteinkinase. Proc. Natl. Acad. Sci. USA 94: 11345–11350.

    Article  CAS  PubMed  Google Scholar 

  • Stanton, V.P.Jr., Nichols, D.W., Laudano, A.P. et al. (1989) Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol. Cell Biol. 9: 639–647.

    CAS  PubMed  Google Scholar 

  • Stevenson, M.A., Pollock, S.S., Coleman, C.N. et al. (1994) X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res. 54: 12–15.

    CAS  PubMed  Google Scholar 

  • Stewart, C.E. and Rotwein, P. (1996) Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol. Rev. 76: 1005–1026.

    CAS  PubMed  Google Scholar 

  • Storm, S.M., Cleveland, J.L. and Rapp, U.R. (1990) Expression of raf family proto-oncogenes in normal mouse tissues. Oncogene 5: 345–351.

    CAS  PubMed  Google Scholar 

  • Strasser A., Harris, A.W., Jacks, T. et al. (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79: 329–339.

    Article  CAS  PubMed  Google Scholar 

  • Suy S., Anderson, W.B., Dent, P. et al. (1997) Association of Grb2 with Sos and Ras with Raf-1 upon gamma irradiation of breast cancer cells. Oncogene 15: 53–61.

    Article  CAS  PubMed  Google Scholar 

  • Taccioli, G.E., Gottlieb, T.M., Blunt, T. et al. (1994) Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 265: 1442–1445.

    Article  CAS  PubMed  Google Scholar 

  • Tatsuka M., Owada, M.K. and Mitsui, M. (1992) Expression of platelet-derived growth factor-independent phenotypes in BALB/c3T3 cell variant with high susceptibility to chemically or physically induced neoplastic cell transformation: dissociation from activation of protein kinase C. Cancer Res. 52: 4232–4241.

    CAS  PubMed  Google Scholar 

  • Thompson, L.H. and Jeggo, P.A. (1995) Nonmenclature of human genes involved in ionising radiation sensitivity. Mutat. Res. 337: 131–134.

    Article  CAS  PubMed  Google Scholar 

  • Toyoshima, H. and Hunter, T. (1994) p27, a novel inhibitor of G1 cyclin-cdk protein kinase activity, is related to p21. Cell 78: 67–74.

    Article  CAS  PubMed  Google Scholar 

  • Treisman, R. (1996) Regulation of transcription by MAP kinase cascades. Curr. Opin. Cell Biol. 8: 205–215.

    Article  CAS  PubMed  Google Scholar 

  • Troppmair, J. Cleveland, J.L., Askew, D.S. et al (1992) v-Raf/v-Myc synergism in abrogation of IL-3 dependence: v-Raf suppresses apoptosis. Curr. Top. Microbiol. Immunol. 182: 453–460.

    Article  CAS  PubMed  Google Scholar 

  • Uckun, F.M., Tuel-Ahlgren L., Song, C.W. et al.. (1992) Ionising radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death. Proc. Natl. Acad. Sci. USA. 89: 9005–9009.

    Article  CAS  PubMed  Google Scholar 

  • Uckun, F.M., Schieven, G.L., Tuel-Ahlgren, L.M. et al. (1993) Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors. Proc. Natl. Acad. Sci. USA. 90: 252–256.

    Article  CAS  Google Scholar 

  • Uckun, F.M., Waddick, K.G., Mahajan, S. et al. (1996) BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B Cells. Science 273: 1096–1100.

    Article  CAS  PubMed  Google Scholar 

  • Van Antwerp, D.J., Martin, S.J., Kafri, T. et al. (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789.

    Article  PubMed  Google Scholar 

  • Vaux, D.L., Cory S., Addams, J.M. (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalise pre-B cells. Nature 335: 440–442.

    Article  CAS  PubMed  Google Scholar 

  • Verheij M., Bose R., Lin, X.H. et al. (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380: 75–79.

    Article  CAS  PubMed  Google Scholar 

  • Waddick, K.G. and Uckun, F.M. (1993) Effects of recombinant interleukin-3 and recombinant interleukin-6 on radiation survival of normal human bone marrow progenitor cells. Radiat.Oncol. Invest. 1: 34–40.

    Article  CAS  Google Scholar 

  • Wakabayashi-Ito, N. and Nagata, S. (1994) Characterization of the regulatory elements in the promoter of the human elongation factor-1 alpha gene. J. Biol. Chem. 269: 29831–29837.

    CAS  PubMed  Google Scholar 

  • Wang, C.-Y., Mayo, M.W. and Baldwin, A.S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science 274: 784–787.

    Article  CAS  PubMed  Google Scholar 

  • Wang, H.G., Rapp, U.R., Reed, J.C. et al (1996a). Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87: 629–638.

    Article  CAS  PubMed  Google Scholar 

  • Wang, H.G., Takayama S., Rapp, U.R. et al. (1996b). Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc. Natl. Acad. Sci. USA 93: 7063–7068.

    Article  CAS  PubMed  Google Scholar 

  • Wang, X.W., Yeh H., Schaeffer, L. et al. (1995) p53 modulation of TFIIH-associated nucleotide excision repair activity. Nature Genet. 10: 188–195.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y.A., Elson, A. and Leder, P. (1997) Loss of p21 increases sensitivity to ionising radiation and delays the onset of lymphoma in atm-deficient mice. Proc. Natl. Acad. Sci. USA. 94: 14590–14595.

    Article  CAS  PubMed  Google Scholar 

  • Wasylyk, C, Wasylyk B., Heidecker, G. et al. (1989) Expression of raf oncogenes activates the PEA1 transcription factor motif. Mol. Cell. Biol. 9: 2247–2250.

    CAS  PubMed  Google Scholar 

  • Weichselbaum, R.R., Beckett, M.A., Schwartz, J.L. et al. (1988) Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy. Int. J. Radiat. Oncol.Biol. Phys. 15: 575–579.

    Article  CAS  PubMed  Google Scholar 

  • Weissinger, E.M., Eissner G., Grammar, C. et al. (1997) Inhibition of the Raf-1 kinase by cyclic AMP agonists causes apoptosis of v-abl-transformed cells. Mol. Cell. Biol. 17: 3229–3241.

    CAS  PubMed  Google Scholar 

  • Williams, G.T., Smith, C.A., Spooncer, E. et al. (1990) Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature 343: 76–79.

    Article  CAS  PubMed  Google Scholar 

  • Winston, J.T., Coats, S.R., Wang, Y.Z. et al. (1996) Regulation of the cell cycle machinery by oncogenic ras. Oncogene 12: 127–134.

    CAS  PubMed  Google Scholar 

  • Woloschak, G.E., Chang-Liu, C.-M and Shearin-Jones, P. (1990) Regulation of protein kinase C by ionzing radiation. Cancer Res. 50: 3963–3967.

    CAS  PubMed  Google Scholar 

  • Wong, K.-K., Zou X., Merrell, K.T. et al. (1995) v-Abl activates c-myc transcription through the E2F site. Mol. Cell. Biol. 15: 6535–6544.

    CAS  PubMed  Google Scholar 

  • Wood, K.W., Qi H., D‘Arcangelo, G. et al. (1993) The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. Proc. Natl. Acad. Sci USA. 90: 5016–5020.

    Article  CAS  PubMed  Google Scholar 

  • Woods D., Parry D., Cherwinski, H. et al. (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol. Cell. Biol. 17: 5598–5611.

    CAS  PubMed  Google Scholar 

  • Wooster R., Neuhausen, S.L., Mangion, J. et al. (1994) Localization of a breast cancer susceptibility gene, BRCA 2, to chromosome 13q12-13. Nature 265: 2088–2090.

    CAS  Google Scholar 

  • Wu J., Dent P., Jelinek, T. et al. (1993) Inhibition of the EGF-activated MAP kinase signalling pathway by adenosine 3’, 5’-monophosphate. Science 262: 1065–1069.

    Article  CAS  PubMed  Google Scholar 

  • Wu J., Spiegel, S. and Sturgill, T.W. (1995) Sphingosine 1-phosphate rapidly activates the mitogen-activated protein kinase pathway by a G protein-dependent mechanism. J. Biol. Chem. 270: 11484–11488.

    Article  CAS  PubMed  Google Scholar 

  • Xia Z., Dickens M., Raingeaud, J. et al. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326–1331.

    Article  CAS  PubMed  Google Scholar 

  • Yang E., Zha J., Jockel, J. et al. (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80: 285–291.

    Article  CAS  PubMed  Google Scholar 

  • Yang J., Liu X., Bhalla, K. et al. (1997) Prevention of apoptosis by Bcl-2 release of cytochrome C from mitochondria blocked. Science 275: 1129–1132.

    Article  CAS  PubMed  Google Scholar 

  • Yuan, Z.-M., Huang Y., Whang, Y. et al. (1997) Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature 382: 272–274.

    Article  Google Scholar 

  • Zampetti-Bosseler, F. and Scott, D. (1981) Cell death, chromosome damage and mitotic delay in normal human, ataxia telangectasia and retinoblastoma fibroblasts after X-irradiation. Int. J. Radiat. Biol. 39: 547–558.

    Article  CAS  Google Scholar 

  • Zamzami, N. Susin A., Marchetti, P. et al. (1996). Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183: 1533–1544.

    Article  CAS  PubMed  Google Scholar 

  • Zha, J., Harada H., Yang, E. et al (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not Bcl-XL. Cell 87: 619–628.

    Article  CAS  PubMed  Google Scholar 

  • Zhan Q., Fan S., Bae, I. et al. (1994) Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 9: 3743–3751

    CAS  PubMed  Google Scholar 

  • Zhan Q., Alamo I., Yu, K. et al. (1996) The apoptosis-associated γ-ray response of Bcl-XL depends on normal p53 function. Oncogene 13: 2287–2293.

    CAS  PubMed  Google Scholar 

  • Zhou, G. and Kuo, M.T. (1997) NF-κB-mediated induction of mdrlb expression by insulin in rat hepatoma cells. J. Biol. Chem. 272: 15174–15183

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Radiation Medicine and Biochemistry and Molecular Biology, Lombardi Cancer Center, Georgetown University Medical Center, Washington D.C., 20007, USA

    Usha Kasid & Simeng Suy

Authors
  1. Usha Kasid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simeng Suy
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Epithelial Biology Laboratory, CRC Section of Cell and Tumour Biology, Patterson Institute for Cancer Research, Manchester, M20 4BX, UK

    James W. Wilson , Catherine Booth  & Christopher S. Potten ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kasid, U., Suy, S. (1998). Stress-responsive signal transduction: emerging concepts and biological significance. In: Wilson, J.W., Booth, C., Potten, C.S. (eds) Apoptosis Genes. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5287-1_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-5287-1_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7412-1

  • Online ISBN: 978-1-4615-5287-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation