Apoptosis in human disease: a new skin for the old ceremony?

Naturally occurring cell death or apoptosis is essential for the maintenance of tissue homeostasis and serves to remove extraneous or dangerous cells in a swift and unobtrusive manner. Recent studies have indicated a role for apoptosis in a plethora of human diseases. Hence, dysregulation of apoptosis has been implicated in autoimmune disease, acquired immune deficiency syndrome, and other viral (and bacterial) infections, as well as in neurodegenerative disorders and cancer. Furthermore, dysregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis and atherosclerosis and perhaps on the process of aging itself. The present review provides an overview of human diseases, which are associated with defective or inadvertent apoptosis, with examples of pathological conditions in which putative apoptosis defects have been elucidated at the molecular level. Novel apoptosis-modulating therapeutic strategies are also discussed.

[1]  John Calvin Reed,et al.  Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. , 1991, Cancer research.

[2]  Alan G. Porter,et al.  Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis* , 1998, The Journal of Biological Chemistry.

[3]  R. Tanzi,et al.  Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. , 1997, Science.

[4]  R. Voll,et al.  Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. , 1998, Arthritis and rheumatism.

[5]  Lars Holmgren,et al.  Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression , 1995, Nature Medicine.

[6]  P. Vito,et al.  Interfering with Apoptosis: Ca2+-Binding Protein ALG-2 and Alzheimer's Disease Gene ALG-3 , 1996, Science.

[7]  P. Dent,et al.  Loss of the bcl-2 phosphorylation loop domain increases resistance of human leukemia cells (U937) to paclitaxel-mediated mitochondrial dysfunction and apoptosis. , 1999, Biochemical and biophysical research communications.

[8]  David L. Vaux,et al.  Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells , 1988, Nature.

[9]  D. Altieri,et al.  A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma , 1997, Nature Medicine.

[10]  A. Wyllie,et al.  Cell death: the significance of apoptosis. , 1980, International review of cytology.

[11]  P. Doherty,et al.  Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells , 1998, Nature.

[12]  T. Yue,et al.  Apoptosis and congestive heart failure. , 1997, Trends in cardiovascular medicine.

[13]  Matthew J. Brauer,et al.  Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. , 1994, Science.

[14]  K. Wiman p53: emergency brake and target for cancer therapy. , 1997, Experimental cell research.

[15]  J. Blenis,et al.  Caspase-8 Is Required for Cell Death Induced by Expanded Polyglutamine Repeats , 1999, Neuron.

[16]  F. Shanahan,et al.  The Fas counterattack: cancer as a site of immune privilege. , 1999, Immunology today.

[17]  A. Rosen,et al.  Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes , 1994, The Journal of experimental medicine.

[18]  C. Harley,et al.  Extension of life-span by introduction of telomerase into normal human cells. , 1998, Science.

[19]  P. Sansonetti,et al.  Perspectives series: host/pathogen interactions. Apoptosis in bacterial pathogenesis. , 1997, The Journal of clinical investigation.

[20]  David Smith,et al.  Involvement of Caspases in Proteolytic Cleavage of Alzheimer’s Amyloid-β Precursor Protein and Amyloidogenic Aβ Peptide Formation , 1999, Cell.

[21]  T. Griffith,et al.  TRAIL: a molecule with multiple receptors and control mechanisms. , 1998, Current opinion in immunology.

[22]  C. Franceschi,et al.  Genomic Instability and Aging , 1992 .

[23]  B. Zhivotovsky,et al.  Cleavage of Bcl-2 is an early event in chemotherapy-induced apoptosis of human myeloid leukemia cells , 1999, Leukemia.

[24]  A. Shah,et al.  Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. , 1998, The Journal of clinical investigation.

[25]  B. Yankner,et al.  Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro , 1995, Nature.

[26]  M. Dubois‐Dauphin,et al.  Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. , 1997, Science.

[27]  C. Smith,et al.  Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals , 1995, The Journal of experimental medicine.

[28]  P. Debré,et al.  Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients , 1999, Nature Medicine.

[29]  W. Hong,et al.  Retrovirus–mediated wild–type P53 gene transfer to tumors of patients with lung cancer. , 1996, Nature Medicine.

[30]  D. Lane,et al.  p53, guardian of the genome , 1992, Nature.

[31]  J P Luzio,et al.  Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. , 1998, Science.

[32]  T. Landowski,et al.  Mutations in the Fas antigen in patients with multiple myeloma. , 1997, Blood.

[33]  C. Rudin,et al.  Signal transduction pathways that regulate cell survival and cell death , 1998, Oncogene.

[34]  P. Tsao,et al.  Regression of atherosclerosis: role of nitric oxide and apoptosis. , 1999, Circulation.

[35]  C. Portera-Cailliau,et al.  Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  E. Meinl,et al.  Anti-apoptotic strategies of lymphotropic viruses. , 1998, Immunology today.

[37]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[38]  L. Guarente,et al.  Molecular Biology of Aging , 1999, Cell.

[39]  T. Rudel,et al.  Neisserial porin (PorB) causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases , 1999, The EMBO journal.

[40]  F. Fassy,et al.  Evidence for CPP32 Activation in the Absence of Apoptosis during T Lymphocyte Stimulation* , 1997, The Journal of Biological Chemistry.

[41]  L. Montagnier,et al.  Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. , 1996, Journal of immunology.

[42]  M. Rymaszewski,et al.  TRAIL Death Pathway Expression and Induction in Thyroid Follicular Cells* , 1999, The Journal of Biological Chemistry.

[43]  D. Bellgrau,et al.  A role for CD95 ligand in preventing graft rejection , 1995, Nature.

[44]  T. Griffith,et al.  The role of FasL-induced apoptosis in immune privilege. , 1997, Immunology today.

[45]  D. Botstein,et al.  Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer , 1998, Nature.

[46]  J B Schulz,et al.  Caspases as treatment targets in stroke and neurodegenerative diseases , 1999, Annals of neurology.

[47]  S. Korsmeyer,et al.  Bax suppresses tumorigenesis and stimulates apoptosis in vivo , 1997, Nature.

[48]  D. Pode,et al.  Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. , 1999, The Journal of clinical investigation.

[49]  N. Haigwood,et al.  Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis , 1992, The Journal of experimental medicine.

[50]  M. Hengartner Genetic control of programmed cell death and aging in the nematode Caenorhabditis elegans , 1997, Experimental Gerontology.

[51]  D. Nance,et al.  Inhibition of Apoptosis in Chlamydia-infected Cells: Blockade of Mitochondrial Cytochrome c Release and Caspase Activation , 1998, The Journal of experimental medicine.

[52]  Pier Paolo Pandolfi,et al.  Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies , 1998, Nature Genetics.

[53]  I. Herr,et al.  Involvement of the CD95 (APO–1/Fas) receptor/ligand system in drug–induced apoptosis in leukemia cells , 1996, Nature Medicine.

[54]  H. Steller,et al.  Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants , 1998, Nature.

[55]  P. Rorsman,et al.  Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes. , 1993, Science.

[56]  J. Tschopp,et al.  Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors , 1997, Nature.

[57]  S. Orrenius,et al.  The role of calcium in the regulation of apoptosis. , 1996, Journal of leukocyte biology.

[58]  C A Beltrami,et al.  Apoptosis in the failing human heart. , 1997, The New England journal of medicine.

[59]  S. Itohara,et al.  Prions prevent neuronal cell-line death , 1999, Nature.

[60]  Y. Koga,et al.  Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer , 1999, Gut.

[61]  C. Thompson,et al.  Bcl-2-family proteins: the role of the BH3 domain in apoptosis. , 1998, Trends in cell biology.

[62]  Warren Strober,et al.  Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome , 1995, Cell.

[63]  John Calvin Reed,et al.  Tumor suppressor p53 is a direct transcriptional activator of the human bax gene , 1995, Cell.

[64]  A. Nègre-Salvayre,et al.  Bcl‐2 alters the balance between apoptosis and necrosis, but does not prevent cell death induced by oxidized low density lipoproteins , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[65]  D. Spandidos,et al.  Rodent fibroblast tumours expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression. , 1987, British Journal of Cancer.

[66]  W. Earnshaw Apoptosis: A cellular poison cupboard , 1999, Nature.

[67]  C. Stoeckert,et al.  Prevention of Islet Allograft Rejection with Engineered Myoblasts Expressing FasL in Mice , 1996, Science.

[68]  E. White,et al.  Inhibition of apoptosis in human immunodeficiency virus-infected cells enhances virus production and facilitates persistent infection , 1995, Journal of virology.

[69]  J. Cleveland,et al.  Neuroprotection by a caspase inhibitor in acute bacterial meningitis , 1999, Nature Medicine.

[70]  Lisa Garrett,et al.  Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA , 1998, Nature Genetics.

[71]  S. Korsmeyer,et al.  Cell Death in Development , 1999, Cell.

[72]  Qingrong Chen,et al.  Activation of Cytosolic Phospholipase A2 by Platelet-derived Growth Factor Is Essential for Cyclooxygenase-2-dependent Prostaglandin E2 Synthesis in Mouse Osteoblasts Cultured with Interleukin-1* , 1997, The Journal of Biological Chemistry.

[73]  Xiaodong Wang,et al.  Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3 , 1997, Cell.

[74]  Guido Kroemer,et al.  Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution , 1997, Cell Death and Differentiation.

[75]  Natalie A. Lissy,et al.  Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein , 1999, Nature Medicine.

[76]  E. White,et al.  Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells , 1994, Journal of virology.

[77]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

[78]  M. Moskowitz,et al.  Activation and Cleavage of Caspase-3 in Apoptosis Induced by Experimental Cerebral Ischemia , 1998, The Journal of Neuroscience.

[79]  David W. Anderson,et al.  Altered expression of bcl‐2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons , 1996, Annals of neurology.

[80]  P. Knapp,et al.  Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury , 1999, Nature Medicine.

[81]  P. Schur,et al.  Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. , 1996, The Journal of clinical investigation.

[82]  S. Lowe,et al.  Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. , 1999, Science.

[83]  I. Gamstorp,et al.  Progressive Spinal Muscular Atrophies , 1984 .

[84]  J. Roth,et al.  Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression , 1995, Molecular and cellular biology.

[85]  S. Kügler,et al.  Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma , 1999, Cell Death and Differentiation.

[86]  G. Evan,et al.  Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. , 1997, Science.

[87]  R. Weichselbaum,et al.  Combined effects of angiostatin and ionizing radiation in antitumour therapy , 1998, Nature.

[88]  J. Kerr,et al.  Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. , 1992, International journal of radiation biology.

[89]  N. D’alessandro,et al.  The CD95/CD95 ligand system is not the major effector in anticancer drug-mediated apoptosis , 1998, Cell Death and Differentiation.

[90]  Gerard I. Evan,et al.  Induction of apoptosis in fibroblasts by c-myc protein , 1992, Cell.

[91]  G. Salvesen,et al.  Target Protease Specificity of the Viral Serpin CrmA , 1997, The Journal of Biological Chemistry.

[92]  A. Kimchi,et al.  Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6 , 1991, Nature.

[93]  J C Reed,et al.  IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases , 1998, The EMBO journal.

[94]  B. Barres,et al.  Programmed cell death and the control of cell survival: lessons from the nervous system. , 1993, Science.

[95]  K. Schulze-Osthoff,et al.  The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. , 1999, Immunity.

[96]  D. Blacker,et al.  The genetics of Alzheimer disease: current status and future prospects. , 1998, Archives of neurology.

[97]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[98]  V. Metelev,et al.  Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. , 1995, Science.

[99]  W. Schaper,et al.  The role of Fas/APO 1 and apoptosis in the development of human atherosclerotic lesions. , 1997, Atherosclerosis.

[100]  L. Notarangelo,et al.  Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. , 1997, Blood.

[101]  W. Fiers,et al.  Dual Signaling of the Fas Receptor: Initiation of Both Apoptotic and Necrotic Cell Death Pathways , 1998, The Journal of experimental medicine.

[102]  T. Curiel,et al.  Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes , 1995, Nature Medicine.

[103]  C. Duckett,et al.  The iap genes: unique arbitrators of cell death. , 1997, Trends in cell biology.

[104]  G. Evan,et al.  c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. , 1999, Genes & development.

[105]  R. Colvin,et al.  Expression of heme oxygenase-1 can determine cardiac xenograft survival , 1998, Nature Medicine.

[106]  J. Bertin,et al.  Apoptotic suppression by baculovirus P35 involves cleavage by and inhibition of a virus-induced CED-3/ICE-like protease , 1996, Journal of virology.

[107]  J. Buxbaum,et al.  Calsenilin: A calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment , 1998, Nature Medicine.

[108]  S. D. Brady,et al.  Haem oxygenase-1 prevents cell death by regulating cellular iron , 1999, Nature Cell Biology.

[109]  J. Freyssinet,et al.  Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. , 1999, Circulation.

[110]  Marcel Leist,et al.  Caspase inhibition reduces apoptosis and increases survival of nigral transplants , 1999, Nature Medicine.

[111]  J. Cusack,et al.  Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB , 1999, Nature Medicine.

[112]  G. Cortopassi,et al.  Mitochondria in organismal aging and degeneration. , 1999, Biochimica et biophysica acta.

[113]  D. H. Burgess,et al.  Human skeletal muscle cytosols are refractory to cytochrome c-dependent activation of type-II caspases and lack APAF-1 , 1999, Cell Death and Differentiation.

[114]  Z. Wang,et al.  Bisindolylmaleimide VIII facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases , 1999, Nature Medicine.

[115]  P. Guldberg,et al.  Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. , 1998, Blood.

[116]  A. Capron,et al.  Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. , 1991, Immunology today.

[117]  Seamus J. Martin,et al.  Acid Sphingomyelinase–Deficient Human Lymphoblasts and Mice Are Defective in Radiation-Induced Apoptosis , 1996, Cell.

[118]  L. Turka,et al.  Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes , 1998, Nature Medicine.

[119]  K. Hall,et al.  Serum from patients with type 2 diabetes with neuropathy induces complement-independent, calcium-dependent apoptosis in cultured neuronal cells. , 1998, The Journal of clinical investigation.

[120]  P. Roberson,et al.  Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. , 1999, The Journal of clinical investigation.

[121]  T. Myers,et al.  Expression and location of pro-apoptotic Bcl-2 family protein BAD in normal human tissues and tumor cell lines. , 1998, The American journal of pathology.

[122]  J. Antel,et al.  Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death , 1996, The Journal of experimental medicine.

[123]  J. Puck,et al.  Inherited Human Caspase 10 Mutations Underlie Defective Lymphocyte and Dendritic Cell Apoptosis in Autoimmune Lymphoproliferative Syndrome Type II , 1999, Cell.

[124]  K. Okumura,et al.  CD95 ligand in graft rejection , 1996, Nature.

[125]  M. Todaro,et al.  Potential Involvement of Fas and Its Ligand in the Pathogenesis of Hashimoto's Thyroiditis , 1997, Science.

[126]  Biochemical and genetic control of apoptosis: relevance to normal hematopoiesis and hematological malignancies. , 1999 .

[127]  G. Robertson,et al.  Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus , 1997, Nature Medicine.

[128]  G. Anderson Resolution of chronic inflammation by therapeutic induction of apoptosis. , 1996, Trends in pharmacological sciences.

[129]  I. Ferrer Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis? , 1999, Acta Neuropathologica.

[130]  W. Dalton,et al.  Selection for drug resistance results in resistance to Fas-mediated apoptosis. , 1997, Blood.

[131]  D. Green,et al.  Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege , 1995, Science.

[132]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[133]  D. Harrison,et al.  Apoptosis: an overview of the process and its relevance in disease. , 1997, Advances in pharmacology.

[134]  A. Chinnaiyan,et al.  The inhibition of pro-apoptotic ICE-like proteases enhances HIV replication , 1997, Nature Medicine.

[135]  K. Elkon,et al.  Apoptosis in the effector phase of autoimmune diabetes, multiple sclerosis and thyroiditis , 1999, Cell Death and Differentiation.

[136]  M. Hayden,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 , 1998, Cell Death and Differentiation.

[137]  M. Bennett,et al.  Apoptosis of vascular smooth muscle cells in atherosclerosis. , 1998, Atherosclerosis.

[138]  S. Lipton,et al.  Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function , 1995, Neuron.

[139]  Junying Yuan,et al.  Inhibition of ICE slows ALS in mice , 1997, Nature.

[140]  F. Miedema,et al.  Programmed death of T cells in HIV-1 infection. , 1992, Science.

[141]  A. Fattaey,et al.  An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells , 1996, Science.

[142]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[143]  P. Gregersen,et al.  Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4 , 1998, Nature.

[144]  M. Moskowitz,et al.  Attenuation of Delayed Neuronal Death after Mild Focal Ischemia in Mice by Inhibition of the Caspase Family , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[145]  K. Sullivan,et al.  Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. , 1996, The New England journal of medicine.

[146]  F. Miedema,et al.  Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease. , 1994, The Journal of clinical investigation.

[147]  P. Galle,et al.  Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. , 1998, The Journal of clinical investigation.

[148]  G. Robertson,et al.  Attenuation of Ischemia-Induced Cellular and Behavioral Deficits by X Chromosome-Linked Inhibitor of Apoptosis Protein Overexpression in the Rat Hippocampus , 1999, The Journal of Neuroscience.

[149]  P. Walker,et al.  CD95 (Fas/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation? , 1999, Journal of immunology.

[150]  C. Haslett,et al.  Phagocyte recognition of cells undergoing apoptosis. , 1993, Immunology today.

[151]  M. Matsuoka,et al.  Mutation of CD95 (Fas/Apo-1) Gene in Adult T-Cell Leukemia Cells , 1998 .

[152]  A. Zychlinsky,et al.  A bacterial invasin induces macrophage apoptosis by binding directly to ICE. , 1996, The EMBO journal.

[153]  J. W. Saunders,et al.  Death in Embryonic Systems , 1966, Science.

[154]  B. Zhivotovsky,et al.  All along the watchtower: on the regulation of apoptosis regulators , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[155]  B. Pettmann,et al.  Neuronal Cell Death , 1998, Neuron.

[156]  F. Ramsdell,et al.  Fas and FasL in the homeostatic regulation of immune responses. , 1995, Immunology today.

[157]  Y. Matsuzawa,et al.  Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice , 1997, The Journal of experimental medicine.

[158]  J. Weinberg,et al.  Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury , 1998, Oncogene.

[159]  J. Bergh,et al.  Higher spontaneous apoptotic index in small cell compared with non-small cell lung carcinoma cell lines; lack of correlation with Bcl-2/Bax. , 1998, Lung cancer.

[160]  G. Ruvkun,et al.  The genetics of aging. , 1997, Annual review of genomics and human genetics.

[161]  G. Forloni,et al.  Neurotoxicity of a prion protein fragment , 1993, Nature.

[162]  T Kotani,et al.  Apoptosis in thyroid tissue from patients with Hashimoto's thyroiditis. , 1995, Autoimmunity.

[163]  T. McDonnell,et al.  Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. , 1996, Leukemia.

[164]  M. Hayden,et al.  Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract , 1996, Nature Genetics.

[165]  B. Zhivotovsky,et al.  Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. , 1998, The Journal of biological chemistry.

[166]  J. Bertin,et al.  Human CARD4 Protein Is a Novel CED-4/Apaf-1 Cell Death Family Member That Activates NF-κB* , 1999, The Journal of Biological Chemistry.

[167]  Y. Yazaki,et al.  Apoptotic cell death in atherosclerotic plaques of hyperlipidemic knockout mice. , 1997, Atherosclerosis.

[168]  J. Thyberg,et al.  Ca2+ channel blockers verapamil and nifedipine inhibit apoptosis induced by 25-hydroxycholesterol in human aortic smooth muscle cells. , 1997, Journal of lipid research.

[169]  F. Rieux-Laucat,et al.  Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. , 1995, Science.

[170]  J. Kerr,et al.  An electron‐microscope study of the mode of cell death induced by cancer‐chemotherapeutic agents in populations of proliferating normal and neoplastic cells , 1975, The Journal of pathology.

[171]  P. Ernst,et al.  Review article: the role of inflammation in the pathogenesis of gastric cancer , 1999, Alimentary pharmacology & therapeutics.

[172]  S. Nagata,et al.  Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. , 1999, The Journal of clinical investigation.

[173]  S. Nagata,et al.  Apoptosis by Death Factor , 1997, Cell.

[174]  T. Crawford,et al.  The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy , 1995, Cell.