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Current concepts in apoptosis: The physiological suicide program revisited

Cellular & Molecular Biology Letters volume 11, pages 506–525 (2006)Cite this article

Abstract

Apoptosis, or programmed cell death (PCD), involves a complex network of biochemical pathways that normally ensure a homeostatic balance between cellular proliferation and turnover in nearly all tissues. Apoptosis is essential for the body, as its deregulation can lead to several diseases. It plays a major role in a variety of physiological events, including embryonic development, tissue renewal, hormone-induced tissue atrophy, removal of inflammatory cells, and the evolution of granulation tissue into scar tissue. It also has an essential role in wound repair. The various cellular and biochemical mechanisms involved in apoptosis are not fully understood. However, there are two major pathways, the extrinsic pathway (receptor-mediated apoptotic pathway) and the intrinsic pathway (mitochondria-mediated apoptotic pathway), which are both well established. The key component in both is the activation of the caspase cascade. Caspases belong to the family of proteases that ultimately, by cleaving a set of proteins, cause disassembly of the cell. Although the caspase-mediated proteolytic cascade represents a central point in the apoptotic response, its initiation is tightly regulated by a variety of other factors. Among them, Bcl-2 family proteins, TNF and p53 play pivotal roles in the regulation of caspase activation and in the regulation of apoptosis. This review summarizes the established concepts in apoptosis as a physiological cell suicide program, highlighting the recent and significant advances in its study.

Abbreviations

Apaf-1:

apoptosis protease activating factor-1

Bcl:

B-cell lymphoma family

BH:

Bcl-2 homology

tBid:

truncated Bid

BIR:

baculoviral IAP repeat

BRUCE:

BIR repeat-containing ubiquitin-conjugating enzyme

CARD:

caspase recruitment domain

CDR:

cysteine-rich extracellular domain

DISC:

death-inducing signaling complex

DD:

death domain

DED:

death effector domain

DR:

death-inducing receptor

ER:

endoplasmic reticulum

FADD:

Fas-associated death domain protein

FLIP:

FADD-like-ICE-inhibitory protein or FLICE inhibitory protein

G1:

GAP1

IAP:

inhibitor of apoptosis

IL:

interleukin

MOMP:

mitochondrial outer membrane permeabilization

PCD:

programmed cell death

PUMA:

p53-up-regulated modulator of apoptosis

PS:

phosphatidylserine

PTP:

permeability transition pore

RIP:

receptor interacting protein

TACE:

TNF alpha-converting enzyme

TGF-β:

transforming growth factor-β

TNF-α:

tumor necrosis factor α

TNFR-1:

tumor necrosis factor receptor-1

TRAIL:

TNF-related apoptosis-inducing ligand

TRADD:

TNF-receptor associated protein with death domain

TUNEL:

terminal deoxynucleotidyl transferase-mediated (TdT-mediated) dUTP-digoxigenin nick end labeling

VDAC:

voltage-dependent anion channel

References

  1. Vaux, D.L. and Korsmeyer, S.J. Cell death in development. Cell 96 (1999) 245–254.

    Article  PubMed  CAS  Google Scholar 

  2. Kerr, J.F.R. An electron-microscope study of liver cell necrosis due to Albitocin. Pathology 2 (1970) 251–259.

    PubMed  CAS  Google Scholar 

  3. Kerr, J.F.R. Shrinkage necrosis: A distinct mode of cellular death. J. Path. 105 (1971) 13–20.

    Article  PubMed  CAS  Google Scholar 

  4. Kerr, J.F. Wyllie, A.H. and Currie, A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26 (1972) 239–257.

    PubMed  CAS  Google Scholar 

  5. Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267 (1995) 1456–1462.

    Article  PubMed  CAS  Google Scholar 

  6. Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 15 (2001) 2922–2933.

    PubMed  CAS  Google Scholar 

  7. Hortvitz, H.R. Worm, life and death (Nobel lecture). Chembiochem. 4 (2003) 697–711.

    Article  Google Scholar 

  8. Danial, N.N. and Krosmeyer, S.J. Cell death: critical control points. Cell 116 (2004) 205–219.

    Article  PubMed  CAS  Google Scholar 

  9. Schwartzman, R.A. and Cidlowski, J.A. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr. Rev. 14 (1993) 133–51.

    Article  PubMed  CAS  Google Scholar 

  10. Cohen, J.J. Apoptosis. Immunol. Today 14 (1993) 126–130.

    Article  PubMed  CAS  Google Scholar 

  11. Vaux, D.L. and Strasser, A. The molecular biology of apoptosis. Proc. Natl. Acad. Sci. USA 93 (1996) 2239–2244.

    Article  PubMed  CAS  Google Scholar 

  12. Levine, B. and Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115 (2005) 2679–2688.

    Article  PubMed  CAS  Google Scholar 

  13. Clarke, P.G. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. (Berl.) 181 (1990) 195–213.

    Article  CAS  Google Scholar 

  14. Bursch, W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 8 (2001) 569–581.

    Article  PubMed  CAS  Google Scholar 

  15. Majno, G. and Joris, I. Apoptosis, oncosis and necrosis. An overview of cell death. Am. J. Pathol. 146 (1995) 3–15.

    PubMed  CAS  Google Scholar 

  16. Broker, L.E., Kruyt, F. and Giaccone, G. Cell death independent of caspases: a review. Clin. Cancer Res. 11 (2005) 3155–3162.

    Article  PubMed  Google Scholar 

  17. Castedo, M., Perfettini, J.L., Roumier, T., Andreau, K., Medema, R. and Kroemer, G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 23 (2004) 2825–2837.

    Article  PubMed  CAS  Google Scholar 

  18. Earnshaw, W.C. Nuclear changes in apoptosis. Cur. Opin. Cell Biol. 7 (1995) 337–343.

    Article  CAS  Google Scholar 

  19. Au, J.L., Panchal, N., Li, D. and Gan, Y. Apoptosis: a new pharmacodynamic endpoint. Pharm. Res. 14 (1997) 1659–1671.

    Article  PubMed  CAS  Google Scholar 

  20. Gong, J., Traganos, F. and Darsynkiewicz, Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal. Biochem. 218 (1994) 314–319.

    Article  PubMed  CAS  Google Scholar 

  21. Bortner, C.D., Oldenburg, N.D. and Cidlowski, J.A. The role of DNA fragmentation in apoptosis. Trends Cell Biol. 5 (1995) 21–26.

    Article  PubMed  CAS  Google Scholar 

  22. Dive, C., Gregory, C.D., Phopps, D.J., Evans, D.L., Milner, A.E. and Wyllie, A.H. Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochem. Biophys. Acta 1133 (1992) 275–285.

    Article  PubMed  CAS  Google Scholar 

  23. Hamel, W., Dazin, P. and Israel, M. Adaptation of a simple flow cytometric assay to identify different stages during apoptosis. Cytometry 25 (1996) 173–181.

    Article  PubMed  CAS  Google Scholar 

  24. Gavrieli, Y., Sherman, Y. and Benassan, S.A. Identification of programmed cell death in situ via special labeling of nuclear DNA fragments. J. Cell Biol. 119 (1992) 493–501.

    Article  PubMed  CAS  Google Scholar 

  25. Charriaut-Malangue, C. and Ben-Ari, Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport 7 (1995) 61–64.

    Google Scholar 

  26. Lecoeur, H., Prevost, M.C. and Gougeon, M.L. Oncosis is associated with exposure of phosphatidylserine residues on the outside layer of the plasma membrane: a reconsideration of the specificity of the annexin V/propidium iodide assay. Cytometry 44 (2001) 65–72.

    Article  PubMed  CAS  Google Scholar 

  27. Alnemri, E.S., Livingston, D.W., Nicholson, D.W., Salvesen, G., Thornberry, N.A., Wong, W.W. and Yuan, J. Human ICE/CED-3 protease nomenclature. Cell 87 (1996) 171.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Lavarik, I.N., Golks, A. and Krammer, P.H. Caspases: pharmacological manipulation of cell death. J. Clin. Invest. 115 (2005) 2665–2672.

    Article  Google Scholar 

  30. Yuan, J., Shahan, S., Ledoux, S., Ellis, H.M. and Horvitz, H.R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta converting enzyme. Cell 75 (1993) 641–652.

    Article  PubMed  CAS  Google Scholar 

  31. Shi, Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell 9 (2002) 459–470.

    Article  PubMed  CAS  Google Scholar 

  32. Yan, N. and Shi, Y. Mechanisms of apoptosis through structural biology. Ann. Rev. Cell Dev. Biol. 21 (2005) 35–56.

    Article  CAS  Google Scholar 

  33. Stennicke, H.R. and Salvesen, G.S. Properties of the caspases. Biochim. Biophys. Acta 1387 (1998) 17–31.

    PubMed  CAS  Google Scholar 

  34. Grutter, M.G. Caspases: Key players in programmed cell death. Curr. Opin. Struct. Biol. 10 (2000) 649–655.

    Article  PubMed  CAS  Google Scholar 

  35. Roth, K.A. Caspases, apoptosis, and Alzheimer’s disease: causation, correlation, and confusion. J. Neuropathol. Exp. Neurol. 60 (2001) 829–838.

    PubMed  CAS  Google Scholar 

  36. Cohen, G.M. Caspases: the executioners of apoptosis. Biochem. J. 326 (1997) 1–16.

    PubMed  CAS  Google Scholar 

  37. Marshman, E., Ottewell, P.D., Potten, C.S. and Watson, A.J. Caspase activation during spontaneous and radiation-induced apoptosis in the murine intestine. J. Pathol. 195 (2001) 285–292.

    Article  PubMed  CAS  Google Scholar 

  38. Clerk, A., Cole, S.M., Cullingford, T.E., Harrison, J.C., Jormakka, M. and Valks, D.M. Regulation of cardiac myocyte cell death. Pharmacol. Ther. 97 (2003) 223–61.

    Article  PubMed  CAS  Google Scholar 

  39. Nagata, S. Apoptotic DNA fragmentation. Exp. Cell Res. 256 (2000) 12–18.

    Article  PubMed  CAS  Google Scholar 

  40. Earnshaw, W.C., Martins, L.M. and Kaufmann, S.H. Mammalian caspases: Structure, activation, substrates and functions during apoptosis. Ann. Rev. Biochem. 68 (1999) 383–424.

    Article  PubMed  CAS  Google Scholar 

  41. Liu, X., Kim, C.N., Yang, J., Jemmerson, R. and Wang, X. Induction of apoptosis program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 86 (1996) 147–157.

    Article  PubMed  CAS  Google Scholar 

  42. Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., and Nagata, S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391 (1998) 43–50.

    Article  PubMed  CAS  Google Scholar 

  43. Coleman, M.L., Sahai, E.A., Yeo, M., Bosch, M., Dewar, A. and Olson, M.F. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat. Cell Biol. 3 (2001) 339–345.

    Article  PubMed  CAS  Google Scholar 

  44. Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory disease. Cell 117 (2004) 561–574.

    Article  PubMed  CAS  Google Scholar 

  45. Roy, N., Mahadevan, M.S., McLean, M., Shutler, G., Yaraghi, Z., Farahani, R., Baird, S., Benser-Johnson, A., Lefebvre, C., Kang, X., Salih, M., Aubry, H., Tamai, K., Guan, X., Ioannou, P., Crawford, T.O., de Jong, P.J., Surh, L., Ikeda, J.E., Korneluk, R.G. and Mac Kenzie, A. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80 (1995) 167–178.

    Article  PubMed  CAS  Google Scholar 

  46. Cheng, E.H., Levine, B., Boise, L.H., Thompson, C.B. and Hardwick, J.M. Bax-independent inhibition of apoptosis by Bcl-XL. Nature 379 (1996) 554–556.

    Article  PubMed  CAS  Google Scholar 

  47. Salvesen, G.S. and Duckett, C.S. IAP proteins: blocking the road to death’s door. Nat. Rev. Mol. Cell Biol. 3 (2002) 401–410.

    Article  PubMed  CAS  Google Scholar 

  48. Deveraux, Q.L. and Reed, J.C. IAP family proteins: suppressors of apoptosis. Genes Dev. 13 (1999) 239–252.

    PubMed  CAS  Google Scholar 

  49. Ekert, P.G., Silke, J. and Vaux, D.L. Caspase inhibitor. Cell Death Differ. 6 (1999) 1081–1086.

    Article  PubMed  CAS  Google Scholar 

  50. Birnbaum, M.J., Clem, R.J. and Miller, L.K. An apoptosis inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J. Virol. 68 (1994) 2521–2528.

    PubMed  CAS  Google Scholar 

  51. Deveraux, Q.L., Takahashi, R., Salvesen, G.S. and Reed, J.C. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388 (1997) 300–304.

    Article  PubMed  CAS  Google Scholar 

  52. Deveraux, Q.L., Roy, H.R., Stennicke, H.R., Van Arsdale, T., Zhou, Q., Srinivasula, M., Alnemri, E.S., Salvesen, G.S. and Reed, J.C. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17 (1998) 2215–2223.

    Article  PubMed  CAS  Google Scholar 

  53. Roy, N., Deveraux, Q.I., Takashashi, R., Salvesen, G.S. and Reed, J.C. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16 (1997) 6914–6925.

    Article  PubMed  CAS  Google Scholar 

  54. Miller, L.K. An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol. 9 (1999) 323–328.

    Article  PubMed  CAS  Google Scholar 

  55. Xu, G., Cirilli, M., Huang, Y., Rich, R.L., Myszka, D.G. and Wu, H. Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex. Nature 410 (2001) 494–497.

    Article  PubMed  CAS  Google Scholar 

  56. Renatus, M., Zhou, Q., Stennicke, H.R., Snipas, S.J., Turk, D., Bankston, L.A., Liddington, R.C. and Salvesen, G.S. Crystal structure of the apoptotic suppressor CrmA in its cleaved form. Structure Fold. Des. 8 (2000) 789–797.

    Article  PubMed  CAS  Google Scholar 

  57. Sato, T., Irie, S., Krajewski, S. and Reed, J.C. Cloning and sequencing of a cDNA encoding the rat Bcl2 protein. Gene 140 (1994) 291–292.

    Article  PubMed  CAS  Google Scholar 

  58. Adams, J.M. and Cory, S. The Bcl-2 protein family: Arbiters of cell survival. Science 281 (1998) 1322–26.

    Article  PubMed  CAS  Google Scholar 

  59. Burlacu, A. Regulation of apoptosis by Bcl-2 family proteins. J. Cell. Mol. Med. 7 (2003) 249–257.

    PubMed  CAS  Google Scholar 

  60. Tsujimoto, Y., Cossman, J., Jaffe, E. and Croce, C.M. Involvement of the Bcl-2 gene in human follicular lymphoma. Science 228 (1985) 1440–1443.

    Article  PubMed  CAS  Google Scholar 

  61. Cory, S. and Adams, J.M. The Bcl2 family: regulators of the cellular life or death switch. Nat. Rev. Cancer 2 (2002) 647–656.

    Article  PubMed  CAS  Google Scholar 

  62. Puthalakath, H. and Strasser, A. Keeping killers on a tight leash: transcriptional and post-transcriptional control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 9 (2002) 505–512.

    Article  PubMed  CAS  Google Scholar 

  63. Zhu, W., Cowie, A., Wasfy, G.W., Penn, L.Z., Leber, B. and Andrew, D.W. Bcl2 mutants with restricted sub cellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J. 15 (1996) 4130–4141.

    PubMed  CAS  Google Scholar 

  64. Griffiths, G.J., Dubrez, L., Morgan, C.P., Jones, N.A., Whitehouse, J., Corfe, B.M., Dive, C. and Hickman, J.A. Cell damage-induced conformational changes of the pro-apoptotic protein Bak in-vivo precede the onset of apoptosis. J. Cell Biol. 144 (1999) 903–914.

    Article  PubMed  CAS  Google Scholar 

  65. Krajewski, S., Tanaka, S., Takayama, S., Schibler, M.J., Fenton, W. and Reed, J.C. Investigation of the Bcl-2 oncoprotein: Residence in the nuclear envelop, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res. 53 (1993) 4701–4714.

    PubMed  CAS  Google Scholar 

  66. Nguyen, M., Millar, D.G., Yong, V.W., Korsmeyer, S.J. and Shore, G.C. Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J. Biol. Chem. 268 (1993) 25265–25268.

    PubMed  CAS  Google Scholar 

  67. Hussein, M.R., Haemel, A.K. and Wood, G.S. Apoptosis and melanoma: molecular mechanism. J. Pathol. 199 (2003) 275–288.

    Article  PubMed  CAS  Google Scholar 

  68. Gross, A., Mcdonnell, J.M. and Krosmeyer, S.J. Bcl-2 family members and the mitochondria in apoptosis. Genes Develop. 13 (1999) 1899–1911.

    PubMed  CAS  Google Scholar 

  69. Erster, S. and Moll, U.M. Stress induced p53 runs a transcription-independent death program. Biochem. Biophys. Res. Commun. 331 (2005) 843–850.

    Article  PubMed  CAS  Google Scholar 

  70. Owen-Schaub, L.B., Angelo, L.S., Radinsky, R., Ware, C.F., Gesner, T.G. and Bartos, D.P. Soluble FAS/APO-1 in tumor cells: a potential regulator of apoptosis? Cancer Lett. 94 (1995) 1–8.

    Article  PubMed  CAS  Google Scholar 

  71. Park, D.S., Stefanis, L. and Greene, L.A. Ordering the multiple pathways of apoptosis. Trends Cardiovasc. Med. 7 (1997) 294–299.

    Article  CAS  Google Scholar 

  72. Duensing, A. and Duensing, S. Guilt by association? p53 and development of aneuploidy in cancer. Biochem. Biophys. Res. Commun. 331 (2005) 694–700.

    Article  PubMed  CAS  Google Scholar 

  73. Aggarwal, B.B. Tumor necrosis factor receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kB. Ann. Rheum. Dis. 59 (2000) 6–16.

    Article  Google Scholar 

  74. Idriss, H.T. and Naismith, J.H. TNF alpha and the TNF receptor super family: structure-function relationship(s). Micro. Res. Tech. 50 (2000) 184–195.

    Article  CAS  Google Scholar 

  75. MacEwan, D.J. TNF ligands and receptors — a matter of life and death. Br. J. Pharm. 135 (2002) 855–875.

    Article  CAS  Google Scholar 

  76. Wajant, H., Pfizenmaier, K. and Scheurich, P. Tumor necrosis factor signaling. Cell Death Diff. 10 (2003) 45–65.

    Article  CAS  Google Scholar 

  77. Hussein, M.R., Haemel, A.K. and Wood, G.S. p53 related pathways and the molecular pathogenesis of melanoma. Eur. J. Cancer Prev. 12 (2003) 93–100.

    Article  PubMed  CAS  Google Scholar 

  78. Green, D. and Reed, J. Mitochondria and apoptosis. Science 281 (1998) 1309–1312.

    Article  PubMed  CAS  Google Scholar 

  79. Tsujimoto, Y. and Shimizu, S. The voltage-dependent anion channel: an essential player in apoptosis. Biochimie 84 (2002) 187–193.

    Article  PubMed  CAS  Google Scholar 

  80. Reed, J.C. Bcl-2 family proteins. Oncogene 17 (1998) 3225–3236.

    Article  PubMed  Google Scholar 

  81. Shimizu, S., Narita, M. and Tsujimoto, Y. Bcl-2 family protein regulates the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399 (1999) 483–487.

    Article  PubMed  CAS  Google Scholar 

  82. Ashkenazi, A. and Dixit, V.M. Death receptors: signaling and modulation. Science 281 (1998) 1305–1308.

    Article  PubMed  CAS  Google Scholar 

  83. Schulze-Osthoff, K., Ferrari, D., Los, M., Wesselborg, S. and Peter, M.E. Apoptosis signaling by death receptors. Eur. J. Biochem. 254 (1998) 439–459.

    Article  PubMed  CAS  Google Scholar 

  84. Peter, M.E. and Krammer, P.H. Mechanisms of CD95 (APO-1/ Fas)-mediated apoptosis. Curr. Opin. Immunol. 10 (1998) 545–551.

    Article  PubMed  CAS  Google Scholar 

  85. Peter, M.E. and Krammer, P.H. The CD95 (APO-1/ Fas) DISC and beyond. Cell Death Differ. 10 (2003) 26–35.

    Article  PubMed  CAS  Google Scholar 

  86. Li, H., Zhu, H., Xu, C.J. and Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94 (1998) 491–501.

    Article  PubMed  CAS  Google Scholar 

  87. Luo, X., Budihardjo, I., Zou, H., Slaughter, C. and Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94 (1998) 481–490.

    Article  PubMed  CAS  Google Scholar 

  88. Chaudhary, P.M., Eby, M., Jasmin, A., Bookwalter, A., Murray, J. and Hood, L. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappa B pathway. Immunity 7 (1997) 821–830.

    Article  PubMed  CAS  Google Scholar 

  89. Stennicke, H.R., Jurgensmeier, J.M., Shin, H., Deveraux, Q., Wolf, B.B., Yang, X., Zhou, Q., Ellerby, H.M., Ellerby, L.M., Bredesen, D., Green, D.R., Reed, J.C., Froelich, C.J. and Salvesen, G. S. Procaspase-3 is a major physiologic target of caspase-8. J. Biol. Chem. 273 (1998) 27084–27090.

    Article  PubMed  CAS  Google Scholar 

  90. Scaffidi, C., Schmitz, I., Krammer, P.H. and Peter, M.E. The role of c-FLIP in modulation of CD95 induced apoptosis. J. Biol. Chem. 274 (1999) 1541–1548.

    Article  PubMed  CAS  Google Scholar 

  91. Golks, A., Brenner, D., Fritsch, C., Krammer, P.H. and Lavrik, L.N. cFLIPR: a new regulator of death receptor-induced apoptosis. J. Biol. Chem. 280 (2005) 14507–14513.

    Article  PubMed  CAS  Google Scholar 

  92. Harris, S.L. and Levine, A.J. The p53 pathway: positive and negative feed back loops. Oncogene 24 (2005) 2899–2908.

    Article  PubMed  CAS  Google Scholar 

  93. Li, F., Srinivasam, A., Wang, Y., Armstrong, R.C., Tomaselli, K.J. and Fritz, L.C. Cell-specific induction of apoptosis by microinjection of cytochrome c. J. Biol. Chem. 272 (1997) 30299–30305.

    Article  PubMed  CAS  Google Scholar 

  94. Hengartner, M.O. The biochemistry of apoptosis. Nature 407 (2000) 770–776.

    Article  PubMed  CAS  Google Scholar 

  95. Xu, C., Bailly-Maitre, B. and Reed, J.C. Endoplasmic reticulam stress: cell life and death decisions. J. Clin. Invest. 115 (2005) 2656–2664.

    Article  PubMed  CAS  Google Scholar 

  96. Hick, S.W. and Machamer, C.E. Golgi structure in stress sensing and apoiptosis. Biochem. Biophys. Acta 1744 (2005) 406–414.

    Article  Google Scholar 

  97. Wu, Y., Tibrewal, N. and Brige, R.B. Phospohatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol. 16 (2006) 189–197.

    Article  PubMed  CAS  Google Scholar 

  98. Savill, J. Recognition and phagocytosis of cells undergoing apoptosis. Br. Med. Bull. 53 (1997) 491–508.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, GA, USA

    Indrajit Chowdhury & Ganapathy K. Bhat

  2. Department of Neurology, Scott and White Clinic, The Texas A & M University Health Science Center, College of Medicine, Temple, Texas, USA

    Binu Tharakan

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  1. Indrajit Chowdhury
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  2. Binu Tharakan
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Chowdhury, I., Tharakan, B. & Bhat, G.K. Current concepts in apoptosis: The physiological suicide program revisited. Cell Mol Biol Lett 11, 506–525 (2006). https://doi.org/10.2478/s11658-006-0041-3

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Key words

  • Apoptosis
  • Programmed cell death
  • Pathways
  • Caspases
  • Bcl-2
  • p53
  • TNF
  • Apaf

Cellular & Molecular Biology Letters

ISSN: 1689-1392

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