SUMMARY AND CONCLUSION
From the initial description as a merely morphological phenomenon, the concept of apoptosis has evolved into an extremely complex, highly regulated biochemical and genetic process.
Its crucial role in animal development and preservation of tissue homeostasis is documented by the presence of an evolutionarily conserved apoptotic machinery in virtually every organism. The capability of eliminating aged and potentially harmful cells in a controlled cellular environment is critical for maintaining the health of an organism, and it is not surprising that alterations in apoptosis, either leading to increased or reduced cell death, are generally associated with the development of pathologic conditions.Although apoptosis can be triggered by many different extracellular or intracellular stimuli, the intracellular signaling proceeds generally through two main pathways: an intrinsic, mitochondria- mediated pathway and an extrinsic, death receptor-mediated pathway. Both pathways ultimately lead to the activation of effector caspases that are directly responsible for the degradation of cellular substrates. In a simplified version of the overall process of cell death, apoptotic stresses acting through the intrinsic pathway trigger the activation of proapoptotic members of the Bcl-2 family, the most important regulators of mitochondrial function. The balance of pro- and antiapoptotic Bcl- 2 proteins determines the outcome of the process. Sufficient activation of the proapoptotic proteins results in permeabilization of the outer mitochondrial membrane and release of several proapop- togenic proteins, including cytochrome c and Smac/DIABLO. The release of cytochrome c triggers the formation of a complex (apoptosome) where initiator caspase-9 is activated. At the same time, Smac/DIABLO antagonizes the caspase-inhibiting effect of the endogenous IAPs.
Apoptotic signals initiated at the level of plasma membrane after engagement of the death receptors result in activation of the initiator caspase-8, -10, and, possibly, -2. These caspases, then, can activate downstream caspases directly or indirectly by triggering the mitochondrial pathway via cleavage and activation of the BH3-only protein Bid. Ultimately, the two pathways converge when activated initiator caspases (caspase-8, -9, and -10) cleave and activate downstream caspases, such as caspase-3 and -7.ACKNOWLEDGMENT
This work was supported by grants from the National Institute of Health DK 41876 (to G.J.G.) and the Mayo Foundation, Rochester, Minnesota.
REFERENCES
1. Kerr, J.F.R., Wyllie, A.H. and Currie, A.R., Apoptosis: a basic biological phenomenon with wide- ranging implications in tissue kinetics, Br. J. Cancer, 26, 239, 1972.
2. Jacobson, M.D., Weil, M. and Raff, M.C., Programmed cell death in animal development, Cell, 88, 347, 1997.
3. Wyllie, A.H., Kerr, J.F. and Currie, A.R., Cell death: the significance of apoptosis, Int. Rev. Cytol., 68, 251, 1980.
4. Leist, M. and Jaattela, M., Four deaths and a funeral: from caspases to alternative mechanisms, Nat. Rev. Mol. Cell Biol., 2, 589, 2001.
5. Nicholson, D.W. and Thornberry, N.A., Caspases: killer proteases, Trends Biochem. Sci., 22, 299, 1997.
6. Earnshaw, W.C., Martins, L.M. and Kaufmann, S.H., Mammalian caspases: structure, activation, substrates, and functions during apoptosis, Annu. Rev. Biochem., 68, 383, 1999.
7. Vaux, D.L., Cory, S. and Adams, J.M., Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells, Nature, 335, 440, 1988.
8. Cory, S. and Adams, J.M., The Bcl2 family: regulators of the cellular life-or-death switch, Nat. Rev. Cancer, 2, 647, 2002.
9. Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Martinou, I., Bernasconi, L., Bernard, A., Mermod, J.J., Mazzei, G., Maundrell, K., Gambale, F., Sadoul, R.
and Martinou, J.C., Inhibition of Bax channel-forming activity by Bcl-2, Science, 277, 370, 1997.10. Hsu, Y.T. and Youle, R.J., Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations, J. Biol. Chem., 272, 10777, 1998.
11. Antonsson, B., Montessuit, S., Sanchez, B. and Martinou, J.C., Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells, J. Biol. Chem., 276, 11615, 2001.
12. Nechushtan, A., Smith, C.L., Lamensdorf, I., Yoon, S.H. and Youle, R.J., Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis, J. Cell Biol., 153, 1265, 2001.
13. Wei, M.C., Lindsten, T., Mootha, V.K., Weiler, S., Gross, A., Ashiya, M., Thompson, C.B., and Korsmeyer, S.J., tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c, Genes Dev., 14, 2060, 2000.
14. Wang, K., Yin, X.M., Chao, D.T., Milliman, C.L. and Korsmeyer, S.J., BID: a novel BH3 domain- only death agonist, Genes Dev., 10, 2859, 1996.
15. Cheng, E.H., Wei, M.C., Weiler, S., Flavell, R.A., Mak, T.W., Lindsten, T. and Korsmeyer, S.J., BCL- 2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis, Mol. Cell, 8, 705, 2001.
16. Wei, M.C., Zong, W.X., Cheng, E.H., Lindsen, T., Panoutsakopoulou, V., Ross, A.J., Roth, K.A., MacGregor, G.R., Thompson, C.B. and Korsmeyer, S.J., Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death, Science, 292, 727, 2001.
17. Lindsten, T., Ross, A.J., King, A., Zong, W.X., Rathmell, J.C., Shiels, H.A., Ulrich, E., Waymire, K.G., Mahar, P., Frauwirth, K., Chen, Y., Wei, M., Eng, V.M., Adelman, D.M., Simon, M.C., Ma, A., Golden, J.A., Evan, G., Korsmeyer, S.J., MacGregor, G.R. and Thompson, C.B., The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues, Mol. Cell, 6, 1389, 2000.
18. Deveraux, Q.L. and Reed, J.C., IAP family proteins — suppressors of apoptosis, Genes Develop., 13, 239, 1999.
19. Miller, L.K., An exegesis of IAPs: salvation and surprises from BIR motifs, Trends Cell. Biol., 9, 323, 1999.
20. Duckett, C.S., Nava, V.E., Gedrich, R.W., Clem, R.J., Van Dongen, J.L., Gilfilan, M.C. and al., e., A conserved family of cellular genes related to the baculovirus IAP gene and encoding apoptosis inhibitors, EMBO J., 15, 2685, 1996.
21. Uren, A.G., Pakusch, M., Hawkins, C.J., Puls, K.L. and Vaux, D.L., Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors, Proc. Natl. Acad. Sci. U.S.A., 93, 4974, 1996.
22. Roy, N., Deveraux, Q.L., Takahashi, 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, 6914, 1997.
23. Huang, H., Joazeiro, C.A., Bonfoco, E., Kamada, S., Leverson, J.D. and Hunter, T., The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspase-3 and -7, J. Biol. Chem., 275, 26661, 2000.
24. Yang, Y., Fang, S., Jensen, J.P., Weissman, A.M. and Ashwell, J.D., Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli, Science, 288, 874, 2000.
25. Du, C., Fang, M., Li, Y., Li, L. and Wang, X., Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition, Cell, 102, 33, 2000.
26. Verhagen, A.M., Ekert, P.G., Pakusch, M., Solke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J. and Vaux, D.L., Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins, Cell, 102, 43, 2000.
27. Meinl, E., Fickenscher, H., Thome, M. and Tschopp, J., Anti-apoptotic strategies of lymphotropic viruses, Immunol. Today, 19, 474, 1998.
28. Tschopp, J., Irmler, M. and Thome, M., Inhibition of Fas death signals by FLIPs, Curr. Opin. Immunol., 10, 552, 1998.
29. Scaffidi, C., Sanchez, I., Krammer, P.H. and Peter, M.E., The role of c-FLIP in modulation of CD95- induced apoptosis, J. Biol. Chem., 274, 1541, 1999.
30. Krueger, A., Baumann, S., Krammer, P.H. and Kirchhoff, S., FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis, Mol. Cell Biol., 21, 8247, 2001.
31. Green, D.R. and Reed, J.C., Mitochondria and apoptosis, Science, 281, 1309, 1998.
32. Antonsson, B., Montessuit, S., Lauper, S., Eskes, R. and Martinou, J.C., Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria, Biochem. J., 345, 271, 2000.
33. Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R.J., Matsuda, H. and Tsujimoto, Y., Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria, Proc. Natl. Acad. Sci. U.S.A., 95, 14681, 1998.
34. Vander Heiden, M.G., Chandel, N.S., Williamson, E.K., Schumacker, P.T. and Thompson, C.B., Bcl- xL regulates the membrane potential and volume homeostasis of mitochondria, Cell, 91, 627, 1997.
35. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S. and Wang, X., Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell, 91, 479, 1997.
36. Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K. and Takahashi, R., A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death, Mol. Cell, 8, 613, 2001.
37. Suzuki, Y., Takahashi-Niki, K., Akagi, T., Hashikawa, T. and Takahashi, R., Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways, Cell Death Differ., 11, 208, 2004.
38. Susin, S.A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M.
and Kroemer, G., Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J. Exp. Med., 184, 1331, 1996.39. Daugas, E., Susin, S.A., Zamzami, N., Ferri, K.F., Irinopoulou, T., Larochette, N., Prevost, M.C., Leber, B., Andrews, D., Penninger, J. and Kroemer, G., Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis, FASEB J., 14, 729, 2000.
40. Li, L.Y., Luo, X. and Wang, X., Endonuclease G is an apoptotic DNase when released from mitochondria, Nature, 412, 95, 2001.
41. van Loo, G., Schotte, P., van Gurp, M., Demol, H., Hoorelbeke, B., Gevaert, K., Rodriguez, I., Ruiz- Carrillo, A., Vandekerckhove, J., Declercq, W., Beyaert, R. and Vandenabeele, P., Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation, Cell Death Differ., 8, 1136, 2001.
42. Ashkenazi, A. and Dixit, V.M., Death receptors: signaling and modulation, Science, 281, 1305, 1998.
43. Locksley, R.M., Killeen, N. and Lenardo, M.J., The TNF and TNF receptor superfamily: integrating mammalian biology, Cell, 104, 487, 2001.
44. Nagata, S., Apoptosis by death factor, Cell, 88, 355, 1997.
45. Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K.J., Debatin, K.M., Krammer, P.H. and Peter, M.E., Two CD95 (APO-1/Fas) signaling pathways, EMBO J., 17, 1675, 1998.
46. 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, 491, 1998.
47. 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, 481, 1998.