, Volume 11, Issue 4, pp 375–382 | Cite as

The role of calcium in apoptosis

  • Joachim Krebs


In this chapter various aspects of apoptosis or programmed cell death (PCD) influenced by calcium as a mediator of signal transduction have been reviewed. Attention has been focused on recently described calcium-binding proteins such as ALG-2 or on a new calcium/calmodulin-dependent kinase, the death asso-ciated protein kinase or DAP-kinase. Both play a central role in apoptotic processes. Calcineurin, which normally is involved in the regulation of T-cell proliferation, is reported to interact with the apoptosis protec-tion protein bcl-2. Its possible involvement in the decision process whether T-cell activation leads to prolif-eration or apoptosis is discussed.© Kluwer Academic Publishers

apoptosis programmed cell death (PCD) calcium DAP-Kinase calcineurin ALG-2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Altschul, S.F., Gish, W., Miller, W., Myers, E.W., Lipman, D.J. (1990) Basic local alignment search tool. J. Mol. Biol. 215, 403–410.Google Scholar
  2. Altschul, S.F., Madden, T.L., Schäffer, A.A., Zhang, J., Zhang, Z., Miller, W., Lipman, D.J. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25: 3389–3402.Google Scholar
  3. Blanchard, H., Grochulski, P., Li, Y., Arthur, S.C., Davies, P.L., Elce, J.S., Cygler, M. (1997) Structure of a calpain Ca(2+)-binding domain reveals a novel EF-hand and Ca(2+)-induced conformational changes. Nat. Struct. Biol. 4, 532–538.Google Scholar
  4. Chinnaiyan, A.M., O'Rourke, K., Lane, B.R., Dixit, V.M. (1997) Interaction of ced-4 with ced-3 and ced-9: A molecular framework for cell death. Science 275, 1122–1126.Google Scholar
  5. Cohen, O., Feinstein, E., Kimchi, A. (1997) DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J. 16, 998–1008.Google Scholar
  6. Deiss, L.P., Kimchi, A. (1991) A genetic tool used to identify thioredoxin as a mediator of a growth inhibitory signal. Science 252, 117–120.Google Scholar
  7. Deiss, L.P., Feinstein, E., Berissi, H., Cohen, O., Kimchi, A. (1995) Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 9, 15–30.Google Scholar
  8. Duke, R.C., Cohen, J.J. (1986) IL-2 addition: withdrawal of growth factor activates a suicide program in dependent T-cells Lymphokine Res. 5, 289–299.Google Scholar
  9. Ellis, R.E., Yuan, J., Horvitz, H.R. (1991) Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698.Google Scholar
  10. Fleckenstein, A. (1984) Calcium antgonism: history and prospects for a multifaceted pharmacodynamic principle. In: Calcium Antagonists and Cardiovascular Disease (Opie, L.H., ed.). Raven, New York, 9–28.Google Scholar
  11. Gaido, M.L., Cidlowski, J.A. (1991) Identification, purification, and characterization of a calcium-dependent endonuclease (NUC18) from apototic rat thymocytes. J. Biol. Chem. 266, 18580–18585.Google Scholar
  12. Guerini, D. (1998) The Ca2+-pumps and the Na+/Ca2+Exchangers. BioMetals, this issue.Google Scholar
  13. Hengartner, M.O., Ellis, R.E., Horvitz, H.R. (1992) C. elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494–499.Google Scholar
  14. Inbal, B., Cohen, O., Polak-Charcon, S., Kopolovic, J., Vadai, E., Eisenbach, L., Kimchi, A. (1997) DAP kinase links the control of apoptosis to metastasis. Nature 390, 180–184.Google Scholar
  15. Jayaraman, T., Ondriasova, E., Ondrias, K., Harnick, D.J., Marks, A.R. (1995) The inositol 1,4,5-trisphosphate is essential for T-cell receptor signaling. Proc. Natl. Acad. Sci. USA 92, 6007–6011.Google Scholar
  16. Jayaraman, T., Ondrias, K., Ondriasova, E., Marks, A.R. (1996) Regulation of the inositol 1,4,5-trisphosphate receptor by tyrosine phosphorylation. Science 272, 1492–1494.Google Scholar
  17. Jayaraman, T., Marks, A.R. (1997) T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. Mol. Cell. Biol. 17, 3005–3012.Google Scholar
  18. Kaiser, N., Edelman, I.S. (1977) Calcium dependence of glucocorticoid-induced lymphocytolysis. Proc. Natl. Acad. Sci. USA 74, 638–642.Google Scholar
  19. Kawasaki, H., Nakayama, S., Kretsinger, R.H. (1998) Classification and Evolution of EF-hand Proteins. BioMetals, this issueGoogle Scholar
  20. Kerr, J.F.R., Wyllie, A.H., Currie, A.R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257.Google Scholar
  21. Khan, A.A., Soloski, M.J., Sharp, A.H., Schilling, G., Sabatini, S.-H., Li, C., Ross, A., Snyder, S.H. (1996) Lymphocyte apoptosis: mediation by increased type 3 inositol 1,4,5-trisphosphate receptor. Science 273, 503–507.Google Scholar
  22. Kimchi, A. (1998) DAP genes: novel apoptotic genes isolated by a functional approach to gene cloning Biochim. Biophys. Acta 1377, F13–F33.Google Scholar
  23. Kissil, J., Feinstein, E., Cohen, O., Jones, P.A., Tsai, Y.C., Knowles, M.A., Eydmann, M.E., Kimchi, A. (1997) DAP-kinase loss of expression in B-cell leukemia and bladder carcinoma cell lines: possible implications for role as tumor suppressor gene. Oncogene 15, 403–407.Google Scholar
  24. Kretsinger, R.H. (1975) Hypothesis: Calcium modulated proteins contain EF Hands in Calcium Transport in Contraction and Secretion (eds. E. Carafoli, F. Clementi, W. Drabikowski & A. Margreth) pp. 469–478 (Elsevier North-Holland Publishing Co., Amsterdam, 1975)Google Scholar
  25. Kuida, K., Lippke, J.A., Ku, G., Harding, M.W., Livingston, D.J., Su, M.S., Flavell, R.A. (1995) Altered cytokine export and apoptosis in mice deficient in interleukin-1beta converting enzyme. Science 267, 2000–2003.Google Scholar
  26. Lacana, E., Ganjei, J.K., Vito, P., D'Adamio, L. (1997) Dissociation of apoptosis and activation of IL-1β-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG-3. J. Immunol. 158, 5129–5135.Google Scholar
  27. Li, P., Allen, H., Banerjee, S., Franklin, S., Herzog, L., Johnston, C., McDowell, J., Paskind, M., Rodman, L., Salfeld, J. (1995) Mice deficient in IL-1beta-converting enzyme are defective in production of mature IL-1beta and resistant to endotoxic shock. Cell 80, 401–411.Google Scholar
  28. Lin, G.D., Chattopadhyay, D., Maki, M., Wang, K.K., Carson, M., Jin, L., Yuen, P.W., Takano, E., Hatanaka, M., DeLucas, L.J., Narayana, S.V. (1997) Crystal structure of calcium bound domain VI of calpain at 1.9 A resolution and its role in enzyme assembly, regulation, and inhibitor binding. Nat. Struct. Biol. 4, 539–547.Google Scholar
  29. Los, M., Van de Craen, M., Penning, L.C., Schenk, H., Westendorp, M., Baeuerle, P.A., Droge, W., Krammer, P.H., Fiers, W., Schulze-Osthoff, K. (1995) Requirement of an ICE/CED-3 protease for Fas/APO-1 mediated apoptosis. Nature 375, 81–83.Google Scholar
  30. Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A., Jacks, T. (1993) p53 is required for radiation-induced apoptosis in mouse lymphocytes Nature 362, 847–849.Google Scholar
  31. Maki, M., Narayana, S.V.L., Hitomi, K. (1997) A growing family of the Ca2+-binding proteins with five EF-hand motifs. Biochem. J. 328, 718–720.Google Scholar
  32. McConkey, D.J., Nicotera, P., Hartzell, P., Bellomo, G., Wyllie, A.H., Orrenius, S. (1989) Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration. Arch. Biochem. Biophys. 269, 365–370.Google Scholar
  33. McConkey, D.J., Orrenius, S. (1997) The role of calcium in the regulation of apoptosis. Biochem. Biophys. Res. Commun. 239, 357–366.Google Scholar
  34. Montague, J.W., Gaido, M.L., Frye, C., Cidlowski, J.A. (1994) A calcium-dependent nuclease from apoptotic rat thymocytes is homologous with cyclophilin. Recombinant cyclophilins A, B, and C have nuclease activity. J. Biol. Chem. 269, 18877–18880.Google Scholar
  35. Montague, J.W., Hughes Jr., F.M., Cidlowski, J.A. (1997) Native recombinant cyclophilins A,B, and C degrade DNA independently of peptidylprolyl cis-transisomerase activity. Potential roles of cyclophilins in apoptosis. J. Biol. Chem. 272, 6677–6684.Google Scholar
  36. Nelson, M.R., Chazin, W.J. (1998) Structures of EF-hand Ca2+-binding Proteins: Diversity in the Organization, Packing and Response to Ca2+-Binding. BioMetals, this issue.Google Scholar
  37. Nicotera, P., Orrenius, S. (1998) The role of calcium in apoptosis. Cell Calcium 23, 173–180.Google Scholar
  38. Owen-Schaub, L.B., Yonehara, S., Crump, W.L., Grimm, E. (1992) DNA fragmentation and cell death is selectively triggered in activated human T lymphocytes by fas antigen engagement. Cell Immunol. 140, 197–205.Google Scholar
  39. Peitsch, M.C., Polzar, B., Stephan, H., Crompton, T., MacDonald, H.R., Mannherz, H.G., Tschopp, J. (1993) Characterization of the endogenous deoxyribonuclease involved in nuclear DNA degradation during apoptosis (programmed cell death) EMBO J. 12, 371–377.Google Scholar
  40. Penninger, J.M., Kroemer, G. (1998) Molecular and Cellular Mechanisms of T Lymphocyte Apoptosis. Adv. Immunol. 68, 51–144.Google Scholar
  41. Reed, J.C. (1997) Double identity for proteins of the BCL-2 family. Nature 387, 773–776.Google Scholar
  42. Rhee, S.G., Choi, K.D. (1992) Regulation of inositol phospholipid specific phospholipase C isozymes. J. Biol. Chem. 267, 12393–12396.Google Scholar
  43. Schieven, G.L., Kirihara, J.M., Gilliland, L.K., Uckun, F.M., Ledbetter, J.A. (1993) Ultraviolett radiation rapidly induces tyrosine phosphorylation and calcium signaling in lymphocytes. Mol. Biol. Cell. 4, 523–530.Google Scholar
  44. Shaham, S., Horvitz, H.R. (1996) An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell 86, 201–208.Google Scholar
  45. Shibasaki, F., McKeon, F. (1995) Calcineurin functions in Ca2+-activated cell death in mammalian cells J. Cell Biol. 131, 735–743.Google Scholar
  46. Shibasaki, F., Kondo, E., Akagi, T., McKeon, F. (1997) Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and bcl-2. Nature 386, 728–731.Google Scholar
  47. Shibasaki, F., Price, E.R., Milan, D., McKeon, F. (1996) Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature 382, 370–373.Google Scholar
  48. Spielberg, H., June, C.H., Blair, O.C., Nystron-Rosander, C., Cereb, N., Deeg, H.J. (1991). UV irradiation of lymphocytes triggers an increase in intracellular Ca2+and prevents lectin-stimulated Ca2+ mobilization: evidence for UV-and nifedipine-sensitive Ca2+ channels. Exp. Hematol. 19, 4742–4748.Google Scholar
  49. Thompson, E.B. (1998) Apoptosis. Annu. Rev. Physiol. 60, 525–665.Google Scholar
  50. Vito, P., Lacana, E., D'Adamio, L. (1996) Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 271, 521–525.Google Scholar
  51. Wang, H.-G., Rapp, U.R., Reed, J.C. (1996) Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87, 629–638.Google Scholar
  52. Wu, D., Wallen, H.D., Nunez, G. (1997) Interaction and regulation of subcellular localization of ced-4 by ced-9. Science 275, 1126–1129.Google Scholar
  53. Wyllie, A.H. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555–556.Google Scholar
  54. Yao, X.R., Scott, D.W. (1993) Antisense oligodeoxynucleotides to the blk tyrosine kinase prevent antimmediated growth inhibition and apoptosis in a B-cell lymphoma. Proc. Natl. Acad. Sci. USA 90, 7946–7950.Google Scholar
  55. Yuan, J., Shaham, S., Ledoux, S., Ellis, H.M., Horvitz, H.R. (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75, 641–652.Google Scholar
  56. Zou, H., Henzel, W.J., Liu, X., Lutschg, A., Wang, X. (1997) Apaf-1, a human protein homologous to C. elegans ced-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90, 405–413.Google Scholar

Copyright information

© Chapman and Hall 1998

Authors and Affiliations

  • Joachim Krebs
    • 1
  1. 1.Institute of BiochemistrySwiss Federal Institute of Technology (ETH)ZurichSwitzerland

Personalised recommendations