Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

Controlling TRAIL-mediated caspase-3 activation

Leukemia volume 18, pages 1578–1580 (2004)Cite this article

This commentary is addressed at the paper by Dr Han and his co-workers in the current issue of Leukemia (‘Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells’). In this paper, the authors show the preferential use of Bax over Bak for the induction of mitochondrial apoptotic events in leukemic cell exposed to TRAIL.1 These findings are consistent with previous studies involving Bax in TRAIL-mediated apoptosis in the colon carcinoma cell line HCT116.2, 3, 4 The redundant function of Bak and Bax was initially demonstrated in lymphocytes subjected to various apoptotic stimuli.5, 6, 7, 8 Hence, simultaneous Bax and Bak gene inactivation results in a profound effect on the control of lymphocyte survival upon growth factor or glucose deprivation.9 Whereas, Bak inactivation, alone, appears to have no effect, Bax inactivation, however, slightly affected lymphocyte survival.9 These data could therefore suggest that Bax and Bak may not be so redundant after all. Accordingly, the use of Jurkat clones deficient for both Bak and Bax by Han and co-workers, revealed that Bax and Bak could exhibit differential functions, at least in the studied cell type system, as only Bax re-expression could restore caspase-3 processing and sensitization to TRAIL-induced cell death.1

Loss of function mutations of Bax are often found both in colon carcinomas10 and in leukemias.11, 12 Therefore, since both death domain containing receptors and chemotherapeutic agents may require Bax for the triggering of the apoptotic process,2, 13 this information may be important for future cancer therapeutic approaches using TRAIL or TRAIL receptor agonists either alone or in combination with chemotherapeutic agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Han J, Goldstein LA, Gastman BR, Rabinovitz A, Wang G-Q, Fang B et al. Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells. Leukemia 2004; 18: 1671–1680.

    Article  CAS  PubMed  Google Scholar 

  2. LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P et al. Tumor-cell resistance to death receptor–induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 2002; 8: 274–281.

    Article  CAS  PubMed  Google Scholar 

  3. Deng Y, Lin Y, Wu X . TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 2002; 16: 33–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim M, Park SY, Pai HS, Kim TH, Billiar TR, Seol DW . Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by blocking Bax translocation. Cancer Res 2004; 64: 4078–4081.

    Article  CAS  PubMed  Google Scholar 

  5. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389–1399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB . BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15: 1481–1486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Plas DR, Rathmell JC, Thompson CB . Homeostatic control of lymphocyte survival: potential origins and implications. Nat Immunol 2002; 3: 515–521.

    Article  CAS  PubMed  Google Scholar 

  8. Degenhardt K, Sundararajan R, Lindsten T, Thompson C, White E . Bax and Bak independently promote cytochrome C release from mitochondria. J Biol Chem 2002; 277: 14127–14134.

    Article  CAS  PubMed  Google Scholar 

  9. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ . Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995; 270: 96–99.

    Article  CAS  PubMed  Google Scholar 

  10. Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–969.

    Article  CAS  PubMed  Google Scholar 

  11. Brimmell M, Mendiola R, Mangion J, Packham G . BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. Oncogene 1998; 16: 1803–1812.

    Article  CAS  PubMed  Google Scholar 

  12. Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 1998; 91: 2991–2997.

    CAS  PubMed  Google Scholar 

  13. Naumann U, Weller M . Retroviral BAX gene transfer fails to sensitize malignant glioma cells to CD95L-induced apoptosis and cancer chemotherapy. Int J Cancer 1998; 77: 645–648.

    Article  CAS  PubMed  Google Scholar 

  14. de Vries EG, Timmer T, Mulder NH, van Geelen CM, van der Graaf WT, Spierings DC et al. Modulation of death receptor pathways in oncology. Drugs Today (Barc) 2003; 39 (Suppl C): 95–109.

    CAS  Google Scholar 

  15. Creagh EM, Conroy H, Martin SJ . Caspase-activation pathways in apoptosis and immunity. Immunol Rev 2003; 193: 10–21.

    Article  CAS  PubMed  Google Scholar 

  16. Thorburn A . Death receptor-induced cell killing. Cell Signal 2004; 16: 139–144.

    Article  CAS  PubMed  Google Scholar 

  17. Martinon F, Tschopp J . Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004; 117: 561–574.

    Article  CAS  PubMed  Google Scholar 

  18. Nicholson DW . Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 1999; 6: 1028–1042.

    Article  CAS  PubMed  Google Scholar 

  19. Salvesen GS, Dixit VM . Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 1999; 96: 10964–10967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM et al. A unified model for apical caspase activation. Mol Cell 2003; 11: 529–541.

    Article  CAS  PubMed  Google Scholar 

  21. Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem 2002; 277: 45162–45171.

    Article  CAS  PubMed  Google Scholar 

  22. Renatus M, Stennicke HR, Scott FL, Liddington RC, Salvesen GS . Dimer formation drives the activation of the cell death protease caspase 9. Proc Natl Acad Sci USA 2001; 98: 14250–14255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Martinon F, Burns K, Tschopp J . The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417–426.

    Article  CAS  PubMed  Google Scholar 

  24. Sordet O, Rebe C, Plenchette S, Zermati Y, Hermine O, Vainchenker W et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood 2002; 100: 4446–4453.

    Article  CAS  PubMed  Google Scholar 

  25. Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA . Caspase 3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci USA 2002; 99: 11025–11030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kroemer G, Reed JC . Mitochondrial control of cell death. Nat Med 2000; 6: 513–519.

    Article  CAS  PubMed  Google Scholar 

  27. Yamada H, Tada-Oikawa S, Uchida A, Kawanishi S . TRAIL causes cleavage of bid by caspase-8 and loss of mitochondrial membrane potential resulting in apoptosis in BJAB cells. Biochem Biophys Res Commun 1999; 265: 130–133.

    Article  CAS  PubMed  Google Scholar 

  28. Werner AB, de Vries E, Tait SW, Bontjer I, Borst J . TRAIL receptor and CD95 signal to mitochondria via FADD, caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid. J Biol Chem 2002; 277: 40760–40767.

    Article  CAS  PubMed  Google Scholar 

  29. Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC . Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998; 95: 4997–5002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kandasamy K, Srinivasula SM, Alnemri ES, Thompson CB, Korsmeyer SJ, Bryant JL et al. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res 2003; 63: 1712–1721.

    CAS  PubMed  Google Scholar 

  31. Roucou X, Montessuit S, Antonsson B, Martinou JC . Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein. Biochem J 2002; 368: 915–921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang Y, Rich RL, Myszka DG, Wu H . Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac. J Biol Chem 2003; 278: 49517–49522.

    Article  CAS  PubMed  Google Scholar 

  33. Du C, Fang M, Li Y, Li L, Wang X . Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.

    Article  CAS  PubMed  Google Scholar 

  34. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277: 432–438.

    Article  CAS  PubMed  Google Scholar 

  35. Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z et al. The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J Biol Chem 2003; 278: 38699–38706.

    Article  CAS  PubMed  Google Scholar 

  36. Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277: 439–444.

    Article  CAS  PubMed  Google Scholar 

  37. Hasenjager A, Gillissen B, Muller A, Normand G, Hemmati PG, Schuler M et al. Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-x(L) in a strictly caspase-3-dependent manner in human carcinoma cells. Oncogene 2004; 23: 4523–4535.

    Article  PubMed  Google Scholar 

  38. Suzuki Y, Nakabayashi Y, Takahashi R . Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 2001; 98: 8662–8667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Creagh EM, Murphy BM, Duriez PJ, Duckett CS, Martin SJ . Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins. J Biol Chem 2004; 64: 334–345.

    Google Scholar 

  40. Chen L, Smith L, Wang Z, Smith JB . Preservation of caspase-3 subunits from degradation contributes to apoptosis evoked by lactacystin: any single lysine or lysine pair of the small subunit is sufficient for ubiquitination. Mol Pharmacol 2003; 64: 334–345.

    Article  CAS  PubMed  Google Scholar 

  41. Kim S, Choi K, Kwon D, Benveniste EN, Choi C . Ubiquitin–proteasome pathway as a primary defender against TRAIL-mediated cell death. Cell Mol Life Sci 2004; 61: 1075–1081.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang HG, Wang J, Yang X, Hsu HC, Mountz JD . Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 2004; 23: 2009–2015.

    Article  CAS  PubMed  Google Scholar 

  43. Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM . Caspase activation inhibits proteasome function during apoptosis. Mol Cell 2004; 14: 81–93.

    Article  CAS  PubMed  Google Scholar 

  44. He Q, Montalbano J, Corcoran C, Jin W, Huang Y, Sheikh MS . Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis. Oncogene 2003; 22: 2674–2679.

    Article  CAS  PubMed  Google Scholar 

  45. Nutt LK, Chandra J, Pataer A, Fang B, Roth JA, Swisher SG et al. Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. J Biol Chem 2002; 277: 20301–20308.

    Article  CAS  PubMed  Google Scholar 

  46. Nutt LK, Pataer A, Pahler J, Fang B, Roth J, McConkey DJ et al. Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores. J Biol Chem 2002; 277: 9219–9225.

    Article  CAS  PubMed  Google Scholar 

  47. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 2003; 300: 135–139.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Eric Solary and Sophie Launay for helpful advices and valuable discussions.

Author information

Authors and Affiliations

  1. U517 INSERM, Faculté de Médecine et de Pharmacie, 7 Bd Jeanne d'Arc, Dijon, 21000, France

    O Micheau & D Mérino

Authors
  1. O Micheau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Mérino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O Micheau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Micheau, O., Mérino, D. Controlling TRAIL-mediated caspase-3 activation. Leukemia 18, 1578–1580 (2004). https://doi.org/10.1038/sj.leu.2403497

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403497

This article is cited by

Search

Advanced search

Quick links