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.

  • Review Article
  • Published:

The proto-oncogene Bcl-2 and its role in regulating apoptosis

An Erratum to this article was published on 01 August 1997

Abstract

The mechanism of action of Bcl-2 provides clues for therapeutic interventions

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Kroemer, G., Petit, P.X. Zamzami, N. Vayssière, J.-L. & Mignotte, B. The biochemistry of apoptosis. FASEB J. 9, 1277–1287 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Reed, J.C. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124, 1–6 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Yang, E. & Korsmeyer, S.J. Molecular thanatopsis: A discourse on the Bcl-2 family and cell death. Blood 88, 386–401 (1996).

    CAS  PubMed  Google Scholar 

  5. Zoratti, M. & Szabd, I. The mitochondrial permeability transition. Biochim. Biophys. Ada – Rev. Biomembr. 1241, 139–176 (1996).

    Article  Google Scholar 

  6. Kroemer, G., Zamzami, N. & Susin, S.A. Mitochondrial control of apoptosis. Immunol. Today 18, 44–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Carayon, P. et al. Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical species. Blood 87, 3170–3178 (1996).

    CAS  PubMed  Google Scholar 

  8. Tanaka, S., Saito, K. & Reed, J.C. Structure-function analysis of the Bcl-2 oncoprotein: Addition of a heterologous transmembrane domain to portions of the Bcl-2p protein restores function as a regulator of cell survival. J. Biol. Chem. 268, 10920–10926 (1993).

    CAS  PubMed  Google Scholar 

  9. Hockenbery, D.M., Oltvai, Z.N., Yin, X.-M., Milliman, C.L. & Korsmeyer, S.J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75, 241–251 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, H.-C., Rapp, U.R. & Reed, J. C. Bcl-2 targets the protein kinase raf-1 to mitochondria. Cell 87, 629–638 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Wu, D., Wallen, H.D. & Nu–ez, C. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275, 1126–1129 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Zhu, W. Bcl-2 mutants with restricted subcellular localization reveal spatially distinct pathways for apoptosis in different cell types. EMBO J. 15, 4130–4141 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zha, H. et al. Structure-function comparisons of the pro-apoptotic protein Bax in yeast and mammalian cells. Mol. Cell. Biol. 16, 6494–6508 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chinnaiyan, A.M., O'Rourke, K., Lane, B.R. & Dixit, V.M. Interaction of CED-4 with CED-3 and CED-9: A molecular frame for cell death. Science 275, 1122–1126 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Kane, D. J. et al. Bcl-2 inhibition of neural death: Decreased generation of reactive oxygen species. Science 262, 1274–1277 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Zha, H., Aime-Sempre, C., Sato, T. & Reed, J.C. Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J. Biol. Chem. 271, 7440–7444 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Hunter, J.J. & Parslow, T.G. A peptide sequence from Bax that converts Bcl-2 into an activator of apoptosis. J. Biol. Chem. 271, 8521–8524 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Sattler, M. Structure of Bcl-x(L)-Bak peptide complex: Recognition between regulators of apoptosis. Science 275, 983–986 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Boyd, J.M. et al. (1995) Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11, 1921–1928.

    CAS  PubMed  Google Scholar 

  21. Wang, K., Yin, X.M., Chao, D.T., Milliman, C.L. & Korsmeyer, S.J. BID: A novel BH3 domain-only death agonist. Genes & Development 10, 2859–2869 (1996).

    Article  CAS  Google Scholar 

  22. Hanada, M., Aimesempe, C., Sato, T. & Reed, J.C. Structure-function analysis of Bcl-2 protein identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax J. Biol. Chem. 270, 11962–11969 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Hunter, J.J., Bond, B.L. & Parslow, T.C. Functional dissection of the human Bcl2 protein: Sequence requirements for inhibition of apoptosis. Mol. Cell. Biol. 16, 877–883 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, H.G., Takayama, S., Rapp, U.R. & Reed, J.C. Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc. Natl. Acad. Sci. USA 93, 7063–7068 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shibasaki, F., Kondo, E., Akagi, T. & McKeon, F. Suppression of signalling through transcription factor NF-AT by interaction between calcineurin and Bcl-2. Nature 386, 728–731 (1996).

    Article  Google Scholar 

  26. Strack, P.R. et al. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc. Natl. Acad. Sci. USA 93, 9571–9576 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Haldar, S., Chintapalli, J. & Croce, CM. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Research 56, 1253–1255 (1996).

    CAS  PubMed  Google Scholar 

  28. Uhlmann, E.J. et al. Deletion of a nonconserved region of Bcl-2 confers a novel gain of function: Suppression of apoptosis with concomitant cell proliferation. Cancer Res. 56, 2506–2509 (1996).

    CAS  PubMed  Google Scholar 

  29. Zha, J.P., Harada, H., Yang, E., Jockel, J. & Korsmeyer, S.J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BGL-X(L). Cell 87, 619–628 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Bardelli, A. et al. HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO Journal 15, 6205–6212 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Muchmore, S.W. et al. X-ray and NMR structure of human Bcl-XL, and inhibitor of programmed cell death. Nature 381, 335–341 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Minn, A.J. et al. Bcl-XL form an ion channel in synthetic lipid membranes. Nature 385, 353–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Lam, M. et al. Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc. Natl. Acad. Sci. USA 85, 6569–6573 (1994).

    Article  Google Scholar 

  34. Marin, M.C. et al. Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+. Oncogene 12, 2259–2266 (1996).

    CAS  PubMed  Google Scholar 

  35. Baffy, G., Miyashati, T., Williamson, J.R. & Reed, J.C. Apoptosis induced by withdrawal of interleukin-3 (IL-3) dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncogene production. J. Biol. Chem. 268, 6511–6519 (1993).

    CAS  PubMed  Google Scholar 

  36. Murphy, A.N., Bredesen, D.E., Cortopassi, G., Wang, E. & Fiskum, G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc. Natl. Acad. Sci. USA 93, 9893–9898 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Reynolds, J.E. & Eastman, A. Intracellular calcium stores are not required for Bcl-2-mediated protection from apoptosis. J. Biol. Chem. 271, 27739–27743 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Chinnaiyan, A.M. et al. Molecular ordering of the cell death pathway — Bcl-2 and Bcl-X(L) function upstream of the CED-3-like apoptotic proteases. J. Biol. Chem. 271, 4573–4576 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Zamzami, N. et al. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J. Exp. Med. 182, 367–377 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Yang, J. et al. Prevention of apoptosis by Bcl-2: Release of cytochrome cfrom mitochondria blocked. Science 275, 1129–1132 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Kluck, R.M., Bossy-Wetzel, E., Green, D.R. & Newmeyer, D.D. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275,,1132–1136 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Zamzami, N. et al. Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183, 1533–1544 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Shimizu, S. et al. Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13, 21–29. (1996).

    CAS  PubMed  Google Scholar 

  45. Kantrow, S.P. & Piantadosi, C.A. Release of cytochrome cfrom liver mitochondria during permeability transition. Biochem. Biophys. Res. Commun. 232, 669–671 (1997).

    Article  CAS  Google Scholar 

  46. Xiang, J., Chao, D.T. & Korsmeyer, S.J. Bax-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc. Natl. Acad. Sci. USA 93, 14559–14563 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shimizu, S. et al. Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-XL. Nature 374, 811–813 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Newmeyer, D.D., Farschon, D.M. & Reed, C. Cell-free apoptosis in Xenopus egg extracts: Inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79, 353––364 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Susin, S.A. et al. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med. 84, 1331–1342 (1996).

    Article  Google Scholar 

  50. Weil, M. et al. Constitutive expression of the machinery for programmed cell death. J. Cell Biol. 133, 1053–1059 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Martinou, J.C. et al. Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13, 1017–1030 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Chen, D.F., Schneider, G.E., Martinou, J.-C. & Tonegawa, S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385, 434–439 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Lawrence, M.S., Ho, D.Y., Sun, G.H., Steinberg, G.K. & Sapolsky, R.M. Over-expression of bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. J. Neurosci. 16, 486–496 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. McCarthy, N.J., Whyte, M. K.B., Gilbert, C.S. & Evan, G.I. Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J. Cell Biol. 136, 215–227 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Strobel, T., Swanson, L., Korsmeyer, S. & Cannistra, S.A. BAX enhances paclitaxel-induced apoptosis through a p53-independent pathway. Proc. Natl. Acad. Sci. USA 93, 14094–14099 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brady, H.J.M., Salomons, G.S., Bobeldijk, R.C. & Berns, A.J.M. T cells from bax alpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. EMBO J. 15, 1221–1230 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang, D.C.S., Cory, S. & Strasser, A. Bcl-2, Bcl-XL, and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. Oncogene 14, 405–414 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Evtodienki, Y.V., Teplova, V.V., Sidashi, S.S., Ichas, F. & Mazat, J.-P. Microtubule-active drugs suppress the closure of the permeability transition pore in tumour mitochondria. FEBS Lett. 393, 86–88 (1996).

    Article  Google Scholar 

  59. Jacobson, M.D., Burne, J.F. & Raff, M.C. Programmed cell death and Bcl-2 protection in the absence of a nucleus. EMBO J. 13, 1899–1910 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tsao, N. & Lei, H.Y. Activation of the Na+/H+ antiporter, Na+/HCO3/CO32 cotrans-porter, or CI/HCO3 exchanger in spontaneous thymocyte apoptosis. J. Immunol. 157, 1107–1116 (1996).

    CAS  PubMed  Google Scholar 

  61. Martin, S.J. et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: Inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 182, 1545–1556 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Ellerby, L.M. etal. Shift of the cellular oxidation-reduction potential in neural cells expressing bcl-2. J. Neurochem. 67, 1259–1267 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Reynolds, J.E., Li, J.F., Craig, R.W. & Eastman, A. Bcl-2 and Mcl-1 expression in Chinese hamster ovary cells inhibits intracellular acidification and apoptosis induced by staurosporine. Exp. Cell Res. 225, 430–436 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Hennet, T., Bertoni, G., Richter, C. & Peterhans, E. Expression of BCL-2 protein enhances the survival of mouse fibrosarcoid cells in tumor necrosis factor-mediated cytotoxicity. Cancer Res. 53, 1456–1460 (1993).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kroemer, G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 3, 614–620 (1997). https://doi.org/10.1038/nm0697-614

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0697-614

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing