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.

  • Article
  • Published:

Bcl-2 and Bax function independently to regulate cell death

Abstract

The BCL-2 family has various pairs of antagonist and agonist proteins that regulate apoptosis. Whether their function is interdependent is uncertain. Using a genetic approach to address this question, we utilized gain- and loss-of-function models of Bcl-2 and Bax and found that apoptosis and thymic hypoplasia characteristic of Bcl-2–deficient mice are largely absent in mice also deficient in Bax. A single copy of Bax promoted apoptosis in the absence of Bcl-2. In contrast, overexpression of Bcl-2 still repressed apoptosis in the absence of Bax. While an in vivo competition exists between fiaxand Bax and Bcl-2, each is able to regulate apoptosis independently.

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. Bakhshi, A. et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899–906 (1985).

    Article  CAS  Google Scholar 

  2. Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E. & Croce, C.M. The t(14:18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229, 1390–1393 (1985).

    Article  CAS  Google Scholar 

  3. Cleary, M.L. & Sklar, J. Nucleotide sequence of a t(14:18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Atal. Acad. Sci. USA. 82, 7439–7443 (1995).

    Article  Google Scholar 

  4. Vaux, D.L., Cory, S. & Adams, J.M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    Article  CAS  Google Scholar 

  5. McDonnell, T.J. et al. Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57, 79–88 (1989).

    Article  CAS  Google Scholar 

  6. Yang, E. & Korsmeyer, S.J. Molecular thanatopsis: a discourse on the Bcl2 family and cell death. Blood 88, 386–401 (1996).

    CAS  Google Scholar 

  7. Farrow, S.N. & Brown, R. New members of the BCL-2 family and their protein partners. Curr. Opin. Gen. Dev. 6, 45–49 (1996).

    Article  CAS  Google Scholar 

  8. Veis, D.J., Sorenson, C.M., Shutter, J.R. & Korsmeyer, S.J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. cell 75, 229–240 (1993).

    Article  CAS  Google Scholar 

  9. Nakayama, K., Negishi, I., Kuida, K., Sawa, H. & Loh, D.Y. Targeted disruption of Bcl-2 ab in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc. Atal. Acad. Sci. USA 91, 3700–3704 (1994).

    Article  CAS  Google Scholar 

  10. Kamada, S. et al. Bcl-2 deficiency in mice leads to pleitrophic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res. 55, 354–359 (1995).

    CAS  PubMed  Google Scholar 

  11. Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x–deficient mice. Science 267, 1506–1510 (1995).

    Article  CAS  Google Scholar 

  12. Ma, A. et al. Bclx regulates the survival of double-positive thymocytes. Proc. Atal. Acad. Sci. USA 92, 4763–4767 (1995).

    Article  CAS  Google Scholar 

  13. Knudson, C.M., Tung, K.S., Tourtellotte, W.G., Brown, G.A. & Korsmeyer, S.J. Bax-deficient mice with lymphoid hyperplasia and male gerrn cell death. Science 270, 96–99 (1995).

    Article  CAS  Google Scholar 

  14. Deckwerth, T.L. et al. Bax is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411 (1996).

    Article  CAS  Google Scholar 

  15. Sedlak, T.W. et al. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc. Atal. Acad. Sci. USA 92, 7834–7838 (1995).

    Article  CAS  Google Scholar 

  16. Sato, S. et al. Interactions among members of the BCL-2 protein family analyzed with a yeast two-hybrid system. Proc. Atal. Acad. Sci. USA 91, 9238–9242 (1994).

    Article  CAS  Google Scholar 

  17. Yin, X.-M., Oltvai, Z.N. & Korsmeyer, S.J. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369, 321–323 (1994).

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Chittenden, T. et al. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 14, 5589–5596 (1995).

    Article  CAS  Google Scholar 

  20. Veis, D.J., Sentman, C.L., Bach, E.A. & Korsmeyer, S.J. Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J. Immunol. 151, 2546–2554 (1993).

    CAS  PubMed  Google Scholar 

  21. Veis-Novack, D.J. & Korsmeyer, S.J. Bcl-2 protein expression during murine development. Am. J. Pathol. 145, 61–73 (1994).

    Google Scholar 

  22. Sentman, C.L., Shutter, J.R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S.J. Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 67, 879–888 (1991).

    Article  CAS  Google Scholar 

  23. Linette, G.P., Li, Y, Roth, K.A, rsmeyer, S.J. Crosstalk between cell death and cell cycle progression: Bcl-2 regulates NFAT-mediated activation. Proc. Atal. Acad. Sci. USA 93, 9545–9552 (1996).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Raff, M.C. Social controls on cell survival and cell death [review]. Nature 356, 397–400 (1992).

    Article  CAS  Google Scholar 

  26. Shaham, S. & Horvitz, H.R. Developing Caenorhabditis elegans neurons may contain both cell-death protective and killer activities. Genes Dev. 10, 578–591 (1996).

    Article  CAS  Google Scholar 

  27. Martin, S.J. & Green, D.R. Protease activation during apoptosis: death by a thousand cuts. cell 82, 349–352 (1995).

    Article  CAS  Google Scholar 

  28. Boulakia, C.A. et al. Bcl-2 and adenovirus E1B 19 kda protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase. Oncogene 12, 529–535 (1996).

    CAS  PubMed  Google Scholar 

  29. Armstrong, R.C. et al. Fas-induced activation of the cell death-related protease CPP32 is inhibited by Bcl-2 and by ICE family protease inhibitors. J .Biol. Chem. 271, 16850–16855 (1996).

    Article  CAS  Google Scholar 

  30. Chinnaiyan, A.M. et al. Molecular ordering of the cell death pathway—Bcl-2 and Bcl-xL function upstream of the ced-3-like apoptotic proteases. j. Biol. Chem. 271, 4573–4576 (1996).

    Article  CAS  Google Scholar 

  31. Shimizu, S., Eguchi, Y., Kamiike, W., Matsuda, H. & Tsujimoto, Y. Bcl-2 expression prevents activation of the ice protease cascade. Oncogene 12, 2251–2257 (1996).

    CAS  PubMed  Google Scholar 

  32. Shaham, S. & Horvitz, H.R. An alternatively spliced C . elegans ced-4 RNA encodes a novel cell death inhibitor. cell 86, 201–208 (1996).

    Article  CAS  Google Scholar 

  33. Shaham, S. & Horvitz, H.R. Developing caenorhabditis elegans neurons may contain both cell-death protective and killer activities [review]. Genes Dev. 10, 578–591 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R.D. & Korsmeyer, S.J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336 (1990).

    Article  CAS  Google Scholar 

  36. Chao, D.T. et al. Bcl-XL and Bcl-2 repress a common pathway of cell death. J. Exp. Med. 182, 821–828 (1995).

    Article  CAS  Google Scholar 

  37. Oltvai, Z.N., Milliman, C.L. & Korsmeyer, S.J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619 (1993).

    Article  CAS  Google Scholar 

  38. Linette, G.P. et al. Bcl-2 is upregulated at the CD4+CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1, 197–205 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Yang, E. et al. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. cell. 80, 285–291 (1995).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knudson, C., Korsmeyer, S. Bcl-2 and Bax function independently to regulate cell death. Nat Genet 16, 358–363 (1997). https://doi.org/10.1038/ng0897-358

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0897-358

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