Skip to main content

Thank you for visiting 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.

Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c


Following exposure of cells to stimuli that trigger programmed cell death (apoptosis), cytochrome c is rapidly released from mitochondria into the cytoplasm where it activates proteolytic molecules known as caspases that specifically cleave the amino-acid sequence DEVD and are crucial for the execution of apoptosis1,2,3,4. The protein Bcl-2 interferes with this activation of caspases by preventing the release of cytochrome c2,3,4. Here we study these molecular interactions during apoptosis induced by the protein Bax, a pro-apoptotic homologue of Bcl-2 (refs 5, 6). We show that in cells transiently transfected with bax, Bax localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Caspase inibitors do not affect Bax-induced cytochrome c release but block caspase-3 activation and nuclear fragmentation. Unexpectedly, Bcl-2 also fails to prevent Bax-induced cytochrome c release, although it co-localizes with Bax to mitochondria. Cells overexpressing both Bcl-2 and Bax show no signs of caspase activation and survive with significant amounts of cytochrome c in the cytoplasm. These findings indicate that Bcl-2 can interfere with Bax killing downstream of and independently of cytochrome c release.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Bax co-localizes with mitochondrial cytochrome c oxidase VIc (COX) and Bcl-2.
Figure 2: Quantification of ectopic Bax expression, cytosolic cytochrome c and fragmented nuclei following bax transfection into R6 and SK2 cells.
Figure 3: Bax induces cytochrome c release irrespective of Bcl-2 inhibition.
Figure 4: Apoptotic morphology, cytochrome c release, caspase-3 activation and DNA fragmentation in response to Bax or Bax/Bcl-2 expression.


  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    Yang, al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Kluck, R. al. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 16, 4639–4649 (1997).

    CAS  Article  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    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).

    ADS  CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Otter, al. The binding properties and biological activities of Bcl-2 and Bax in cells exposed to apoptotic stimuli. J. Biol. Chem. (in the press).

  9. 9

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

    ADS  CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Zou, H., Henzel, W. J., Liu, X., Lutschg, A. & Wang, X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90, 405–413 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Borner, al. The protein bcl-2α does not require membrane attachment, but two conserved domains to suppress apoptosis. J. Cell Biol. 126, 1059–1068 (1994).

    CAS  Article  Google Scholar 

  13. 13

    Nicholson, D. al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995).

    ADS  CAS  Article  Google Scholar 

Download references


We thank D. Nicholson for the anti-caspase-3 antibody, and S. Rusconi, J.-L. Dreyer and M. Wymann for critically reading the manuscript. This research was supported by the Swiss National Science Foundation, the Swiss Cancer League and the Foundation for Aging Research (AETAS). B.J. was supported by the Austrian Science Foundation.

Author information



Corresponding author

Correspondence to Christoph Borner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rossé, T., Olivier, R., Monney, L. et al. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391, 496–499 (1998).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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