Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 May;17(5):2468–2474. doi: 10.1128/mcb.17.5.2468

Human Bak induces cell death in Schizosaccharomyces pombe with morphological changes similar to those with apoptosis in mammalian cells.

B Ink 1, M Zörnig 1, B Baum 1, N Hajibagheri 1, C James 1, T Chittenden 1, G Evan 1
PMCID: PMC232095  PMID: 9111315

Abstract

Apoptosis as a form of programmed cell death (PCD) in multicellular organisms is a well-established genetically controlled process that leads to elimination of unnecessary or damaged cells. Recently, PCD has also been described for unicellular organisms as a process for the socially advantageous regulation of cell survival. The human Bcl-2 family member Bak induces apoptosis in mammalian cells which is counteracted by the Bcl-x(L) protein. We show that Bak also kills the unicellular fission yeast Schizosaccharomyces pombe and that this is inhibited by coexpression of human Bcl-x(L). Moreover, the same critical BH3 domain of Bak that is required for induction of apoptosis in mammalian cells is also required for inducing death in yeast. This suggests that Bak kills mammalian and yeast cells by similar mechanisms. The phenotype of the Bak-induced death in yeast involves condensation and fragmentation of the chromatin as well as dissolution of the nuclear envelope, all of which are features of mammalian apoptosis. These data suggest that the evolutionarily conserved metazoan PCD pathway is also present in unicellular yeast.

Full Text

The Full Text of this article is available as a PDF (787.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ameisen J. C., Idziorek T., Billaut-Mulot O., Loyens M., Tissier J. P., Potentier A., Ouaissi A. Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival. Cell Death Differ. 1995 Oct;2(4):285–300. [PubMed] [Google Scholar]
  2. Ameisen J. C. The origin of programmed cell death. Science. 1996 May 31;272(5266):1278–1279. doi: 10.1126/science.272.5266.1278. [DOI] [PubMed] [Google Scholar]
  3. Brown D. G., Sun X. M., Cohen G. M. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem. 1993 Feb 15;268(5):3037–3039. [PubMed] [Google Scholar]
  4. Chittenden T., Flemington C., Houghton A. B., Ebb R. G., Gallo G. J., Elangovan B., Chinnadurai G., Lutz R. J. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 1995 Nov 15;14(22):5589–5596. doi: 10.1002/j.1460-2075.1995.tb00246.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chittenden T., Harrington E. A., O'Connor R., Flemington C., Lutz R. J., Evan G. I., Guild B. C. Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 1995 Apr 20;374(6524):733–736. doi: 10.1038/374733a0. [DOI] [PubMed] [Google Scholar]
  6. Christensen S. T., Wheatley D. N., Rasmussen M. I., Rasmussen L. Mechanisms controlling death, survival and proliferation in a model unicellular eukaryote Tetrahymena thermophila. Cell Death Differ. 1995 Oct;2(4):301–308. [PubMed] [Google Scholar]
  7. Cornillon S., Foa C., Davoust J., Buonavista N., Gross J. D., Golstein P. Programmed cell death in Dictyostelium. J Cell Sci. 1994 Oct;107(Pt 10):2691–2704. doi: 10.1242/jcs.107.10.2691. [DOI] [PubMed] [Google Scholar]
  8. Dbaibo G. S., Pushkareva M. Y., Jayadev S., Schwarz J. K., Horowitz J. M., Obeid L. M., Hannun Y. A. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1347–1351. doi: 10.1073/pnas.92.5.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dobrowsky R. T., Hannun Y. A. Ceramide stimulates a cytosolic protein phosphatase. J Biol Chem. 1992 Mar 15;267(8):5048–5051. [PubMed] [Google Scholar]
  10. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  11. Farrow S. N., White J. H., Martinou I., Raven T., Pun K. T., Grinham C. J., Martinou J. C., Brown R. Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature. 1995 Apr 20;374(6524):731–733. doi: 10.1038/374731a0. [DOI] [PubMed] [Google Scholar]
  12. Gougeon M. L., Montagnier L. Apoptosis in AIDS. Science. 1993 May 28;260(5112):1269–1270. doi: 10.1126/science.8098552. [DOI] [PubMed] [Google Scholar]
  13. Greenhalf W., Stephan C., Chaudhuri B. Role of mitochondria and C-terminal membrane anchor of Bcl-2 in Bax induced growth arrest and mortality in Saccharomyces cerevisiae. FEBS Lett. 1996 Feb 12;380(1-2):169–175. doi: 10.1016/0014-5793(96)00044-0. [DOI] [PubMed] [Google Scholar]
  14. Hanada M., Aimé-Sempé 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. 1995 May 19;270(20):11962–11969. doi: 10.1074/jbc.270.20.11962. [DOI] [PubMed] [Google Scholar]
  15. Hannun Y. A., Bell R. M. The sphingomyelin cycle: a prototypic sphingolipid signaling pathway. Adv Lipid Res. 1993;25:27–41. [PubMed] [Google Scholar]
  16. Hannun Y. A. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem. 1994 Feb 4;269(5):3125–3128. [PubMed] [Google Scholar]
  17. Harrington E. A., Fanidi A., Evan G. I. Oncogenes and cell death. Curr Opin Genet Dev. 1994 Feb;4(1):120–129. doi: 10.1016/0959-437x(94)90100-7. [DOI] [PubMed] [Google Scholar]
  18. Hengartner M. O., Horvitz H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell. 1994 Feb 25;76(4):665–676. doi: 10.1016/0092-8674(94)90506-1. [DOI] [PubMed] [Google Scholar]
  19. Hurle J. M. Cell death in developing systems. Methods Achiev Exp Pathol. 1988;13:55–86. [PubMed] [Google Scholar]
  20. Jarvis W. D., Kolesnick R. N., Fornari F. A., Traylor R. S., Gewirtz D. A., Grant S. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):73–77. doi: 10.1073/pnas.91.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jayadev S., Liu B., Bielawska A. E., Lee J. Y., Nazaire F., Pushkareva MYu, Obeid L. M., Hannun Y. A. Role for ceramide in cell cycle arrest. J Biol Chem. 1995 Feb 3;270(5):2047–2052. doi: 10.1074/jbc.270.5.2047. [DOI] [PubMed] [Google Scholar]
  22. Kiefer M. C., Brauer M. J., Powers V. C., Wu J. J., Umansky S. R., Tomei L. D., Barr P. J. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature. 1995 Apr 20;374(6524):736–739. doi: 10.1038/374736a0. [DOI] [PubMed] [Google Scholar]
  23. Kolesnick R. Ceramide: a novel second messenger. Trends Cell Biol. 1992 Aug;2(8):232–236. doi: 10.1016/0962-8924(92)90310-j. [DOI] [PubMed] [Google Scholar]
  24. Kolesnick R., Golde D. W. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell. 1994 May 6;77(3):325–328. doi: 10.1016/0092-8674(94)90147-3. [DOI] [PubMed] [Google Scholar]
  25. Liston P., Roy N., Tamai K., Lefebvre C., Baird S., Cherton-Horvat G., Farahani R., McLean M., Ikeda J. E., MacKenzie A. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature. 1996 Jan 25;379(6563):349–353. doi: 10.1038/379349a0. [DOI] [PubMed] [Google Scholar]
  26. Liu J., Mathias S., Yang Z., Kolesnick R. N. Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase. J Biol Chem. 1994 Jan 28;269(4):3047–3052. [PubMed] [Google Scholar]
  27. Maundrell K. nmt1 of fission yeast. A highly transcribed gene completely repressed by thiamine. J Biol Chem. 1990 Jul 5;265(19):10857–10864. [PubMed] [Google Scholar]
  28. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  29. Moreno S., Klar A., Nurse P. Molecular genetic analysis of fission yeast Schizosaccharomyces pombe. Methods Enzymol. 1991;194:795–823. doi: 10.1016/0076-6879(91)94059-l. [DOI] [PubMed] [Google Scholar]
  30. Naito T., Kusano K., Kobayashi I. Selfish behavior of restriction-modification systems. Science. 1995 Feb 10;267(5199):897–899. doi: 10.1126/science.7846533. [DOI] [PubMed] [Google Scholar]
  31. Nickels J. T., Broach J. R. A ceramide-activated protein phosphatase mediates ceramide-induced G1 arrest of Saccharomyces cerevisiae. Genes Dev. 1996 Feb 15;10(4):382–394. doi: 10.1101/gad.10.4.382. [DOI] [PubMed] [Google Scholar]
  32. Obeid L. M., Linardic C. M., Karolak L. A., Hannun Y. A. Programmed cell death induced by ceramide. Science. 1993 Mar 19;259(5102):1769–1771. doi: 10.1126/science.8456305. [DOI] [PubMed] [Google Scholar]
  33. Oberhammer F., Wilson J. W., Dive C., Morris I. D., Hickman J. A., Wakeling A. E., Walker P. R., Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J. 1993 Sep;12(9):3679–3684. doi: 10.1002/j.1460-2075.1993.tb06042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Oppenheim R. W. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501. doi: 10.1146/annurev.ne.14.030191.002321. [DOI] [PubMed] [Google Scholar]
  35. Raff M. C. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. doi: 10.1038/356397a0. [DOI] [PubMed] [Google Scholar]
  36. Roy N., Mahadevan M. S., McLean M., Shutler G., Yaraghi Z., Farahani R., Baird S., Besner-Johnston A., Lefebvre C., Kang X. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995 Jan 13;80(1):167–178. doi: 10.1016/0092-8674(95)90461-1. [DOI] [PubMed] [Google Scholar]
  37. Sato T., Hanada M., Bodrug S., Irie S., Iwama N., Boise L. H., Thompson C. B., Golemis E., Fong L., Wang H. G. Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9238–9242. doi: 10.1073/pnas.91.20.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shub D. A. Bacterial viruses. Bacterial altruism? Curr Biol. 1994 Jun 1;4(6):555–556. doi: 10.1016/s0960-9822(00)00124-x. [DOI] [PubMed] [Google Scholar]
  39. Tokuyasu K. T. Use of poly(vinylpyrrolidone) and poly(vinyl alcohol) for cryoultramicrotomy. Histochem J. 1989 Mar;21(3):163–171. doi: 10.1007/BF01007491. [DOI] [PubMed] [Google Scholar]
  40. Vito P., Lacanà E., D'Adamio L. Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science. 1996 Jan 26;271(5248):521–525. doi: 10.1126/science.271.5248.521. [DOI] [PubMed] [Google Scholar]
  41. Welburn S. C., Dale C., Ellis D., Beecroft R., Pearson T. W. Apoptosis in procyclic Trypanosoma brucei rhodesiense in vitro. Cell Death Differ. 1996 Apr;3(2):229–236. [PubMed] [Google Scholar]
  42. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  43. Wyllie A. H. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview. Cancer Metastasis Rev. 1992 Sep;11(2):95–103. doi: 10.1007/BF00048057. [DOI] [PubMed] [Google Scholar]
  44. Yarmolinsky M. B. Programmed cell death in bacterial populations. Science. 1995 Feb 10;267(5199):836–837. doi: 10.1126/science.7846528. [DOI] [PubMed] [Google Scholar]
  45. Yuan J., Shaham S., Ledoux S., Ellis H. M., Horvitz H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993 Nov 19;75(4):641–652. doi: 10.1016/0092-8674(93)90485-9. [DOI] [PubMed] [Google Scholar]
  46. Zha H., Fisk H. A., Yaffe M. P., Mahajan N., Herman B., Reed J. C. Structure-function comparisons of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell Biol. 1996 Nov;16(11):6494–6508. doi: 10.1128/mcb.16.11.6494. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES