Bcl‐2 and Fas/APO‐1 regulate distinct pathways to lymphocyte apoptosis.
Open accessAbstract
Activation of the cell surface receptor Fas/APO-1 (CD95) induces apoptosis in lymphocytes and regulates immune responses. The cytoplasmic membrane protein Bcl-2 inhibits lymphocyte killing by diverse cytotoxic agents, but we found it provided little protection against Fas/APO-1-transduced apoptosis in B lymphoid cell lines, thymocytes and activated T cells. In contrast, the cowpox virus protease inhibitor CrmA blocked Fas/APO-1-transduced apoptosis, but did not affect cell death induced by gamma-radiation or serum deprivation. Signalling through Fas/APO-1 did not down-regulate Bcl-2 or induce its antagonists Bax and Bcl-xS. In Fas/APO-1-deficient lpr mice, Bcl-2 transgenes markedly augmented the survival of antigen-activated T cells and the abnormal accumulation of lymphocytes (although they did not interfere with deletion of auto-reactive cells in the thymus). These data raise the possibility that Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis.
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In type I cells (e.g., thymocytes and mature lymphocytes), CASP8-dependent proteolytic maturation of executioner CASP3 and CASP7 suffices to drive RCD, which cannot be inhibited by transgene-driven overexpression of anti-apoptotic BCL2 proteins, co-deletion of Bax and Bak1, or loss of BID.
“In so-called “type I cells” (e.g., thymocytes and mature lymphocytes) the CASP8-dependent proteolytic maturation of executioner CASP3 and CASP7 suffices to drive RCD, which cannot be inhibited by the transgene-driven overexpression of anti-apoptotic BCL2 proteins, the co-deletion of Bax and Bak1, or the loss of BID [308, 309].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [309]
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Gross, A., Yin, X.-M., Wang, K., Wei, M. C., Jockel, J., Milliman, C., Erdjument-Bromage, H., Tempst, P., & Korsmeyer, S. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.1156 · Cited by 1,045 · see citing works
The many roles of FAS receptor signaling in the immune system
Strasser, A., Jost, P. J., & Nagata, S. (2009) · Immunity · doi:10.1016/j.immuni.2009.01.001 · Cited by 968 · see citing works
Self-citationThirty years of BCL-2: translating cell death discoveries into novel cancer therapies
Delbridge, A. R. D., Grabow, S., Strasser, A., & Vaux, D. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.17 · Cited by 752 · see citing works
Self-citationBarnhart, B. C., Alappat, E. C., & Peter, M. E. (2003) · Seminars in Immunology · doi:10.1016/s1044-5323(03)00031-9 · Cited by 419 · see citing works
VDAC2 enables BAX to mediate apoptosis and limit tumor development
Chin, H. S., Li, M. X., Tan, I. K. L., Ninnis, R. L., Reljic, B., Scicluna, K., Dagley, L. F., Sandow, J. J., Kelly, G. L., Samson, A. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07309-4 · Cited by 196 · see citing works
Self-citationLee, E., Song, C.-H., Bae, S.-J., Ha, K.-T., & Karki, R. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01069-y · Cited by 164 · see citing works
Regulation of Apoptosis in Myeloid Cells by Interferon Consensus Sequence–Binding Protein
Gabriele, L., Phung, J., Fukumoto, J., Segal, D., Wang, I.-M., Giannakakou, P., Giese, N. A., Ozato, K., & Morse, H. C. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.3.411 · Cited by 114 · see citing works
BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice
Ke, F., Voss, A., Kerr, J. B., O'Reilly, L. A., Tai, L., Echeverry, N., Bouillet, P., Strasser, A., & Kaufmann, T. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.210 · Cited by 113 · see citing works
Self-citationPender, M. P. (1999) · Immunology & Cell Biology · doi:10.1046/j.1440-1711.1999.00818.x · Cited by 77 · see citing works
The Role of Apoptosis in the Resolution of T Cell-Mediated Cutaneous Inflammation
Orteu, C. H., Poulter, L. W., Rustin, M. H. A., Sabin, C. A., Salmon, M., & Akbar, A. N. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.4.1619 · Cited by 73 · see citing works
Consequences of the combined loss of BOK and BAK or BOK and BAX
Ke, F., Bouillet, P., Kaufmann, T., Strasser, A., Kerr, J., & Voss, A. K. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.176 · Cited by 72 · see citing works
Self-citation
- Authors
- Strasser, A., Harris, A. W., Huang, D. C., Krammer, P. H., & Cory, S.
- Affiliations
- The Royal Melbourne Hospital (AU)
- Venue
- The EMBO Journal
- Published
- 1995-12-01
- Volume
- 14
- Issue
- 24
- Pages
- 6136-6147
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC394738
- OpenAlex
- W1587890084
- Cited by
- 784
- References
- 83
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 13 · 2021: 10 · 2020: 12 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 4 · 2014: 10 · 2013: 15 · 2012: 79
- FWCI
- 16.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council
- National Health and Medical Research Council
- National Cancer Institute (R01CA043540, CA 43540)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Bcl-2, Fas/APO-1, lymphocyte apoptosis, CrmA, Bax, Bcl-x, lpr mice, T cell survival, thymocyte deletion, autoreactive T cells, immune regulation, radiation-induced cell death, serum deprivation
- MeSH terms
- Animals, Base Sequence, Cell Line, Humans, Lymphatic Diseases, Lymphocyte Activation, Lymphocytes, Mice, Transgenic, Molecular Sequence Data, Proto-Oncogene Proteins, Proto-Oncogenes, T-Lymphocytes, Viral Proteins, Signal Transduction, Autoimmunity, Serpins, Gene Expression, Apoptosis, DNA Primers, fas Receptor, Proto-Oncogene Proteins c-bcl-2, Mice
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