Bcl-2 Counters Apoptosis by Bax Heterodimerization-dependent and -independent Mechanisms in the T-cell Lineage

• Published in: The Journal of biological chemistry 1997-11, Vol.272 (46), p.29347-29355
• Main Authors: Clair, Eric G.St, Anderson, Steven J., Oltvai, Zoltán N.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - immunology; Apoptosis; bcl-2-Associated X Protein; Cell Lineage; Cell Survival; Dimerization; Mice; Mice, Transgenic; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Spleen - cytology; Spleen - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.46.29347

The effect of the cell death inhibitor Bcl-2 in relation to its capacity to dimerize with apoptosis promoter Bax or its homologs at their physiological expression levels was explored in the T-cell lineage. Transgenic mice expressing a BH1 mutant Bcl-2 (Bcl-2 mI-3), which fails to heterodimerize with proapoptotic members of the Bcl-2 family, such as Bax, were generated. Bcl-2 mI-3 protected immature CD4+8+ thymocytes from spontaneous, glucocorticoid and anti-CD3-induced apoptosis and altered T cell maturation, resulting in increased percentages of CD3hi and CD4−8+ thymocytes. In contrast, apoptosis of peripheral T-cells was unaffected by transgene expression. This correlated with their high Bax expression level and insensitivity to the caspase inhibitor, zVAD-fmk, a functional hallmark of Bax-like activity. Thus, within the T-cell lineage Bcl-2 can inhibit apoptosis independent of its association with Bax or its homologs; yet, above a threshold level of their physiologic proapoptotic activity, the capacity of Bcl-2 to heterodimerize with Bax or its homologs appears essential for it to counter cell death.