TY - JOUR
T1 - Bcl-2 counters apoptosis by Bax heterodimerization-dependent and - independent mechanisms in the T-cell lineage
AU - St. Clair, Eric G.
AU - Anderson, Steven J.
AU - Oltvai, Zoltán N.
PY - 1997/11/14
Y1 - 1997/11/14
N2 - 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 percent ages of CD3(hi) 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, (z)VAD-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.
AB - 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 percent ages of CD3(hi) 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, (z)VAD-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.
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U2 - 10.1074/jbc.272.46.29347
DO - 10.1074/jbc.272.46.29347
M3 - Article
C2 - 9361016
AN - SCOPUS:0030715642
SN - 0021-9258
VL - 272
SP - 29347
EP - 29355
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 46
ER -