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Volume 272, Number 46, Issue of November 14, 1997 pp. 29347-29355
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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

(Received for publication, May 19, 1997, and in revised form, August 15, 1997)

Eric G. St. Clair , Steven J. Anderson ^§ and Zoltán N. Oltvai

From the Departments of  Pathology and ^§ Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611

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 CD3^hi and CD48⁺ 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.

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