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bcl-X_s-induced Cell Death in 3T3 Cells Does Not Require or Induce Caspase Activation¹

Departments of Pharmacology [J. S. F., J. M.] and Pathology [M. A. B.], University of Michigan Medical School, Ann Arbor, Michigan 48109

Using a tetracycline-regulated expression system, we have shown that expression of bcl-X_S is sufficient to induce acute cell death in 3T3 cells, and that the manner in which these cells die is both morphologically and biochemically different from Fas/CD95-induced apoptosis. bcl-X_S expression causes loss of the inner mitochondrial membrane potential (m) but does not induce caspase activation. Loss of viability, as determined by mitochondrial function and ethidium bromide exclusion, was not inhibited by the broad-spectrum caspase inhibitor zVAD-fmk or by expression of a dominant negative caspase 9 (9DN). However, zVAD-fmk was efficacious in inhibiting cell death triggered by an activating anti-Fas/CD95 antibody. In addition, bcl-X_S does not possess the 5^th and 6^th -helices (thought to be the membrane-spanning domains in bcl-2, bcl-X_L, and bax) and, therefore, should not be able to form membrane channels, thus eliminating this possible mechanism of action. The finding that bcl-X_S kills 3T3 cells without caspase activation, along with the absence of membrane spanning domains in bcl-X_S, may, therefore, represent a novel cell death pathway for the pro-death bcl-2 family members.

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