Abstract
The ability of proteins of the Bcl-2 family to either induce or inhibit apoptosis is dependent on both cell type and the apoptotic stimulus. We have shown in the murine pro-B cell line FL5.12 that Bcl-2 is incapable of inhibiting tumor necrosis factor alpha (TNFalpha)-induced cell death and is cleaved during this process. One potential explanation for this observation is that caspase activation directly or indirectly inhibits Bcl-2 function. It has been suggested that caspase cleavage of Bcl-2 is responsible for its inability to block certain cell deaths. Consistent with Bcl-2 cleavage being a caspase-mediated event, this cleavage is inhibitable by 50 microM CBZ-Val-Ala-Asp-fluoromethylketone (zVAD-fmk). Furthermore, Bcl-2 can cooperate with the caspase inhibitor zVAD-fmk in a dose-dependent manner to block TNFalpha-induced cell death. Overexpression of Bcl-2 results in a 10-fold decrease in the amount of zVAD-fmk required to inhibit TNFalpha-induced apoptosis. However, cleavage-defective mutants (D31A and D34A) show no enhanced viability relative to wild-type Bcl-2 in response to TNFalpha-induced cell death and also show the same cooperativity with zVAD-fmk. These results suggest that Bcl-2 cleavage is not important for the inhibition of TNFalpha-induced cell death but do not preclude an involvement in a post-commitment phase of apoptosis.
Highlights
Apoptosis, or programmed cell death, is an essential mechanism involved in development and homeostasis
We have shown that Bcl-2 overexpression can block cell death induced by IL-3 withdrawal in the murine pro-B cell line FL5.12 but is unable to block cell death induced by TNF␣ in the presence of the protein synthesis inhibitor cycloheximide
Bcl-2 Can Block Cell Death Induced by IL-3 Withdrawal but Cannot Block TNF␣-induced Cell Death—We have shown that the murine pro-B cell line FL5.12 can be triggered to undergo programmed cell death in response to TNF␣ in the presence of the protein synthesis inhibitor CHX
Summary
Programmed cell death, is an essential mechanism involved in development and homeostasis. Cells that overexpress Bcl-2 require a 10-fold lower concentration of zVAD-fmk to block TNF␣-induced cell death.
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