The cell death machine.

Abstract

Apoptosis, or programmed cell death, is a physiologic process whereby individual cells are purposefully eliminated to achieve homeostasis and proper metazoan development. Recently, numerous genes that control cell death have been identified. How these genes interact in the molecular mechanism of apoptosis remains to be discovered. The primary emphasis of this thesis will be on (1) the signal transduction of the cell death receptor Fas/APO-1 and (2) the mechanism by which core components of the suicide appartus both interact and function. Fas/APO-1 is a member of the TNF receptor family and plays a dominant role in the immune system, down-regulating the immune response and contributing to T cell-mediated cytotoxicity. Activation of Fas/APO-1 by either natural ligand or agonist antibody initiates apoptosis. Until recently, however, the mechanism by which Fas/APO-1 engages the cell death machinery has been an enigma. Here we delineate the molecular mechanism by which this cell surface death receptor signals the suicide response. Genetic studies of the nematode <italic>Caenorhabditis elegans</italic> have identified three important components of the cell death machinery. CED-3 and CED-4 function to kill cells, whereas CED-9 protects cells from death. Here we demonstrate that CED-9 and its mammalian homolog bcl-X_L interact with and inhibit the function of CED-4. Similarly, CED-4 can independently interact with CED-3 and its mammalian counterparts ICE and FLICE. Thus, CED-4 plays a central role in the cell death pathway, biochemically linking the bcl-2/CED-9 family to the proapoptotic ICE/CED-3 family of cysteine proteases.