Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases.

Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes, ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2 and Bcl-xL function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).