Accelerated Publication - The Caenorhabditis elegans sex determination protein FEM-1 is a CED-3 substrate that associates with CED-4 and mediates apoptosis in mammalian cells

Sex-specific elimination of cells by apoptosis plays a role in sex determin ation in Caenorhabditis elegans. Recently, a mammalian pro-apoptotic protei n named F1A alpha has been identified. F1A alpha shares extensive homology throughout the entire protein with the C. elegans protein, FEM-1, which is essential for achieving all aspects of the male phenotype in the nematode. In this report, the role of FEM-1 in apoptosis was investigated. Overexpres sion of FEM-1 induces caspase-dependent apoptosis in mammalian cells. FEM-1 is cleaved in vitro by the C. elegans caspase, CED-3, generating an N-term inal cleavage product that corresponds to the minimal effector domain for a poptosis. Furthermore, CED-4 associates with FEM-1 in vitro and in vivo in mammalian cells and potentiates FEM-1-mediated apoptosis. Similarly, Apaf-1 , the mammalian homologue of CED-4 was found to associate with F1A alpha. T hese data suggest that FEM-1 and F1A alpha may mediate apoptosis by communi cating directly with the core machinery of apoptosis.