ICE-LAP6, A NOVEL MEMBER OF THE ICE CED-3 GENE FAMILY, IS ACTIVATED BY THE CYTOTOXIC T-CELL PROTEASE GRANZYME-B/

Members of the ICE/Ced-3 gene family are likely effector components of the cell death machinery. Here, we characterize a novel member of thi s family designated ICE-LAP6. By phylogenetic analysis, ICE-LAP6 is cl assified into the Ced-3 subfamily which includes Ced-3, Yama/CPP32/apo pain, Mch2, and ICE-LAP3/Mch3/CMH-1. Interestingly, ICE-LAP6 contains an active site QACGG pentapeptide, rather than the QACRG pentapeptide shared by other family members. Overexpression of ICE-LAP6 induces apo ptosis in MCF7 breast carcinoma cells. More importantly, ICE-LAP6 is p roteolytically processed into an active cysteine protease by granzyme B, an important component of cytotoxic T cell-mediated apoptosis. Once activated, ICE-LAP6 is able to cleave the death substrate poly(ADP ri bose) polymerase into signature apoptotic fragments.