title: ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B.
abstract: Members of the ICE/Ced-3 gene family are likely effector components of the cell death machinery. Here, we characterize a novel member of this family designated ICE-LAP6. By phylogenetic analysis, ICE-LAP6 is classified into the Ced-3 subfamily which includes Ced-3, Yama/CPP32/apopain, 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 apoptosis in MCF7 breast carcinoma cells. More importantly, ICE-LAP6 is proteolytically 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-ribose) polymerase into signature apoptotic fragments.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: H
authors.initials: H
authors.lastname: Duan
authors.forename: K
authors.initials: K
authors.lastname: Orth
authors.forename: A M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: G G
authors.initials: GG
authors.lastname: Poirier
authors.forename: C J
authors.initials: CJ
authors.lastname: Froelich
authors.forename: W W
authors.initials: WW
authors.lastname: He
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D029742:Caenorhabditis elegans Proteins; D020170:Caspase 1; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary; D053804:Granzymes; D015801:Helminth Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology*; D014407:Tumor Cells, Cultured
chemical_list: D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D015801:Helminth Proteins; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans; D020170:Caspase 1