title: Human ACAP2 is a homolog of C. elegans CNT-1 that promotes apoptosis in cancer cells.
abstract: Activation of caspases is an integral part of the apoptotic cell death program. Collectively, these proteases target hundreds of substrates, leading to the hypothesis that apoptosis is "death by a thousand cuts". Recent work, however, has demonstrated that caspase cleavage of only a subset of these substrates directs apoptosis in the cell. One such example is C. elegans CNT-1, which is cleaved by CED-3 to generate a truncated form, tCNT-1, that acquires a potent phosphoinositide-binding activity and translocates to the plasma membrane where it inactivates AKT survival signaling. We report here that ACAP2, a homolog of C. elegans CNT-1, has a pro-apoptotic function and an identical phosphoinositide-binding pattern to that of tCNT-1, despite not being an apparent target of caspase cleavage. We show that knockdown of ACAP2 blocks apoptosis in cancer cells in response to the chemotherapeutic antimetabolite 5-fluorouracil and that ACAP2 expression is down-regulated in some esophageal cancers, leukemias and lymphomas. These results suggest that ACAP2 is a functional homolog of C. elegans CNT-1 and its inactivation or downregulation in human cells may contribute to cancer development.
authors: a Department of Molecular, Cellular, and Developmental Biology; University of Colorado ; Boulder , CO , USA.
authors: Kelly D
authors: KD
authors: Sullivan
authors: Akihisa
authors: A
authors: Nakagawa
authors: Ding
authors: D
authors: Xue
authors: Joaquín M
authors: JM
authors: Espinosa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D005472:Fluorouracil / Q000737:chemistry; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: C507017:ACAP1 protein, human; C545104:ACAP2 protein, human; C576670:CNT-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D020690:GTPase-Activating Proteins; D008024:Ligands; D008055:Lipids; D008565:Membrane Proteins; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D005472:Fluorouracil