title: Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein.
abstract: We describe the isolation and characterization of a new apaf-1-interacting protein (APIP) as a negative regulator of ischemic injury. APIP is highly expressed in skeletal muscle and heart and binds to the CARD of Apaf-1 in competition with caspase-9. Exogenous APIP inhibits cytochrome c-induced activation of caspase-3 and caspase-9, and suppresses cell death triggered by mitochondrial apoptotic stimuli through inhibiting the downstream activity of cytochrome c released from mitochondria. Conversely, reduction of APIP expression potentiates mitochondrial apoptosis. APIP expression is highly induced in mouse muscle affected by ischemia produced by interruption of the artery in the hindlimb and in C2C12 myotubes created by hypoxia in vitro, and the blockade of APIP up-regulation results in TUNEL-positive ischemic damage. Furthermore, forced expression of APIP suppresses ischemia/hypoxia-induced death of skeletal muscle cells. Taken together, these results suggest that APIP functions to inhibit muscle ischemic damage by binding to Apaf-1 in the Apaf-1/caspase-9 apoptosis pathway.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.forename: Yeon-Mi
authors.initials: YM
authors.lastname: Hong
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Pyo
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D017386:Sequence Homology, Amino Acid
chemical_list: C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; D012333:RNA, Messenger; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases