title: Caspase-dependent cleavage of c-Abl contributes to apoptosis.
abstract: The nonreceptor tyrosine kinase c-Abl may contribute to the regulation of apoptosis. c-Abl activity is induced in the nucleus upon DNA damage, and its activation is required for execution of the apoptotic program. Recently, activation of nuclear c-Abl during death receptor-induced apoptosis has been reported; however, the mechanism remains largely obscure. Here we show that c-Abl is cleaved by caspases during tumor necrosis factor- and Fas receptor-induced apoptosis. Cleavage at the very C-terminal region of c-Abl occurs mainly in the cytoplasmic compartment and generates a 120-kDa fragment that lacks the nuclear export signal and the actin-binding region but retains the intact kinase domain, the three nuclear localization signals, and the DNA-binding domain. Upon caspase cleavage, the 120-kDa fragment accumulates in the nucleus. Transient-transfection experiments show that cleavage of c-Abl may affect the efficiency of Fas-induced cell death. These data reveal a novel mechanism by which caspases can recruit c-Abl to the nuclear compartment and to the mammalian apoptotic program.
authors.affiliation: Dulbecco Telethon Institute and Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy. Daniela.Barila@uniroma2.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
authors.forename: Karel
authors.initials: K
authors.lastname: Dorey
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D019014:fas Receptor; D016315:Proto-Oncogene Proteins c-abl; D020169:Caspases