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.

ACKNOWLEDGMENTS

We acknowledge M. Pascuccio and J. Kretzschmar for technical support. We are very grateful to P. Vandenabeele for the generous gift of several purified caspases and to T. Koleske for the generous gift of Abl/Arg-deficient cells. We also thank B. Tomassini, F. Malisan, C. Nicolò, and L. Franchi for suggestions and G. Donadel for critical reading of the manuscript.

D.B. is an Assistant Telethon Scientist and is supported by an Italian Telethon grant (TCP 00061) and A.R. and I.C. were supported by the Italian Foundation for Cancer Research (FIRC). This work was supported by grants from the Italian Association for Cancer Research (AIRC), from the Italian Ministry of University and Research (MIUR), from the Italian Space Agency (ASI), from the National Research Council (CNR), and from the European Commission Biomed 2 Program.