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Molecular and Cellular Biology, April 2003, p. 2790-2799, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2790-2799.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Caspase-Dependent Cleavage of c-Abl Contributes to Apoptosis

Daniela Barilà,^1,2* Alessandra Rufini,² Ivano Condò,² Natascia Ventura,² Karel Dorey,^3, Giulio Superti-Furga,³ and Roberto Testi²

Dulbecco Telethon Institute,¹ Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," 00133 Rome, Italy,² Developmental Biology Program, European Molecular Biology Laboratory, 69117 Heidelberg, Germany³

Received 24 June 2002/ Returned for modification 21 August 2002/ Accepted 27 December 2002

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.

Present address: Developmental Signalling Lab, Cancer Research UK, WC2A 3PX London, United Kingdom.

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