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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,{dagger} 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.

* Corresponding author. Mailing address: Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy. Phone: 39-06-7259 6540 or 6507. Fax: 39-06-7259 6505. E-mail: Daniela.Barila{at}uniroma2.it.

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

Molecular and Cellular Biology, April 2003, p. 2790-2799, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2790-2799.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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