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Caspase-dependent cleavage of c-Abl contributes to apoptosis
Daniela Barilà1, Alessandra Rufini, Ivano Condò
1Dulbecco 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
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.
Insights
Caspases cleave the nonreceptor tyrosine kinase c-Abl during apoptosis. This cleavage generates a nuclear-accumulating fragment, revealing a novel mechanism in programmed cell death regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The nonreceptor tyrosine kinase c-Abl plays a role in apoptosis regulation.
- c-Abl activation in the nucleus is crucial for apoptosis execution, particularly after DNA damage.
- The precise mechanism of c-Abl activation during death receptor-induced apoptosis is not fully understood.
Purpose of the Study:
- To elucidate the mechanism of c-Abl activation during death receptor-induced apoptosis.
- To investigate the role of caspases in c-Abl processing and localization during apoptosis.
Main Methods:
- Western blotting to detect c-Abl cleavage.
- Immunofluorescence to track protein localization.
- Transient transfection assays to assess functional impact.
Main Results:
- Caspase-mediated cleavage of c-Abl was observed during tumor necrosis factor (TNF) and Fas receptor-induced apoptosis.
- Cleavage occurs in the cytoplasm, generating a 120-kDa fragment lacking nuclear export signals.
- This fragment accumulates in the nucleus and retains key functional domains (kinase, nuclear localization, DNA-binding).
Conclusions:
- Caspase cleavage of c-Abl is a novel mechanism that facilitates its nuclear accumulation during apoptosis.
- This process may enhance the efficiency of Fas-induced cell death.
- These findings reveal a new pathway for caspase recruitment of c-Abl into the nuclear apoptotic program.