Journal
CELL DEATH AND DIFFERENTIATION
Volume 8, Issue 5, Pages 443-450Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4400840
Keywords
caspases; proteases; cytoskeleton; intermediate filaments; vimentin
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Funding
- NCI NIH HHS [K08-CA01752] Funding Source: Medline
- NIAMS NIH HHS [R01 AR41836] Funding Source: Medline
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Caspases are key mediators of apoptosis, Using a novel expression cloning strategy we recently developed to identify cDNAs encoding caspase substrates, we isolated the intermediate filament protein vimentin as a caspase substrate, vimentin is preferentially cleaved by multiple caspases at distinct sites in vitro, including Asp(85) by caspases-3 and -7 and Asp(259) by caspase-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteolyzed by multiple caspases into similar sized fragments during apoptosis induced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Moreover, caspase proteolysis of vimentin at Asp(85) generates a pro apoptotic amino-terminal fragment whose ability to induce apoptosis is dependent on caspases, Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate filaments and by amplifying the cell death signal via a pro-apoptotic cleavage product.
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