Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP

Details

Serval ID
serval:BIB_B10271B3CCE4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP
Journal
Molecular and Cellular Biology
Author(s)
Yang  J. Y., Widmann  C.
ISSN
0270-7306 (Print)
Publication state
Published
Issued date
08/2001
Volume
21
Number
16
Pages
5346-58
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Aug
Abstract
Activation of caspases 3 and 9 is thought to commit a cell irreversibly to apoptosis. There are, however, several documented situations (e.g., during erythroblast differentiation) in which caspases are activated and caspase substrates are cleaved with no associated apoptotic response. Why the cleavage of caspase substrates leads to cell death in certain cases but not in others is unclear. One possibility is that some caspase substrates generate antiapoptotic signals when cleaved. Here we show that RasGAP is one such protein. Caspases cleave RasGAP into a C-terminal fragment (fragment C) and an N-terminal fragment (fragment N). Fragment C expressed alone induces apoptosis, but this effect could be totally blocked by fragment N. Fragment N could also block apoptosis induced by low levels of caspase 9. As caspase activity increases, fragment N is further cleaved into fragments N1 and N2. Apoptosis induced by high levels of caspase 9 or by cisplatin was strongly potentiated by fragment N1 or N2 but not by fragment N. The present study supports a model in which RasGAP functions as a sensor of caspase activity to determine whether or not a cell should survive. When caspases are mildly activated, the partial cleavage of RasGAP protects cells from apoptosis. When caspase activity reaches levels that allow completion of RasGAP cleavage, the resulting RasGAP fragments turn into potent proapoptotic molecules.
Keywords
Apoptosis/*physiology Caspases/*physiology Enzyme Activation Hela Cells Humans Signal Transduction/physiology Structure-Activity Relationship Substrate Specificity ras GTPase-Activating Proteins/*physiology
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:43
Last modification date
20/08/2019 16:20
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