Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157

Details

Serval ID
serval:BIB_482B750A182A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157
Journal
Molecular Biology of the Cell
Author(s)
Yang  J. Y., Walicki  J., Michod  D., Dubuis  G., Widmann  C.
ISSN
1059-1524 (Print)
Publication state
Published
Issued date
08/2005
Volume
16
Number
8
Pages
3511-20
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Aug
Abstract
RasGAP bears two caspase-3 cleavage sites that are used sequentially as caspase activity increases in cells. When caspase-3 is mildly activated, RasGAP is first cleaved at position 455. This leads to the production of an N-terminal fragment, called fragment N, that activates the Ras-PI3K-Akt pathway and that promotes cell survival. At higher caspase activity, RasGAP is further cleaved at position 157 generating two small N-terminal fragments named N1 and N2. We have now determined the contribution of this second cleavage event in the regulation of apoptosis using cells in which the wild-type RasGAP gene has been replaced by a cDNA encoding a RasGAP mutant that cannot be cleaved at position 157. Our results show that cleavage of fragment N at position 157 leads to a marked reduction in Akt activity. This is accompanied by efficient processing of caspase-3 that favors cell death in response to various apoptotic stimuli. In nontumorigenic cells, fragments N1 and N2 do not modulate apoptosis. Therefore, the role of the second caspase-mediated cleavage of RasGAP is to allow the inactivation of the antiapoptotic function of fragment N so that caspases are no longer hampered in their ability to kill cells.
Keywords
Animals *Apoptosis Aspartic Acid/genetics/metabolism Caspase 3 Caspases/*metabolism Cell Line Down-Regulation Enzyme Activation Fibroblasts Mice Mice, Knockout Mutation/*genetics ras GTPase-Activating Proteins/deficiency/*genetics/*metabolism
Pubmed
Web of science
Create date
24/01/2008 14:43
Last modification date
20/08/2019 13:54
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