Impaired Akt Activity Down-Modulation, Caspase-3 Activation, and Apoptosis in Cells Expressing a Caspase-resistant Mutant of RasGAP at Position 157
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Published:2005-08
Issue:8
Volume:16
Page:3511-3520
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ISSN:1059-1524
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Container-title:Molecular Biology of the Cell
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language:en
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Short-container-title:MBoC
Author:
Yang Jiang-Yan1, Walicki Joël1, Michod David1, Dubuis Gilles1, Widmann Christian1
Affiliation:
1. Department of Cellular Biology and Morphology, Biology and Medicine Faculty, Lausanne University, 1005 Lausanne, Switzerland
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of this second cleavage event in the regulation of apoptosis using cells in which the wild-type RasGAP gene has been replaced by a cDNA encoding a RasGAP mutant that cannot be cleaved at position 157.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.
Publisher
American Society for Cell Biology (ASCB)
Subject
Cell Biology,Molecular Biology
Reference37 articles.
1. Algeciras-Schimnich, A., Barnhart, B. C., and Peter, M. E. (2002). Apoptosis-independent functions of killer caspases.Curr. Opin. Cell Biol.14, 721–726. 2. Allombert-Blaise, C.et al.(2003). Terminal differentiation of human epidermal keratinocytes involves mitochondria- and caspase-dependent cell death pathway.Cell Death Differ.10, 850–852. 3. Bartling, B., Yang, J. Y., Michod, D., Widmann, C., Lewensohn, R., and Zhivotovsky, B. (2004). RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide.Carcinogenesis25, 909–921. 4. Basu, A., Lu, D., Sun, B., Moor, A. N., Akkaraju, G. R., and Huang, J. (2002). Proteolytic activation of protein kinase C-epsilon by caspase-mediated processing and transduction of antiapoptotic signals.J. Biol. Chem.277, 41850–41856. 5. Bentele, M., Lavrik, I., Ulrich, M., Stosser, S., Heermann, D. W., Kalthoff, H., Krammer, P. H., and Eils, R. (2004). Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis.J. Cell Biol.166, 839–851.
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