QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 16, Issue 8, 3511-3520, August 2005

This Article Full Text Full Text (PDF) All Versions of this Article: E05-01-0080v1 16/8/3511    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, J.-Y. Articles by Widmann, C. Search for Related Content PubMed PubMed Citation Articles by Yang, J.-Y. Articles by Widmann, C.

Impaired Akt Activity Down-Modulation, Caspase-3 Activation, and Apoptosis in Cells Expressing a Caspase-resistant Mutant of RasGAP at Position 157

Department of Cellular Biology and Morphology, Biology and Medicine Faculty, Lausanne University, 1005 Lausanne, Switzerland

Submitted January 31, 2005; Revised April 21, 2005; Accepted May 11, 2005
Monitoring Editor: Gerard Evan

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of this second cleavage event in the regulation of apoptosis using cells in which the wild-type RasGAP gene has been replaced by a cDNA encoding a RasGAP mutant that cannot be cleaved at position 157.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.

Abbreviations used: ERK, extracellular signal-regulated kinase; HA, hemagglutinin; MEFs, mouse embryonic fibroblasts.

Address correspondence to: Christian Widmann (Christian.Widmann{at}unil.ch).

This article has been cited by other articles:

				D. R. Hostetter, C. R. K. Loeb, F. Chu, and C. S. Craik Hip Is a Pro-survival Substrate of Granzyme B J. Biol. Chem., September 21, 2007; 282(38): 27865 - 27874. [Abstract] [Full Text] [PDF]

				A. Bosque, J. I. Aguilo, M. A. Alava, E. Paz-Artal, J. Naval, L. M. Allende, and A. Anel The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling Blood, February 15, 2007; 109(4): 1627 - 1635. [Abstract] [Full Text] [PDF]

				A. I Arroba, A. M Lechuga-Sancho, L. M Frago, J. Argente, and J. A Chowen Cell-specific expression of X-linked inhibitor of apoptosis in the anterior pituitary of streptozotocin-induced diabetic rats J. Endocrinol., January 1, 2007; 192(1): 215 - 227. [Abstract] [Full Text] [PDF]

				J.-Y. Yang, J. Walicki, A. Abderrahmani, M. Cornu, G. Waeber, B. Thorens, and C. Widmann Expression of an Uncleavable N-terminal RasGAP Fragment in Insulin-secreting Cells Increases Their Resistance toward Apoptotic Stimuli without Affecting Their Glucose-induced Insulin Secretion J. Biol. Chem., September 23, 2005; 280(38): 32835 - 32842. [Abstract] [Full Text] [PDF]