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Molecular and Cellular Biology, December 2004, p. 10425-10436, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10425-10436.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Partial Cleavage of RasGAP by Caspases Is Required for Cell Survival in Mild Stress Conditions

Jiang-Yan Yang,¹ David Michod,¹ Joël Walicki,¹ Brona M. Murphy,² Shailaja Kasibhatla,³ Seamus J. Martin,² and Christian Widmann^1*

Department of Cellular Biology, Biology and Medicine Faculty, Lausanne University, Lausanne, Switzerland,¹ Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland,² Maxim Pharmaceuticals, San Diego, California³

Received 3 April 2004/ Returned for modification 7 May 2004/ Accepted 3 September 2004

Tight control of apoptosis is required for proper development and maintenance of homeostasis in multicellular organisms. Cells can protect themselves from potentially lethal stimuli by expressing antiapoptotic factors, such as inhibitors of apoptosis, FLICE (caspase 8)-inhibitory proteins, and members of the Bcl2 family. Here, we describe a mechanism that allows cells to survive once executioner caspases have been activated. This mechanism relies on the partial cleavage of RasGAP by caspase 3 into an amino-terminal fragment called fragment N. Generation of this fragment leads to the activation of the antiapoptotic Akt kinase, preventing further amplification of caspase activity. Partial cleavage of RasGAP is required for cell survival under stress conditions because cells expressing an uncleavable RasGAP mutant cannot activate Akt, cannot prevent amplification of caspase 3 activity, and eventually undergo apoptosis. Executioner caspases therefore control the extent of their own activation by a feedback regulatory mechanism initiated by the partial cleavage of RasGAP that is crucial for cell survival under adverse conditions.

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* Corresponding author. Mailing address: IBCM, Bugnon 9, 1005 Lausanne, Switzerland. Phone: 41 21 692 5123. Fax: 41 21 692 5255. E-mail: Christian.Widmann{at}ibcm.unil.ch.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, December 2004, p. 10425-10436, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10425-10436.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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