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Molecular and Cellular Biology, August 2001, p. 5346-5358, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5346-5358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antiapoptotic Signaling Generated by Caspase-Induced Cleavage of RasGAP

Jiang-Yan Yang1 and Christian Widmann1,2,*

Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne,1 and Départment de Médecine Interne, Centre Hospitalier Universitaire Vaudois,2 Lausanne, Switzerland

Received 21 December 2000/Returned for modification 2 February 2001/Accepted 9 May 2001

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.

* Corresponding author. Mailing address: Institut de Biologie Cellulaire et de Morphologie, University of Lausanne, rue du Bugnon 9, 1005 Lausanne, Switzerland. Phone: 41 21 92 5123. Fax: 41 21 692 5255. E-mail: Christian.Widmann{at}ibcm.unil.ch.

Molecular and Cellular Biology, August 2001, p. 5346-5358, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5346-5358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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