Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD
- Christina Berube*,†,
- Louis-Martin Boucher*,†,‡,
- Weili Ma*,†,
- Andrew Wakeham*,†,‡,
- Leonardo Salmena*,†,
- Razqallah Hakem*,†,
- Wen-Chen Yeh*,†,‡,
- Tak W. Mak*,†,‡,§, and
- Samuel Benchimol*,†,§
- *Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, ON, Canada M5G 2M9; ‡Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1; and †Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9
-
Contributed by Tak W. Mak, August 8, 2005
Abstract
The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to diverse stress stimuli. p53-mediated cell death depends in large part on transcriptional up-regulation of target genes. One of these targets, P53-induced protein with a death domain (PIDD), was shown to function as a mediator of p53-dependent apoptosis. Here we show that PIDD is a cytoplasmic protein, and that PIDD-induced apoptosis and growth suppression in embryonic fibroblasts depend on the adaptor protein receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD). We provide evidence that PIDD-induced cell death is associated with the early activation of caspase-2 and later activation of caspase-3 and -7. Our results also show that caspase-2-/-, in contrast to RAIDD-/-, mouse embryonic fibroblasts, are only partially resistant to PIDD. Our findings suggest that caspase-2 contributes to PIDD-mediated cell death, but that it is not the sole effector of this pathway.
Footnotes
-
↵ § To whom correspondence may be addressed. E-mail: tmak{at}uhnres.utoronto.ca or benchimo{at}uhnres.utoronto.ca.
-
Author contributions: C.B., T.W.M., and S.B. designed research; C.B., L.-M.B., W.M., and A.W. performed research; C.B., L.S., R.H., and W.-C.Y. contributed new reagents/analytic tools; C.B. and W.-C.Y. analyzed data; C.B. wrote the paper; and T.W.M. and S.B. supervised and discussed experimental work.
-
Abbreviations: DD, death domain; PIDD, p53-induced protein with a DD; mPIDD, mouse PIDD; RAIDD, receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a DD; LRDD, leucine-rich DD; ts, temperature sensitive; MEF, mouse embryonic fibroblast; FADD, Fas-associated DD; IRES, internal ribosome entry site.
- Copyright © 2005, The National Academy of Sciences
