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p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

AE Sayan, BS Sayan, V Gogvadze, D Dinsdale, U Nyman, TM Hansen, B Zhivotovsky, GM Cohen, RA Knight and G Melino


Oncogene (2008) 27, 4363–4372


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The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription- deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcriptionindependent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.


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