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Genes & Dev. 17 (3): 359-367

Copyright © 2003 by Cold Spring Harbor Laboratory Press.

Vol. 17, No. 3, pp. 359-367, February 1, 2003

CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals

Shengkan Jin,1 Markus Kalkum,2 Michael Overholtzer,1 Archontoula Stoffel,1 Brian T. Chait,2 and Arnold J. Levine1,3

1 Laboratory of Cancer Biology, 2 Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, Rockefeller University, New York, New York 10021, USA

Recently a Drosophila p53 protein has been identified that mediates apoptosis via a novel pathway involving the activation of the Reaper gene and subsequent inhibition of the inhibitors of apoptosis (IAPs). The present study found that CIAP1, a major mammalian homolog of Drosophila IAPs, is irreversibly inhibited (cleaved) during p53-dependent apoptosis and this cleavage is mediated by a serine protease. Serine protease inhibitors that block CIAP1 cleavage inhibit p53-dependent apoptosis. Furthermore, activation of the p53 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interacts with CIAP1 and potentiates apoptosis. These results demonstrate that the mammalian p53 protein may activate apoptosis through a novel pathway functionally similar to that in Drosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.

[Keywords: Inhibitor of apoptosis (IAP); CIAP1; serine protease HTRA2; p53-dependent apoptosis; AEBSF; z-VAD]

3 Corresponding author.

© 2003 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/03 $5.00

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