Editors' ChoiceApoptosis

Cleaved out of Action

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Science's STKE  11 Feb 2003:
Vol. 2003, Issue 169, pp. tw62-TW62
DOI: 10.1126/stke.2003.169.tw62

The pathway by which the transcriptional regulator p53 activates apoptosis appears to diverge between invertebrates and vertebrates. In Drosophila, in response to such cellular stresses as DNA damage, p53 stimulates the expression of Reaper, thereby stimulating ubiquitin-mediated protein degradation of inhibitors of apoptosis (IAPs) and alleviating IAP inhibition of caspase activation. IAP homologs have been identified in mammals, but Reaper homologs have not. Instead, IAP inhibition in mammals is alleviated by Smac, which is released from mitochondria during the apoptotic cascade, or by HTRA2, a serine protease. Jin et al. investigated how a specific IAP, CIAP1, was inactivated in p53-mediated apoptosis and found that it was cleaved in response to DNA damage caused by etoposide treatment of HeLa cells. To determine whether CIAP1 cleavage was a consequence of caspase activation or occurred through a different mechanism, p53-independent apoptosis was triggered by activation of Fas. CIAP1 was cleaved in this apoptotic scenario but produced fragments of different size than those observed during p53-mediated apoptosis. Furthermore, caspase inhibitors did not block the p53-stimulated cleavage of CIAP1. Cleavage of CIAP1 produced by p53 processes required protein synthesis and could be inhibited by treatment of the cells with a serine protease inhibitor. In addition, serine protease inhibitors blocked etoposide-stimulated apoptosis of HeLa and primary mouse thymocytes, which indicates the importance of CIAP1 cleavage. Northern analysis showed that HTRA2 transcripts were increased after etoposide treatment or in response to overexpression of p53. These data suggest that HTRA2 may be a candidate for the serine protease responsible for CIAP1 cleavage during p53-mediated apoptosis.

S. Jin, M. Kalkum, M. Overholtzer, A. Stoffel, B. T. Chiat, A. J. Levine, CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals. Genes Dev. 17, 359-367 (2003). [Abstract] [Full Text]

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