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

Abstract

Recently aDrosophilap53 protein has been identified that mediates apoptosis via a novel pathway involving the activation of theReapergene and subsequent inhibition of the inhibitors of apoptosis (IAPs). The present study found that CIAP1, a major mammalian homolog ofDrosophilaIAPs, 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 theHTRA2gene, 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 inDrosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.