chapter  110
Genetics of Apoptosis
Pages 5

Fas pathway. Interestingly, caspase-cleaved BAP31 (p20BAP31) autonomously induces apoptosis by a mitochondria-dependent pathway (Breckenridge and Shore, unpublished), suggesting that caspase cleavage of BAP31 converts it from an inhibitor to an activator of mitochondrial dysfunction. This phenomenon has been observed with other antiapoptotic proteins such as Bcl-2 and Bcl-xL (Cheng et al, 1997; Clem etai., 1998). 4.2 ВІК

Our group has recently discovered that the ВНЗ-only protein, ВІК, is transcrip­ tionally upregulated by p53 (Mathai et al., 2002). In healthy cells, ВІК is undectable, but after oncogenic or genotoxic stress, ВІК accumulates almost exclu­ sively at the ER membrane. Adenoviral delivery of ВІК potently triggers Cyt.c release and apoptosis independendy of p53, but, unlike other ВНЗ-only molecules, ВІК carries out this function from the ER. Our recent studies suggest that ВІК may activate mitochondrial release of Cyt.c and other death pathways by activating fac­ tors in both ER and cytosol (Germain et al., submitted). Thus, a post-mitochondrial supernatant (primarily containing cytosol and ER microsomes), but not an S-100 fraction, isolated from cells expressing ВІК in the presence of caspase inhibitors, can release Cyt.c from mitochondria isolated from cells lacking ВІК expression. In vivo, ВІК induces Cyt.c release independently of caspases. The ER and cytosolic factors contributing to BIK-induced Cyt.c release are currently under investigation. Given the current model on the mechanism of action of ВНЗ-only molecules at the mitochondria, it is surprising to find that ВІК functions at the ER. As discussed above, this could reflect functions of BAX/BAK at the ER, or provide a mechanism to neutralize ER Bcl-2/Bcl-xL, or represent hitherto unknown actions of certain ВНЗ-only molecules at the ER required for communicating to the mito­ chondria. In this context, it is noteworthy that p53 upregulates numerous BH3only proteins after genotoxic stress (Vogelstein et al., 2000); therefore, the actions of ВІК on the ER, and of PUMA or NOXA at the mitochondria may be required in concert to trigger efficient Cyt.c release and caspase activation.