Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

dependent on their oligomerization and stable insertion into the outer membrane (Chipuk and
Green, 2008).
The most favoured model for BAX and BAK activation suggests that they require both direct
activation by BH3-only proteins and repression of anti-apoptotic Bcl-2 proteins by additional
BH3-only members (Kuwana et al., 2005). Recently, Green and colleagues have proposed
what they call the innocent bystander scenario where they suggest that control of the intrinsic
pathway of apoptosis rests solely with Bcl-2 family mediated MOMP and lacks any input in
terms of signalling mechanisms from within the mitochondria themselves (Chipuk et al.,
2006). Importantly, Bcl-2 proteins are controlled both transcriptionally and post-
translationally, allowing multiple levels of regulation of the apoptotic process. The BH3-only
proteins NOXA and PUMA are trascriptionally regulated by p53, BIM is induced by
FOXO3A and STAT3 upregulates Bcl- and BIM (Oda et al., 2000, Nakano et al., 2001,
Catlett-Falcone et al., 1999, Epling-Burnette et al., 2001). Examples of post-translational
control include BAD and BIM; BAD is normally sequestered in the cytosol by 14-3-3 and
dephosphorylation of BAD following growth factor withdrawal allows it to interact with Bcl-
(Zhou et al., 2000) , BIM can be phosphorylated by ERK which targets it for ubiquitin
mediated proteasomal degradation (Ley et al., 2003).
1.2.4 Inhibitors of Apoptosis (IAPs)
The intrinsic pathway of apoptosis is antagonised by the inhibitor of apoptosis (IAP) family
of proteins including X-linked IAP (XIAP), IAP1 and IAP2 which block cytochrome c
induced apoptosis by inhibiting caspase activity. XIAP is a major constituent of native
apoptosomes where it binds to and inhibits caspase-3, caspase-7 and caspase-9 (Deveraux et
al., 1997, Hill et al., 2004). XIAP is an E3 ubiquitin ligase and cells from mice deficient in
XIAP or harbouring a XIAP protein without the ring finger domain have be shown to have
elevated caspase-3 activity, demonstrating that this ubiquitin ligase activity is essential for
inhibition of caspases (Schile et al., 2008). Following treatment with or TNF- , XIAPdeficient
MEFs show elevated levels of ROS due to reduced expression of anti-oxidant genes
such as superoxide dismutase 1 (SOD1), SOD2, haem oxygenase 1 (HO-1) and glutathione
peroxidise (Gpx-1) (Resch et al., 2008). This was associated with prolonged activation of
JNK and increased susceptibility to apoptosis, suggesting that XIAP may have functions in
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