Chronic stress and induction of apoptosis via the UPR The integrated responses of all three branches of the UPR contribute to an adaptation to ER stress or to the induction of cell death (Xxxxx et al., 2013). It is still unclear at what point the switch between pro-survival and pro-apoptotic signalling occurs and how each branch contributes to the induction of apoptosis (Xxxxx et al., 2011; Xxxxx et al., 2013). IRE1 and ATF6 activity is attenuated under persistent ER stress, contrary to PERK activity which is consistent under persistent ER stress (Xxx et al., 2007). Sustained ATF4 signalling via PERK induces the transcription of pro-apoptotic genes. However PERK signalling also inhibits protein translation in general depleting the cell of proteins. The combination of sustained pro-apoptotic signalling and protein depletion can be deleterious for the cell (Xxxxx et al., 2006). Contrary to that, sustained signalling via the IRE1 pathway enhances cell proliferation (Xxx et al., 2009). A differential activation of the IRE1 and PERK pathways might determine the fate of the cell following ER stress (Xxxxx et al., 2013). Chronic ER stress leads to apoptosis mediated by cross-talk between ER and mitochondria (Xxxxxxxxx et al., 2002; Xxxxxxxx, 2008). This cross-talk is facilitated by members of the Bcl2 protein family (Xxxxx et al., 2000). This protein family contains both pro- and anti-apoptotic members and the balance between the two is essential in the regulation of the transition from a protective to an apoptotic UPR response (Xxxxxxxx et al., 2009; Xxxxx et al., 2010; Xxxxx et al., 2011). Overexpression of anti-apoptotic member Bcl2 protects cells from ER stress induced cell death (Xxxxx et al., 2010). p53 upregulated modulator of apoptosis (PUMA) and Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) are downstream targets of the pro-apoptotic Bcl2 protein family members BAX and XXX and both are strongly induced under chronic ER stress conditions (Xxxxxxxx et al., 2003; Xx et al., 2006). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is another protein strongly induced by all three branches of the UPR under chronic ER stress conditions (Xxxxxxxx et al., 1998) and this induction can lead to apoptosis (Xxxxx et al., 2011). The pro-apoptotic effects of CHOP are linked to a down-regulation of anti-apoptotic Bcl2 and an increased expression of pro- apoptotic factor Bcl2-like protein 11 (BIM) (XxXxxxxxxx et al., 2001; Xxxxx et al., 2011).
