BAD and Bcl-2 regulation are early events linking neuronal endoplasmic reticulum stress to mitochondria-mediated apoptosis

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

“…This led us to the identification of 22 genes (Figure 1c), out of which 7 were validated by kinetic cell death analysis measuring nuclear SytoxGreen fluorescence in death cells (Fluostar Omega fluorescence plate reader, BMG Labtech, Ortenberg, Germany), as previously described 19 (Figures 1d-j and Supplementary Figure 1). Of note, two of these seven genes, Pmaip1 (Noxa) and Bad, are reported mediators of ER stress-induced death, 20,21 confirming the validity of our screen.…”

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

“…In addition, BAX/BAK doubleknockout (DKO) cells are resistant to ER stress-induced apoptosis, a phenotype that is only partially reversed by reintroduction of mitochondria-targeted BAX/BAK . As well, a number of BH3-only proteins, including BAD (Elyaman et al, 2002), PUMA (Luo et al, 2005), NOXA , BID (Gao et al, 2005;Upton et al, 2008) and BIM Puthalakath et al, 2007;Szegezdi et al, 2008) have been linked to ER stress-initiated cell death.…”

“…This interaction is dependent on BAD phosphorylation at specific residues, and BAD dephosphorylation is associated with dissociation from 14-3-3 and BAX/BAKdependent apoptosis (Youle and Strasser, 2008). However, although dephosphorylation of BAD has been observed in response to several ER stress stimuli, a functional role for this protein in ER stress-mediated apoptosis has not been demonstrated (Elyaman et al, 2002;Szegezdi et al, 2008). Of potential interest, given the role of PP2A in ER stress-induced apoptosis, is the observation that survival factor withdrawal-initiated apoptosis involves PP2A-mediated BAD dephosphorylation (Chiang et al, 2001(Chiang et al, , 2003.…”

“…For example, ERrestricted BCL-2 and BCL-xL can inhibit apoptosis initiated by diverse stimuli (Hacki et al, 2000;Germain et al, 2005;Mathai et al, 2005;Bhatt et al, 2008) and BAX/BAK (Nutt et al, 2002b;Zong et al, 2003;Chami et al, 2004), as well as a number of BH3-only proteins (Elyaman et al, 2002;Gao et al, 2005;Luo et al, 2005;Armstrong et al, 2007;Hetz et al, 2007;Puthalakath et al, 2007;Szegezdi et al, 2008;Upton et al, 2008) can promote apoptosis through their activity at the ER. BCL-2 family proteins at the ER regulate apoptosis through both direct modulation of signaling pathways leading to caspase activation and through the modulation of ER Ca 2 þ signaling (Oakes et al, 2006;Rong and Distelhorst, 2008).…”

Adaptation to ER Stress as a Mechanism of Resistance of Melanoma to Treatment

“…BIK has been shown to regulate Bax-and Bak-dependent release of calcium from the ER and mitochondrion-mediated apoptosis in cells under ER stress (Fu, et al, 2007;Mathai, et al, 2005). Another BH3-only protein that has been reported to be activated by ER stress is Bad, which is under physiological conditions phosphorylated and sequestered in the cytoplasm by the protein 14-3-3, but was dephosphorylated in response to several ER stress stimuli (Elyaman, et al, 2002;Szegezdi, et al, 2008). Besides up-regulation/activation of pro-apoptotic Bcl-2 family proteins, down-regulation of anti-apoptotic Bcl-2 family members by ER stress also contribute to ER stress-induced apoptosis.…”