Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrionviaregulation of bim
Szegezdi, E. Reed Herbert, K. Kavanagh, E. T. Samali, A. Gorman, A. M.
Szegezdi, E.
Reed Herbert, K.
Kavanagh, E. T.
Samali, A.
Gorman, A. M.
Publication Date
2008-02-06
Keywords
bim(el), endoplasmic reticulum (er), mitochondria, nerve growth factor (ngf), thapsigargin (tg), endoplasmic-reticulum-stress, induced cell-death, unfolded protein response, pc12 cells, er stress, phosphatidylinositol 3-kinase, cytochrome-c, transcription factor, sympathetic neurons, tyrosine phosphorylation
Type
Article
Downloads
Citation
Szegezdi, E. Reed Herbert, K.; Kavanagh, E. T.; Samali, A.; Gorman, A. M. (2008). Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrionviaregulation of bim. Journal of Cellular and Molecular Medicine 12 (6), 2482-2496
Abstract
This study examined how the neurotrophin, nerve growth factor (NGF), protects PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. ER stress was induced using thapsigargin (TG) that inhibits the sarcoplasmic/ER Ca2+-ATPase pump (SERCA) and depletes ER Ca2+ stores. NGF pre-treatment inhibited translocation of Bax to the mitochondria, loss of mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-3, -7 and -9) and apoptosis induction by TG. Notably, TG also caused a marked induction of Bim(el) mRNA and protein, and knockdown of Bim with siRNA protected cells against TG-induced apoptosis. NGF delayed the induction and increased the phosphorylation of Bim(el). NGF-mediated protection was dependent on phosphatidylinositol-3 kinase (PI3K) signalling since all above apoptotic events, including expression and phosphorylation status of Bim(el) protein, could be reverted by the PI3K inhibitor LY294002. In contrast, NGF had no effect on the TG-mediated induction of the unfolded protein response (increased expression of Grp78, GADD34, splicing of XBP1 mRNA) or ER stress-associated pro-apoptotic responses (induction of C/EBP homologous protein [CHOP], induction and processing of caspase-12). These data indicate that NGF-mediated protection against ER stress-induced apoptosis occurs at the level of the mitochondria by regulating induction and activation of Bim and mitochondrial translocation of Bax.
Funder
Publisher
Wiley-Blackwell
Publisher DOI
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland