Open AccessNerve growth factor blocks thapsigargin‐induced apoptosis at the level of the mitochondrion via regulation of Bim
Author(s) -
Szegezdi E.,
Reed Herbert K.,
Kavanagh E. T.,
Samali A.,
Gorman A. M.
Publication year - 2008
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00268.x
Subject(s) - mitochondrion , nerve growth factor , apoptosis , thapsigargin , microbiology and biotechnology , growth factor , biology , chemistry , endoplasmic reticulum , biochemistry , receptor
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 Ca 2+ ‐ATPase pump (SERCA) and depletes ER Ca 2+ 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.