Induction of Bip mRNA upon programmed cell death of differentiated PC12 cells as well as rat sympathetic neurons.

We have found that expression of the Bip (immunoglobulin heavy chain binding protein)/GRP78 (glucose regulated protein 78) gene is markedly enhanced specifically among the heat shock protein (HSP) 70 gene family during the neuronal cell death of PC12 (22a) cells, that is induced by removal of nerve growth factor (NGF) and blocked by a transcription inhibitor, actinomycin D. The Bip mRNA induction is suppressed when the NGF-deprivation-dependent cell death of PC12 (22a) cells is inhibited by cAMP, cycloheximide or high K+. The Ca2+ ionophore, A23187, caused neuronal cell death accompanied by up-regulation of Bip, HSP90, and HSP70 mRNAs. In addition, a chelator of intracellular Ca2+ (BAPTA) elevated Bip mRNA and induced cell death in a low Ca2+ medium. Alterations of intracellular calcium homeostasis thus appear to induce Bip mRNA expression as well as apoptosis in PC12 (22a) cells. However, release of Ca2+ from intracellular stores by thapsigargin induced Bip mRNA expression but not cell death, indicating that Bip mRNA induction is not sufficient for neuronal death. Induction of Bip mRNA in association with apoptosis was also observed for NGF-deprived sympathetic ganglion cells in primary culture. These lines of evidence suggest that selective induction of Bip mRNA may play an important role in the programmed cell death of neurons deprived of neurotrophic factors and could be a landmark of the neuronal programmed cell death.