Characterization of apoptosis-genes associated with NMDA mediated cell death in the adult rat retina

Laabich, Aïcha; Li, Guangyu; Cooper, Nigel G. F.

doi:10.1016/s0169-328x(01)00116-4

Cited by 45 publications

(24 citation statements)

References 58 publications

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“…The p53-GADD45a signalling pathway has been implicated in the excitotoxicity of neuronal cells mediated by the activation of ionotropic glutamate receptors present on the surface of many types of neurons (Zhu et al, 1997;Culmsee et al, 2001;Laabich et al, 2001). It is not known, however, whether this signalling pathway is also involved in the development of glutamate receptorindependent oxidative toxicity in neuronal cells, which is the focus of our present study.…”

Section: Discussionmentioning

confidence: 93%

Critical role of the JNK‐p53‐GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons

Choi

Kang

Fukui

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEGlutamate-induced oxidative stress plays a critical role in the induction of neuronal cell death in a number of disease states. We sought to determine the role of the c-Jun NH2-terminal kinase (JNK)-p53-growth arrest and DNA damage-inducible gene (GADD) 45a apoptotic cascade in mediating glutamate-induced oxidative cytotoxicity in hippocampal neuronal cells. EXPERIMENTAL APPROACHHT22 cells, a mouse hippocampal neuronal cell line, were treated with glutamate to induce oxidative stress in vitro. Kainic acid-induced oxidative damage to the hippocampus in rats was used as an in vivo model. The signalling molecules along the JNK-p53-GADD45a cascade were probed with various means to determine their contributions to oxidative neurotoxicity. KEY RESULTSTreatment of HT22 cells with glutamate increased the mRNA and protein levels of GADD45a, and these increases were suppressed by p53 knock-down. Knock-down of either p53 or GADD45a also prevented glutamate-induced cell death. Glutamate-induced p53 activation was preceded by accumulation of reactive oxygen species, and co-treatment with N-acetyl-cysteine prevented glutamate-induced p53 activation and GADD45a expression. Knock-down of MKK4 or JNK, or the presence of SP600125 (a JNK inhibitor), each inhibited glutamate-induced p53 activation and GADD45a expression. In addition, we also confirmed the involvement of GADD45a in mediating kainic acid-induced hippocampal oxidative neurotoxicity in vivo. CONCLUSIONS AND IMPLICATIONSActivation of the JNK-p53-GADD45a cascade played a critical role in mediating oxidative cytotoxicity in hippocampal neurons. Pharmacological inhibition of this signalling cascade may provide an effective strategy for neuroprotection.

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Section: Discussionmentioning

confidence: 93%

Critical role of the JNK‐p53‐GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons

Choi

Kang

Fukui

et al. 2010

British J Pharmacology

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“…This notion is supported by recent reports that excitotoxicity associated with NMDA receptor induces GADD153/CHOP production, and activation and phosphorylation of CaMKII-a, leading to neuronal death. [54][55][56] In conclusion, we show here that activation of ER stress signaling pathways constitutes a sequential and inter-related cytotoxic signaling cascade that causes neuronal injury in the ts1-infected brainstem. The potential importance of the Ca 2 þ -ER stress link in the pathogenesis of spongiform encephalopathy by ts1 infection, particularly neuronal degeneration, is now evident.…”

Section: Discussionmentioning

confidence: 96%

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Kim

Waters

Stoica

et al. 2004

Laboratory Investigation

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Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-a. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-a was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca 2 þ ) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca 2 þ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.

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“…Activated CaMKII then enables apoptosis through at least 3 pathways, all of which are necessary for cell death: (a) activation of JNK, which induces Fas; (b) stimulation of calcium uptake by the mitochondria, leading to outer mitochondrial membrane permeabilization and release of apoptogens as well as Δψ m ; and (c) activation of STAT1, which has previously been shown to promote apoptosis in diverse cell types by a number of transcriptional and perhaps nontranscriptional mechanisms (54). Although studies in other cells have shown that proapoptotic mitochondrial dysfunction can be triggered by the mitochondrial uptake of ER-released calcium in the setting of ER stress (41) and that CaMKII can play roles in apoptosis (55)(56)(57)(58)(59), the current study is the first to our knowledge to link these pathways into an integrated model of apoptosis and to show that CaMKII is essential for mitochondrial calcium uptake. Another important point relates to our finding that neither induction of Fas (data not shown) nor mitochondrial depolarization was dependent on STAT1.…”

Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

Timmins¹,

Özcan²,

Seimon³

et al. 2009

J. Clin. Invest.

386

331

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ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/ calmodulin-dependent protein kinase IIγ (CaMKIIγ) and JNK. Remarkably, CaMKIIγ was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIγ-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.

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Characterization of apoptosis-genes associated with NMDA mediated cell death in the adult rat retina

Cited by 45 publications

References 58 publications

Critical role of the JNK‐p53‐GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons

Critical role of the JNK‐p53‐GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

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