Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction

Paschen, Wulf; Gissel, Cornelia; Lindén, Thomas; Althausen, Sonja; Doutheil, Jens

doi:10.1016/s0169-328x(98)00180-6

Cited by 111 publications

(56 citation statements)

References 47 publications

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“…Membranes were hybridized overnight at 68°C in hybridization buffer containing [ 32 P]DNA probes (1 ϫ 10 8 cpm) for HO-1, GADD153, glyceraldehyde-3-phosphate dehydrogenase, or 18 S RNA. DNA probes were generated by RT-PCR (8,28,29) and labeled with [␣-32 P]dCTP using a random priming kit (Amersham Biosciences). After hybridization, membranes were washed and then exposed to x-ray film at Ϫ70°C in the presence of intensifying screens.…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

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Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time-and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.

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Section: Methodsmentioning

confidence: 99%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

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“…The mRNA coding for ATF4 (activating transcription factor 4) is translated by this mechanism (Harding et al, 2000), and the ATF4 transcription factor is known to contribute to chop mRNA transcription (Ma et al, 2002). An upregulation of the chop mRNA is a characteristic feature of ER stress and UPR activation, and was observed in the striatum and hippocampus after transient bilateral occlusion of common carotid arteries (Tajiri et al, 2004), as well as in other models of ischemia and reperfusion (Paschen et al, 1998(Paschen et al, , 2003Roberts et al, 2007;Nakka et al, 2010;Osada et al, 2010). Hippocampal neurons from CHOP À/À mice exhibited a significantly lower rate of cell death, when compared with wildtype animals, indicating that transient ischemia-induced cell death is mediated by CHOP induction (Tajiri et al, 2004).…”

Section: Endoplasmic Reticulum (Er) Stress In Brain Ischemiamentioning

confidence: 97%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…Induction of CHOP mRNA was observed in the rat hippocampus subjected to global cerebral ischemia. 92,93 NO has been implicated in the pathophysiology of brain ischemia. NO causes the depletion of ER Ca 2 þ and induces CHOP mRNA in primary neuronal cultures as well as in pancreatic bcells.…”

Section: Brain Ischemiamentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction

Cited by 111 publications

References 47 publications

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Roles of CHOP/GADD153 in endoplasmic reticulum stress

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