Response of neurons to an irreversible inhibition of endoplasmic reticulum Ca2+-ATPase: relationship between global protein synthesis and expression and translation of individual genes

MENGESDORF, Torsten; Althausen, Sonja; Oberndorfer, Iris; Paschen, Wulf

doi:10.1042/0264-6021:3560805

Cited by 48 publications

(38 citation statements)

References 45 publications

(22 reference statements)

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“…Recently, we confirmed that our primary neuronal cell cultures react to ER stress with an activation of the unfolded protein response (UPR), a severe suppression of the initiation step of protein synthesis and a 100-to 200-fold increase in mRNA levels of genes coding for ER stress proteins, including grp78, grp94, and gadd153 (28). In contrast, the expression of genes such as hsp70, which do not react specifically to ER stress, were only slightly activated (28). We found their degree of activation to be similar to that of parkin.…”

Section: Resultsmentioning

confidence: 64%

“…Besides the moderate increase in neuronal parkin mRNA levels observed in cultures exposed to ER stress, activation of the translation of parkin may be hindered and the extent of this effect is related to the level of suppression of global protein synthesis under our experimental conditions (28). Evidence is indeed accumulating to suggest that the normal stress response of cells is suppressed in neurons.…”

Section: Resultsmentioning

confidence: 99%

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Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no upregulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.

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Section: Resultsmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…GRP78 was present in nontreated control cells and increased in response to treatment with thapsigargin (an inhibitor of sarco ER Ca 2 þ ATPase and a representative inducer of the ER stress response), as previously described. 19 Indomethacin slightly but significantly increased the amount of GRP78 (Figure 2). We also examined the effect of indomethacin on the expression of another ER stress response-related protein, CHOP, a transcription factor, which induces apoptosis.…”

Section: Induction Of Grp78 and Chop By Indomethacin Associated With mentioning

confidence: 94%

“…CHOP was not present in nontreated cells, but was induced by thapsigargin, this being consistent with previously reported results. 19 Indomethacin clearly induced CHOP, and to a greater extent than thapsigargin ( Figure 2). …”

Section: Induction Of Grp78 and Chop By Indomethacin Associated With mentioning

confidence: 94%

Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis

et al. 2004

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Apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved not only in the production of NSAIDinduced gastric lesions but also in the antitumor activity of these drugs. The endoplasmic reticulum (ER) stress response is a cellular mechanism that aids in protecting the ER against ER stressors and is involved in ER stressor-induced apoptosis. Here, we examine the relationship between this response and NSAID-induced apoptosis in cultured guineapig gastric mucosal cells. Exposure of cells to indomethacin, a commonly used NSAID, induced GRP78 as well as CHOP, a transcription factor involved in apoptosis. Three factors that positively regulate CHOP expression (ATF6, ATF4 and XBP-1) were activated and/or induced by indomethacin. NSAIDs other than indomethacin (diclofenac, ibuprofen and celecoxib) also induced CHOP. Monitoring of the transcriptional activities of ATF6 and CHOP by luciferase assay revealed that both were stimulated in the presence of indomethacin. Furthermore, indomethacin-induced apoptosis was suppressed in cultured guinea-pig gastric mucosal cells by expression of the dominant-negative form of CHOP, or in peritoneal macrophages from CHOP-deficient mice. These results suggest that ER stress response-related proteins, particularly CHOP, are involved in NSAID-induced apoptosis.

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“…Likewise, persistent blockade of protein synthesis is associated with brain damage (10), and neuronal survival after focal ischemia may depend on the recovery of protein synthesis (11). Intracellular Ca 2ϩ overload by activation of glutamate receptors (12) or disturbances of endoplasmic reticulum Ca 2ϩ homeostasis decrease protein synthesis (13)(14)(15)(16). Protein synthesis is mainly regulated at the initiation step.…”

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confidence: 99%

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

Petegnief

Friguls

Sanfeliu

et al. 2003

Journal of Biological Chemistry

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Transforming growth factor-␣ (TGF-␣), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-␣ can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-␣ attenuated neuronal cell death induced by a 30-min exposure to 35 M N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca 2؉ elicited by NMDA. TGF-␣ induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-␣ was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [ 3 H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-␣ attenuated this effect. TGF-␣ stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2␣, two proteins involved in translation regulation. PD 98059 abrogated the TGF-␣ effect on eIF4E. Our data demonstrate that TGF-␣ exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.TGF-␣ 1 is protective in models of permanent and transient focal ischemia induced by occlusion of the middle cerebral artery in the rat (1, 2). Although TGF-␣ is known to promote neuronal survival (3) and to induce proliferation and differentiation of astrocytes in vitro (4), little is known about its effects on neural cells. TGF-␣ binds to the epidermal growth factor receptor (EGFR), which stimulation induces its dimerization, autophosphorylation on tyrosine residues, and triggers a cascade of reactions that requires the contribution of adapter proteins and kinases. EGFR activates several signal transduction pathways, among others are phosphatidylinositol 3-kinase/protein kinase B (PI 3-kinase/Akt) and the p44/p42 mitogen-activated protein kinase, also referred to as extracellular signal-regulated kinases 1/2 (Erk1/2) (5).Among the very early consequences of energy depletion after an ischemic insult to the brain are membrane depolarization that induces excitatory amino acid release and inhibition of global protein synthesis, and both significantly contribute to the development of brain infarct (6 -8). Indeed, glutamate receptor overactivation results in an increase in intracellular calcium and extensive neuronal death by excitotoxicity (9). Likewise, persistent block...

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Response of neurons to an irreversible inhibition of endoplasmic reticulum Ca2+-ATPase: relationship between global protein synthesis and expression and translation of individual genes

Cited by 48 publications

References 45 publications

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

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