Hemoglobin Neurotoxicity is Attenuated by Inhibitors of the Protein Kinase CK2 Independent of Heme Oxygenase Activity

Chen-Roetling, Jing; Li, Zhi; Regan, Raymond F.

doi:10.2174/156720208785425684

Cited by 7 publications

(8 citation statements)

References 59 publications

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“…Thus, the regulation of CK2 activity may represent a possible target for therapeutic intervention. Indeed, CK2 inhibition has been shown to exert a protective effect on neurons (44,47,48). In contrast, a recent report has shown that CK2 phosphorylates p62 and stimulates the clearance of protein aggregates via the autophagy-lysosome pathway (49).…”

Section: Discussionmentioning

confidence: 99%

The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression

Tsuchiya

Taniguchi

Ito

et al. 2013

Molecular and Cellular Biology

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c Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.

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Section: Discussionmentioning

confidence: 99%

The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression

Tsuchiya

Taniguchi

Ito

et al. 2013

Molecular and Cellular Biology

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“…The cultures were used on 10th day when the cultures were essentially free of astrocytes [26]. The neurons were treated with Hb at a concentration of 10 μ M which was determined from prior studies [27, 28]. After 1, 3, 6, 12, 24 and 48 hours, the neurons were collected for the electrophoretic mobility shift assay (EMSA), real-time polymerase chain reaction (PCR) and lactate dehydrogenase (LDH) detection.…”

Section: Methodsmentioning

confidence: 99%

Biphasic Activation of Nuclear Factor-Kappa B in Experimental Models of Subarachnoid HemorrhageIn VivoandIn Vitro

You

Wei

Zhuang

et al. 2012

Mediators of Inflammation

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It has been proven that nuclear factor-kappa B (NF-κB) is activated as a well-known transcription factor after subarachnoid hemorrhage (SAH). However, the panoramic view of NF-κB activity after SAH remained obscure. Cultured neurons were signed into control group and six hemoglobin- (Hb-) incubated groups. One-hemorrhage rabbit SAH model was produced, and the rabbits were divided randomly into one control group and five SAH groups. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA) and immunohistochemistry. Real-time polymerase chain reaction (PCR) was performed to assess the downstream genes of NF-κB. NeuN immunofluorescence and lactate dehydrogenase (LDH) quantification were used to estimate the neuron injury. Double drastically elevated NF-κB activity peaks were detected in rabbit brains and cultured neurons. The downstream gene expressions showed an accordant phase peaks. NeuN-positive cells decreased significantly in day 3 and day 10 groups. LDH leakage exhibited a significant increase in Hb-incubated groups, but no significant difference was found between the Hb incubated groups. These results suggested that biphasic increasing of NF-κB activity was induced after SAH, and the early NF-κB activity peak indicated the injury role on neurons; however, the late peak might not be involved in the deteriorated effect on neurons.

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“…Both HO-1 and HO-2 are phosphoproteins, and in vitro are activated by the phosphatidylinositol-3-kinase and protein kinase C/CK2 pathways, respectively (Boehning, et al, 2003, Salinas, et al, 2004). However, we have recently observed that selective inhibitors of these pathways had no effect on HO activity in murine cortical cell cultures (Chen-Roetling, et al, 2008). In the course of these kinase inhibitor experiments, we noted that the MEK 1/2 inhibitor U0126 surprisingly reduced baseline culture HO activity.…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway

Chen-Roetling

Chen

et al. 2009

Neuropharmacology

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Summary Hemoglobin breakdown produces an iron-dependent neuronal injury after experimental CNS hemorrhage that may be attenuated by heme oxygenase (HO) inhibitors. The HO enzymes are phosphoproteins that are activated by phosphorylation in vitro. While testing the effect of kinase inhibitors in cortical cell cultures, we observed that HO activity was consistently decreased by the MEK inhibitor U0126. The present study tested the hypothesis that MEK/ERK pathway inhibitors reduce HO activity and neuronal vulnerability to hemoglobin. The MEK inhibitors U0126 and SL327 and the ERK inhibitor FR180204 reduced baseline culture HO activity by 35–50%, without altering the activity of recombinant HO-1 or HO-2; negative control compounds U0124 and FR180289 had no effect. Hemoglobin exposure for 16 hours produced widespread neuronal injury, manifested by release of 59.2±7.8% of neuronal lactate dehydrogenase and a twelve-fold increase in malondialdehyde; kinase inhibitors were highly protective. HO-1 induction after hemoglobin treatment was also decreased by U0126, SL327, and FR180204. These results suggest that reduction in HO activity may contribute to the protective effect of MEK and ERK inhibitors against heme-mediated neuronal injury.

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Hemoglobin Neurotoxicity is Attenuated by Inhibitors of the Protein Kinase CK2 Independent of Heme Oxygenase Activity

Cited by 7 publications

References 59 publications

The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression

The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression

Biphasic Activation of Nuclear Factor-Kappa B in Experimental Models of Subarachnoid HemorrhageIn VivoandIn Vitro

Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway

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