A critical role for CK2 in cytokine-induced activation of NFκB in pancreatic β cell death

Jaksch, Caroline; Thams, Peter

doi:10.1007/s12020-013-0133-6

Cited by 11 publications

(10 citation statements)

References 40 publications

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“…By using the Human Protein Reference Database, we predicted that CKII may be the kinase to phosphorylate YBX1 on S165. CKII is an important kinase that has been linked to the activation of NF-κB by reactive oxidase species [ROS] [ 23 ] as well as to the NF-κB activation in pancreatic β cells and cancers such as glioblastoma [ 24 , 25 ]. In addition, CKII was reported to be involved in cell cycle control and DNA repair and has been shown to activate the Wnt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

et al. 2015

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Y-box binding protein 1 [YBX1] is a multifunctional protein known to facilitate many of the hallmarks of cancer. Elevated levels of YBX1 protein are highly correlated with cancer progression, making it an excellent marker in cancer. The connection between YBX1 and the important nuclear factor κB [NF-κB] has never been reported. Here, we show that overexpression of wild type YBX1 [WT-YBX1] activates NF-κB, suggesting that YBX1 is a potential NF-κB activator. Furthermore, using mass spectrometry analysis we identified novel phosphorylation of serine 165 [S165] on YBX1. Overexpression of the S165A-YBX1 mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB activating ability as compared with that of WT-YBX1, confirming that S165 phosphorylation is critical for the activation of NF-κB by YBX1. We also show that expression of the S165A-YBX1 mutant dramatically decreased the expression of NF-κB-inducible genes, reduced cell growth, and compromised tumorigenic ability as compared with WT-YBX1. Taken together, we provide the first evidence that YBX1 functions as a tumor promoter via NF-κB activation, and phosphorylation of S165 of YBX1 is critical for this function. Therefore, our important discovery may lead to blocking S165 phosphorylation as a potential therapeutic strategy to treat colon cancer.

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Section: Discussionmentioning

confidence: 99%

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

et al. 2015

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“…However, results vary greatly depending on the cell type and stress model. For example, activation of the proapoptotic pathway by CK2α has been observed in INS-1 cells and isolated islets 35 . Likewise, in our study, CK2α inhibition led to anantiapoptotic effects in renal tubular tissues, which exhibited less tubular injury and enhanced clearance of BUN and creatinine.…”

Section: Discussionmentioning

confidence: 99%

The protein kinase 2 inhibitor tetrabromobenzotriazole protects against renal ischemia reperfusion injury

Hwang

Jang

et al. 2015

Sci Rep

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Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor κB (NF-κB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2α during the reperfusion period, while expression of CK2β remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2α inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2α inhibition were observed for emodin. Renoprotective effects of CK2α inhibition were associated with suppression of NF-κB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2α mediates proapoptotic and proinflammatory signaling, thus the CK2α inhibitor may be used to prevent renal I/R injuries observed in clinical settings.

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“…After functional analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the proportion of viable cells in the treated group compared to the control group, as previously described ( 23 ). The islets were incubated with 500 µ g/ml MTT in RPMI-1640 medium for 3 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

Huang

Cao

2015

International Journal of Molecular Medicine

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The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin-(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

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A critical role for CK2 in cytokine-induced activation of NFκB in pancreatic β cell death

Cited by 11 publications

References 40 publications

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

The protein kinase 2 inhibitor tetrabromobenzotriazole protects against renal ischemia reperfusion injury

Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

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