The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines

Nikulina, Marina; Sandhu, Nitika; Shamim, Zeeshan; Andersen, Niels A.; Oberson, Anne; Dupraz, Philippe; Thorens, Bernard; Karlsen, Allan E.; Bonny, Christophe; Mandrup-Poulsen, Thomas

doi:10.1016/s1043-4666(03)00242-4

Cited by 30 publications

(26 citation statements)

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“…As seen in Fig. 2, inhibition of JNK activity by cell-permeable Tat-JBD fusion protein [8] or by overexpression of JBD [6] did not prevent IL-1β-induced degradation of IκBα (Fig. 2a) or NFκB nuclear translocation and DNA binding (Fig.…”

Section: Il-1β-induced Degradation Of Iκbα Occurs Independently Of Jnmentioning

confidence: 77%

“…The concentrations chosen were based on information previously obtained in rat islets showing complete inhibition of ERK and p38, respectively, without affecting the functionality of the islets [1]. Tat-JBD and the corresponding control, Tat, have been thoroughly characterised previously [6,8].…”

Section: Reagentsmentioning

confidence: 99%

“…Introduction IL-1β is cytotoxic to rodent beta cells, causing inhibition of glucose-stimulated insulin secretion [1][2][3] and expression of the gene (Nos2) encoding inducible nitric oxide synthase (iNOS), which leads to nitric oxide (NO) formation [1,4] and cell death by necrosis and apoptosis [5][6][7][8][9]. In human islets a combination of the proinflammatory cytokines IL-1β and IFNγ or TNFα is required to induce beta cell death, which occurs mainly by apoptosis [7].…”

mentioning

confidence: 99%

“…We have previously demonstrated that ERK and p38 are necessary, albeit not sufficient, to cause NO formation [1], and inhibition of ERK or p38 reduces cytokine-induced beta cell death [12,14]. The JNK-dependency of IL-1β-induced beta cell death has been substantiated, as overexpression of the natural cellular inhibitor and scaffold protein of JNK, islet-brain 1 (IB1), or of the JNK-binding domain (JBD) of IB1 prevents IL-1β-induced beta cell apoptosis [5,6,8,15].…”

mentioning

confidence: 99%

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Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells

et al. 2005

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Aims/hypothesis: The beta cell destruction and insulin deficiency that characterises type 1 diabetes mellitus is partially mediated by cytokines, such as IL-1β, and by nitric oxide (NO)-dependent and -independent effector mechanisms. IL-1β activates mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK), and the nuclear factor kappa B (NFκB) pathway. Both pathways are required for expression of the gene encoding inducible nitric oxide synthase (iNOS) and for IL-1β-mediated beta cell death. The molecular mechanisms by which these two pathways regulate beta cell Nos2 expression are currently unknown. Therefore, the aim of this study was to clarify the putative crosstalk between MAPK and NFκB activation in beta cells. Materials and methods: The MAPKs ERK, p38 and JNK were inhibited by SB203580, PD98059 or Tat-JNK binding domain or by cells overexpressing the JNK binding domain. The effects of MAPK inhibition on IL-1β-induced iNOS production and kappa B inhibitor protein (IκB) degradation were examined by western blotting. NFκB DNA binding was investigated by electrophoretic mobility shift assay, while NFκB-induced gene transcription was evaluated by gene reporter assays. Results: Inhibition of the MAPKs did not affect IκB degradation or NFκB DNA binding. However, inhibition of ERK reduced NFκB-mediated Nos2 expression; serine 276 phosphorylation of the p65 unit of the NFκB complex seemed critical, as evaluated by amino acid mutation analysis. Conclusions/interpretation: ERK activity is required for NFκB-mediated transcription of Nos2 in insulin-producing INS-1E cells, indicating that ERK regulates Nos2 expression by increasing the transactivating capacity of NFκB. This may involve phosphorylation of Ser276 on p65 by an as yet unidentified kinase.

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Section: Il-1β-induced Degradation Of Iκbα Occurs Independently Of Jnmentioning

confidence: 77%

Section: Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells

et al. 2005

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“…5a,b) may be mediated via ERK, as ERK inhibition decreased IL-1β-induced rat islet iNOS and NO production [6], whereas IL-1β-induced iNOS expression was independent of JNK inhibition [35]. The augmentation Fig.…”

Section: Discussionmentioning

confidence: 97%

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

et al. 2006

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Aims/hypothesis: IL-1β is a candidate mediator of apoptotic beta cell destruction, a process that leads to type 1 diabetes and progression of type 2 diabetes. IL-1β activates beta cell c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38, all of which are members of the mitogen-activated protein kinase (MAPK) family. Inhibition of JNK prevents IL-1β-mediated beta cell destruction. In mouse embryo fibroblasts and 3DO T cells, overexpression of the gene encoding growth arrest and DNA-damage-inducible 45β (Gadd45b) downregulates pro-apoptotic JNK signalling. The aim of this study was to investigate if Gadd45b prevents IL-1β-induced beta cell MAPK signalling and apoptosis. Materials: Rat insulinoma INS-1E cells and mouse beta-TC3 cells stably expressing Gadd45b were generated. The effects of Gadd45b expression on signalling by JNK, ERK and p38 were assessed by Western blotting and kinase assays. Apoptosis rate was measured by terminal deoxynucleotidyl-mediated dUTP-biotin nick end-labelling (TUNEL) and an ELISA designed to detect apoptotic nucleosomes. Expression of endogenous Gadd45b mRNA was measured by RT-PCR. Results: In INS-1E and beta-TC3 cells, expression ofGadd45b inhibited IL-1β-induced activation of JNK and ERK, but augmented IL-1β-mediated p38 activity. IL-1β-induced nitric oxide production and decreases in insulin content and secretion were reduced by GADD45β. IL-1β-induced apoptosis was reduced by GADD45β by up to 77%. Although IL-1β stimulated the time-dependent induction of endogenous Gadd45b in INS-1E cells and rat islets, expression levels were lower in these cells than in IL-1β-exposed NIH-3T3 and 3DO T cells.

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Cytoprotection of beta cells: rational gene transfer strategies

McCabe

Samali

O’Brien

2006

Diabetes Metabolism Res

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Gene transfer to pancreatic islets may prove useful in preventing islet cell destruction and prolonging islet graft survival after transplantation in patients with type 1 diabetes mellitus (T1DM). Potentially, a host of therapeutically relevant transgenes may be incorporated into an appropriate gene delivery vehicle and used for islet modification. An increasing understanding of the molecular pathogenesis of immune-mediated beta cell death has served to highlight molecules which have become suitable candidates for promoting islet cell survival in the face of oxidative stress. This review aims to give an overview of some conventional gene transfer strategies aimed at promoting islet cell survival in the face of cytokine onslaught. These strategies target three aspects of islet cell physiology: redox status and antioxidant defence, anti-apoptotic gene expression and mediators of cytokine signal transduction pathways.

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The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines

Cited by 30 publications

References 51 publications

Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells

Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

Cytoprotection of beta cells: rational gene transfer strategies

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