Inactivation of the Poly(ADP-ribose) Polymerase Gene Affects Oxygen Radical and Nitric Oxide Toxicity in Islet Cells

Heller, Birgit; Wang, Zhaoqi; Wagner, Erwin F.; Radons, Jürgen; Bürkle, Alexander; Fehsel, Karin; Burkart, Volker; Kolb, Hubert

doi:10.1074/jbc.270.19.11176

Cited by 262 publications

(138 citation statements)

References 34 publications

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“…NO seems to be a major effector of both autoimmune and STZ-mediated pancreatic beta-cell destruction [9,10,21,22,23]. However, we reported here that Nos2-/-mice, which were previously shown to be resistant to MLDS-diabetes [24], were not protected from HDS-diabetes.…”

Section: Discussioncontrasting

confidence: 66%

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

et al. 2003

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Aims/hypothesis. Streptozotocin is a monofunctional alkylating agent that induces diabetes in a large variety of mammals. While multiple low doses of streptozotocin induce immune-mediated diabetes, a single high dose of streptozotocin causes a strictly toxic diabetes. Among mouse strains, non-obese diabetic (NOD) mice are characterized by an extreme susceptibility to high dose of streptozotocin-induced diabetes whereas C3H/Or mice are particularly resistant. We hypothesized that NOD genes involved in high dose streptozotocin-induced diabetes could be also involved in the autoimmune destruction of pancreatic beta cells that characterizes this mouse strain which is a model of Type 1 diabetes. Methods. We carried out a whole genome linkage scan on a population of (C3H/Or × NOD) × NOD backcross 1 mice in order to identify the genetic loci involved in NOD susceptibility to high dose of streptozotocin-induced diabetes.Results. Two loci, in chromosome 9 (D9Mit135 marker, 48 cM) and in chromosome 11 (D11Mit286 marker, 52 cM), were associated with NOD susceptibility to high dose streptozotocin-induced diabetes, the latter being co-localized with the autoimmune diabetes-predisposing idd4 locus. Moreover, we report here that C57BL/6 mice deficient in Nitric Oxide Synthase 2 were as sensitive as wild-type C57BL/6 mice to high dose streptozotocin-induced diabetes. Conclusion/interpretation. Although the Nitric Oxide Synthase 2 (Nos2) gene, localized at 45.6 cM in chromosome 11, is a good candidate gene, our results suggest that Nitric Oxide Synthase 2 activation might not be a crucial event for streptozotocin-induced destruction of pancreatic beta cells. [Diabetologia (2003[Diabetologia ( ) 46:1291[Diabetologia ( -1295 Keywords Non-obese diabetic mouse, diabetes, autoimmune, streptozotocin, pancreatic beta cells, genetic susceptibility, nitric-oxide synthase, C3H, C57BL/6, idd4, genome scan.

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Section: Discussioncontrasting

confidence: 66%

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

et al. 2003

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“…Studies on islet cells lacking PARP and p53-negative cells suggested an apoptosis pathway distinct from the DNA damage pathway. 80,81 We found that NO causes ER stress by depleting ER Ca 2 þ stores and leads to apoptosis in b-cells via CHOP induction (Figure 4a). 56 Maintenance of Ca 2 þ homeostasis in the ER is essential for protein folding.…”

Section: Diabetesmentioning

confidence: 94%

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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“…The possible mechanism of protection by hsp70 was studied by analysing the integrity of nuclear DNA as a major target for both NO and ROI cytotoxicity [6][7][8]. When DNA strand breaks were determined in individual cell nuclei by in situ nick translation it became apparent that hsp70 overexpression did not reduce the number of radical-damaged nuclei.…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein hsp70 overexpression confers resistance against nitric oxide

et al. 1996

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Heat stress is known to render rat islet cells resistant against the toxic effects of nitric oxide, reactive oxygen intermediates and the islet cell toxin streptozotocin. We report here for the first time that protection against nitric oxide is mediated by the major heat shock protein, hsp70, even in the absence of heat stress. The human hsp70 gene was stably transfected into the rat insulinoma cell line RINm5F. Constitutive expression of hsp70 caused protection from NO-induced cell lysis which was of the same extent as seen after heat stressing cells. Our results identify hsp70 as a defence molecule against nitric oxide.from the depressive effect of IL-1[~ on glucose-induced insulin secretion [18].These findings led us to hypothesize that among the different stress proteins expressed in heat stressed islet cells, hsp70 may confer protection against NO toxicity. To test this hypothesis we transfected a rat insulinoma cell line, RINm5F, with a vector containing the complete coding region of the human hspTO gene [10]. Analysis of the stably transfected clones revealed that hsp70 confers resistance against the cytotoxicity of NO.

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Inactivation of the Poly(ADP-ribose) Polymerase Gene Affects Oxygen Radical and Nitric Oxide Toxicity in Islet Cells

Cited by 262 publications

References 34 publications

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Heat shock protein hsp70 overexpression confers resistance against nitric oxide

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