Uncoupling protein-2 increases nitric oxide production and TNFAIP3 pathway activation in pancreatic islets
| Autor: | Rodolfo Niño Fong, Michael B. Wheeler, Zahra Fatehi-Hassanabad, Hongfang Lu, Catherine B. Chan, Simon C. Lee |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
endocrine system
Blotting Western Apoptosis In Vitro Techniques Biology Nitric Oxide Polymerase Chain Reaction Ion Channels Mitochondrial Proteins Islets of Langerhans Mice 03 medical and health sciences Transactivation 0302 clinical medicine Endocrinology Cyclin D2 In Situ Nick-End Labeling medicine Animals Uncoupling Protein 2 Molecular Biology Tumor Necrosis Factor alpha-Induced Protein 3 Cellular localization 030304 developmental biology 0303 health sciences Kinase Pancreatic islets Intracellular Signaling Peptides and Proteins NF-kappa B Regular Papers Streptozotocin NFKB1 Immunohistochemistry Molecular biology Cysteine Endopeptidases medicine.anatomical_structure Signal transduction 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Journal of Molecular Endocrinology |
| ISSN: | 1479-6813 0952-5041 |
| DOI: | 10.1530/jme-10-0117 |
| Popis: | Mutations in the uncoupling protein 2 (Ucp2) gene are linked to type-2 diabetes. Here, a potential mechanism by which lack of UCP2 is cytoprotective in pancreatic β-cells was investigated. Nitric oxide (NO) production was elevated in Ucp2−/− islets. Proliferation (cyclin D2, Ccnd2) and anti-apoptosis (Tnfaip3) genes had increased expression in Ucp2−/− islets, whereas the mRNA of pro-apoptosis genes (Jun, Myc) was reduced. TNFAIP3 cellular localization was detected in both α- and β-cells of Ucp2−/− islets but in neither α- nor β-cells of UCP2+/+ islets, where it was detected in pancreatic polypeptide-expressing cells. TNFAIP3 distribution was not markedly altered 14 days after streptozotocin treatment. Basal apoptosis was attenuated in Ucp2−/− β-cells, while the nuclear factor κB (NF-κB) pathway was transactivated after islet isolation. Ucp2+/+ and Ucp2−/− islets were treated with cytokines for 24 h. Cytokines did not increase NF-κB transactivation or apoptosis in Ucp2−/− islets and TNFAIP3 was more strongly induced in Ucp2−/− islets. Inhibition of NO production strongly reduced NF-κB activation and apoptosis. These data show that null expression of Ucp2 induces transactivation of NF-κB in isolated islets, possibly due to NO-dependent up-regulation of inhibitor of κB kinase β activity. NF-κB transactivation appears to result in altered expression of genes that enhance a pro-survival phenotype basally and when β-cells are exposed to cytokines. TNFAIP3 is of particular interest because of its ability to regulate NF-κB signaling pathways. |
| Databáze: | OpenAIRE |
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