Dominant Negative Pathogenesis by Mutant Proinsulin in the Akita Diabetic Mouse
| العنوان: | Dominant Negative Pathogenesis by Mutant Proinsulin in the Akita Diabetic Mouse |
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| المؤلفون: | Philippe A. Halban, Tetsuro Izumi, Shengli Zhao, Jie Wang, Toshiyuki Takeuchi, Hiromi Yokota-Hashimoto |
| المصدر: | Diabetes, Vol. 52, No 2 (2003) pp. 409-416 |
| بيانات النشر: | American Diabetes Association, 2003. |
| سنة النشر: | 2003 |
| مصطلحات موضوعية: | Protein Denaturation, Protein Folding, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Mutant, Prohormone, Golgi Apparatus, Endoplasmic Reticulum, Mice, Cricetinae, Multienzyme Complexes/metabolism, Cysteine Endopeptidases/metabolism, Endoplasmic Reticulum/metabolism, Genes, Dominant, Proinsulin, ddc:616, Recombinant Proteins/metabolism, Golgi Apparatus/metabolism, Diabetes Mellitus, Type 1/ genetics/pathology, Protease Inhibitors/pharmacology, Recombinant Proteins, Cell biology, Cysteine Endopeptidases, Protein Transport, symbols, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Heterozygote, Proteasome Endopeptidase Complex, endocrine system, medicine.medical_specialty, CHO Cells, Biology, Transfection, Islets of Langerhans, symbols.namesake, Proinsulin/ genetics/metabolism/secretion, Multienzyme Complexes, Internal medicine, Organelle, Internal Medicine, medicine, Animals, Protease Inhibitors, Cysteine, Secretory pathway, DNA Primers, Base Sequence, Endoplasmic reticulum, Insulin, Golgi apparatus, Mice, Mutant Strains, Diabetes Mellitus, Type 1, Endocrinology, Amino Acid Substitution, Mutagenesis, Site-Directed, Islets of Langerhans/pathology/ physiology/ultrastructure |
| الوصف: | Autosomal dominant diabetes in the Akita mouse is caused by mutation of the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. These heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. Although the results of our previous study suggested that the mutant proinsulin 2 is misfolded and blocked in the transport from the endoplasmic reticulum to the Golgi apparatus, its dominant negative nature has not been fully characterized. In the present study, we investigated the possible pathogenic mechanisms induced by the mutant proinsulin 2. There is no evidence that the mutant proinsulin 2 attenuates the overall protein synthesis rate or promotes the formation of aberrant disulfide bonds. The trafficking of constitutively secreted alkaline phosphatase, however, is significantly decreased in the islets of Akita mice, indicating that the function of early secretory pathways is nonspecifically impaired. Morphological analysis has revealed that secretory pathway organelle architecture is progressively devastated in the β-cells of Akita mice. These findings suggest that the organelle dysfunction resulting from the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita β-cells. |
| تدمد: | 1939-327X 0012-1797 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::429991154605899e87c835f91511a5dd https://doi.org/10.2337/diabetes.52.2.409 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....429991154605899e87c835f91511a5dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
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