SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients
| Autor: | Kira Meyerovich, Caroline Frørup, Simranjeet Kaur, Alessandra K Cardozo, Lotte B. Nielsen, Joachim Størling, Michala Prause, Henrik B. Mortensen, Flemming Pociot, Tina Fløyel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Candidate gene Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism CHOP Biology Nitric oxide 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Métabolisme Internal medicine Internal Medicine medicine Diabétologie Gene knockdown Endoplasmic reticulum Endocrinologie Médecine interne 030104 developmental biology Endocrinology Islet Studies chemistry Apoptosis Phosphoprotein Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Diabetes Diabetes (New York, N.Y.), 70 (2 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the b-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual b-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced ap-optosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-kB (NF-kB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticu-lum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls b-cell sensitivity to cytokines possibly by affecting the NF-kB–inducible nitric oxide synthase– endoplasmic reticulum stress pathway. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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