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An SCFFBXO28 E3 Ligase Protects Pancreatic β-Cells from Apoptosis

Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
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Int. J. Mol. Sci. 2018, 19(4), 975; https://doi.org/10.3390/ijms19040975
Received: 15 March 2018 / Revised: 21 March 2018 / Accepted: 22 March 2018 / Published: 24 March 2018
(This article belongs to the Section Biochemistry)
Loss of pancreatic β-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. β-cell apoptosis contributes to the reduced β-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote β-cell survival in diabetes could lead to a promising therapeutic intervention to block β-cell decline during development and progression of diabetes. In the present study, we identified F-box protein 28 (FBXO28), a substrate-recruiting component of the Skp1-Cul1-F-box (SCF) ligase complex, as a regulator of pancreatic β-cell survival. FBXO28 was down-regulated in β-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired β-cell survival, and restoration of FBXO28 protected β-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with β-cell transcription factor NEUROD1 and FBXO28 depletion also reduced insulin mRNA expression, neither FBXO28 overexpression nor depletion had any significant impact on insulin content, glucose-stimulated insulin secretion (GSIS) or on other genes involved in glucose sensing and metabolism or on important β-cell transcription factors in isolated human islets. Consistently, FBXO28 overexpression did not further alter insulin content and GSIS in freshly isolated islets from patients with type 2 diabetes (T2D). Our data show that FBXO28 improves pancreatic β-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote β-cell survival in diabetes. View Full-Text
Keywords: pancreatic β-cell; diabetes; human islet; apoptosis; FBXO28; insulin secretion; NeuroD1; E3 ligase pancreatic β-cell; diabetes; human islet; apoptosis; FBXO28; insulin secretion; NeuroD1; E3 ligase
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Gorrepati, K.D.D.; He, W.; Lupse, B.; Yuan, T.; Maedler, K.; Ardestani, A. An SCFFBXO28 E3 Ligase Protects Pancreatic β-Cells from Apoptosis. Int. J. Mol. Sci. 2018, 19, 975.

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