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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
Authors to whom correspondence should be addressed.
Shared senior authors.
Int. J. Mol. Sci. 2018, 19(4), 975;
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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