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An SCF^FBXO28 E3 Ligase Protects Pancreatic ?-Cells from Apoptosis.

ABSTRACT: Loss of pancreatic ?-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. ?-cell apoptosis contributes to the reduced ?-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote ?-cell survival in diabetes could lead to a promising therapeutic intervention to block ?-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 ?-cell survival. FBXO28 was down-regulated in ?-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired ?-cell survival, and restoration of FBXO28 protected ?-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with ?-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 ?-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 ?-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote ?-cell survival in diabetes.

SUBMITTER: Gorrepati KDD

PROVIDER: S-EPMC5979299 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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An SCF<sup>FBXO28</sup> E3 Ligase Protects Pancreatic β-Cells from Apoptosis.

Gorrepati Kanaka Durga Devi KDD He Wei W Lupse Blaz B Yuan Ting T Maedler Kathrin K Ardestani Amin A

International journal of molecular sciences 20180324 4

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 (FBXO ...[more]

PMID: 29587369

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An SCFFBXO28 E3 Ligase Protects Pancreatic ?-Cells from Apoptosis.

Publications

An SCF<sup>FBXO28</sup> E3 Ligase Protects Pancreatic β-Cells from Apoptosis.

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An SCF^FBXO28 E3 Ligase Protects Pancreatic ?-Cells from Apoptosis.