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Endocrinology. 2011 Jul;152(7):2599-608. doi: 10.1210/en.2010-1420. Epub 2011 May 3.

Endoplasmic reticulum oxidoreductin-1-like β (ERO1lβ) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in β-cells.

Author information

  • 1Institute for Diabetes, Obesity, and Metabolism and Department of Medicine, University of Pennsylvania School of Medicine, Clinical Research Building 726, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.

Abstract

Hyperglycemia increases insulin flux through the endoplasmic reticulum (ER) of pancreatic β-cells, and the unfolded protein response pathway is required to enhance insulin processing. Pancreatic and duodenal homeobox 1 (PDX1), a key pancreatic transcription factor, regulates insulin along with targets involved in insulin processing and secretion. Here we find that PDX1 is a direct transcriptional regulator of ER oxidoreductin-1-like β (Ero1lβ), which maintains the oxidative environment of the ER to facilitate disulfide bond formation. PDX1 deficiency reduced Ero1lβ transcript levels in mouse islets and mouse insulinoma (MIN6) cells; moreover, PDX1 occupied the Ero1lβ promoter in β-cells. ERO1lβ levels were induced by high glucose concentrations and by the reducing agent dithiothreitol, indicating potential roles in adaptation to increased oxidative protein folding load in the β-cell ER. In MIN6 cells, small interfering RNA-mediated silencing of Ero1lβ decreased insulin content and increased susceptibility to ER stress-induced apoptosis. These findings demonstrate roles for the PDX1 target ERO1lβ in maintaining insulin content and regulating cell survival during ER stress.

PMID:
21540283
[PubMed - indexed for MEDLINE]
PMCID:
PMC3115612
Free PMC Article

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