Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

ABSTRACT: Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca²⁺ ([Ca²⁺]_i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several β-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca²⁺]_i, or pe

SUBMITTER: Darden CM 

PROVIDER: S-EPMC8983383 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature