Searching the Resource Information Network
Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.
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 perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.
Pubmed ID: 35402865
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name Crl:NU(NCr)-Foxn1nu from IMSR.
View all literature mentionsThis monoclonal targets Akt (pan) (C67E7) Rabbit mAb
View all literature mentionsThis monoclonal targets CHOP
View all literature mentionsThis monoclonal targets HDAC1
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets NFATC2
View all literature mentionsCell line MIN6 is a Transformed cell line with a species of origin Mus musculus
View all literature mentionsThe goal of the Integrated Islet Distribution Program (IIDP) is to work with the leading islet isolation centers in the U.S. to distribute high quality human islets to the diabetes research community, in order to advance scientific discoveries and translational medicine.
View all literature mentions