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Int. J. Mol. Sci. 2018, 19(9), 2542; https://doi.org/10.3390/ijms19092542

Isx9 Regulates Calbindin D28K Expression in Pancreatic β Cells and Promotes β Cell Survival and Function

1
Department of Cell Biology, Nestle Institute of Health Sciences, EPFL Campus, 1015 Lausanne, Switzerland
2
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*
Author to whom correspondence should be addressed.
Received: 24 July 2018 / Revised: 13 August 2018 / Accepted: 19 August 2018 / Published: 27 August 2018
(This article belongs to the Section Biochemistry)
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Abstract

Pancreatic β-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of β-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for β-cell function and improves glycemia in a model of β cell regeneration. We further investigated the role of Isx9 in β-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in β cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected β cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation. View Full-Text
Keywords: Isx9; apoptosis; calbindin-D28K; calcium homeostasis; inflammation; serum deprivation; calcineurin; NFAT transcription factor; β cell function Isx9; apoptosis; calbindin-D28K; calcium homeostasis; inflammation; serum deprivation; calcineurin; NFAT transcription factor; β cell function
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Pujol, J.B.; Heikkila, E.; Savoia, C.; Hajibeigi, A.; De Marchi, U.; Battiprolu, P.K.; Öz, O.K.; Dioum, E.H.M. Isx9 Regulates Calbindin D28K Expression in Pancreatic β Cells and Promotes β Cell Survival and Function. Int. J. Mol. Sci. 2018, 19, 2542.

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