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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.
Int. J. Mol. Sci. 2018, 19(9), 2542; https://doi.org/10.3390/ijms19092542
Received: 24 July 2018 / Revised: 13 August 2018 / Accepted: 19 August 2018 / Published: 27 August 2018
(This article belongs to the Section Biochemistry)
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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MDPI and ACS Style

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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