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

International Journal of Molecular Sciences
Julien B PujolEl Hadji M Dioum

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 inflammatio...Continue Reading

References

Dec 1, 1986·Transplantation·R SuttonP J Morris
Apr 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·R K Gill, S Christakos
Apr 18, 1998·Proceedings of the National Academy of Sciences of the United States of America·Q GuoM P Mattson
Jun 5, 1998·The Journal of Biological Chemistry·C B KleeX Wang
May 28, 1998·Cell Calcium·P Nicotera, S Orrenius
Apr 7, 1999·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·J Krebs
Mar 29, 2001·Diabetes·D L Eizirik, M I Darville
Mar 30, 2001·The Journal of Biological Chemistry·N Vo, R H Goodman
Jul 31, 2001·Lancet·M A Atkinson, G S Eisenbarth
May 2, 2002·Cell·Gerald R Crabtree, Eric N Olson
Mar 26, 2004·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Yan LiuSylvia Christakos
Apr 2, 2004·Nature Reviews. Immunology·Camillo Ricordi, Terry B Strom
Mar 9, 2005·Proceedings of the National Academy of Sciences of the United States of America·Xinmin ZhangMarc Montminy
Jun 10, 2006·The EMBO Journal·Tim T LambersRené J Bindels
Jun 29, 2006·Diabetes·Juliet A Emamaullee, A M James Shapiro
Nov 30, 2006·Diabetes·Jean-Claude HenquinMyriam Nenquin
Dec 2, 2006·The Journal of Biological Chemistry·Andras SzollosiJean-Claude Henquin
Aug 22, 2007·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Orhan K OzJoseph E Zerwekh
Feb 19, 2008·Nature Biotechnology·Gary K GeissKrassen Dimitrov
Jun 17, 2008·Nature Chemical Biology·Jay W SchneiderJenny Hsieh
Aug 9, 2008·Molecular and Cellular Endocrinology·Andreia S BernardoKevin Docherty
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michael C LawrenceMelanie H Cobb
Oct 3, 2008·Pediatric Diabetes·Anke AssmannRohit N Kulkarni
Oct 18, 2008·Diabetes, Obesity & Metabolism·A V Matveyenko, P C Butler
Aug 5, 2010·Journal of Cell Science·Chien-Lin ChenHong-Chen Chen
Mar 9, 2011·The Journal of Biological Chemistry·Shimrit OzNathan Dascal
Dec 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Elhadji M DioumMelanie H Cobb
Jul 21, 2012·Developmental Cell·William R GoodyerSeung K Kim
Sep 11, 2012·Molecular Cell·Eric M WausonMelanie H Cobb
Mar 7, 2013·Nature Structural & Molecular Biology·Gabriel E Zentner, Steven Henikoff
May 17, 2013·Endocrinology·Chandra E EberhardRobert A Screaton
Feb 1, 2014·Cell Communication and Signaling : CCS·Alain VandewalleCatherine Werts

❮ Previous
Next ❯

Methods Mentioned

BETA
acetylation
nuclear translocation
ELISA
transgenic
histone acetylation
transfection
Immunoprecipitation
PCR

Software Mentioned

Graph Pad
Prism
GraphPad Prism
Excel

Related Concepts

Related Feeds

Antidiabetic Cellular Plasticity

This feed focuses on mechanisms that underlie cellular plasticity as a treatment for diabetes and other degenerative diseases.