A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response.

Autor:	Pappalardo Z; Diabetes Center, University of California, San Francisco, San Francisco, CA., Gambhir Chopra D; Diabetes Center, University of California, San Francisco, San Francisco, CA., Hennings TG; Diabetes Center, University of California, San Francisco, San Francisco, CA.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA., Richards H; Diabetes Center, University of California, San Francisco, San Francisco, CA., Choe J; Diabetes Center, University of California, San Francisco, San Francisco, CA., Yang K; Diabetes Center, University of California, San Francisco, San Francisco, CA., Baeyens L; Diabetes Center, University of California, San Francisco, San Francisco, CA., Ang K; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA., Chen S; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA., Arkin M; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA., German MS; Diabetes Center, University of California, San Francisco, San Francisco, CA.; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA., McManus MT; Diabetes Center, University of California, San Francisco, San Francisco, CA.; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA., Ku GM; Diabetes Center, University of California, San Francisco, San Francisco, CA gregory.ku@ucsf.edu.; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2017 Jun; Vol. 66 (6), pp. 1703-1712. Date of Electronic Publication: 2017 Feb 28.
DOI:	10.2337/db16-0962
Abstrakt:	Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2 -a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed that Spry2 is a novel UPR target and its upregulation is dependent on PERK. Knockdown of Spry2 resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR. Spry2 deletion in the adult mouse β-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel β-cell link between Spry2 and human diabetes. (© 2017 by the American Diabetes Association.)
Databáze:	MEDLINE
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