title: Thioredoxin-interacting protein regulates insulin transcription through microRNA-204.
abstract: Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes, but despite the growing diabetes epidemic, the molecular mechanisms underlying this disease have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a crucial factor in beta-cell biology and show that beta-cell TXNIP is upregulated in diabetes, whereas TXNIP deficiency protects against diabetes by preventing beta-cell apoptosis. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MAFA, a known insulin transcription factor. In particular, we first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets of Txnip-deficient mice, diabetic mouse models and primary human islets. We then further found that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation. We also identified MAFA as a target that is downregulated by miR-204. Taken together, our results demonstrate that TXNIP controls microRNA expression and insulin production and that miR-204 is involved in beta-cell function. The newly identified TXNIP-miR-204-MAFA-insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.
authors: Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Guanlan
authors: G
authors: Xu
authors: Junqin
authors: J
authors: Chen
authors: Gu
authors: G
authors: Jing
authors: Anath
authors: A
authors: Shalev
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D050053:TRPM Cation Channels / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D007328:Insulin; C574692:MIRN204 microRNA, mouse; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; C445672:Txnip protein, mouse; D013879:Thioredoxins
references: IUBMB Life. 2001 Jul;52(1-2):29-33
references: 11795589
references: Diabetes. 2007 Dec;56(12):2938-45
references: 17804764
references: Diabetes. 2012 Apr;61(4):848-56
references: 22442301
references: Am J Ther. 2005 Nov-Dec;12(6):491-8
references: 16280642
references: Nature. 2004 Nov 11;432(7014):226-30
references: 15538371
references: J Endocrinol. 2006 Feb;188(2):287-94
references: 16461554
references: Genes Dev. 1998 Oct 15;12(20):3168-81
references: 9784492
references: Diabetes. 2010 Jul;59(7):1709-20
references: 20424231
references: Mol Cell Biol. 2005 Jun;25(12):4969-76
references: 15923615
references: Nat Cell Biol. 2009 Mar;11(3):228-34
references: 19255566
references: Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1798-809
references: 21890685
references: Diabetes. 2010 Oct;59(10):2530-9
references: 20627934
references: J Biol Chem. 2007 Jan 19;282(3):1577-84
references: 17142462
references: Nature. 2005 Dec 1;438(7068):685-9
references: 16258535
references: Mol Cell Biol. 1999 Jan;19(1):704-13
references: 9858593
references: Diabetes. 2011 Jul;60(7):1832-7
references: 21709278
references: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5813-8
references: 19289822
references: Biochem Biophys Res Commun. 2005 Oct 28;336(3):770-8
references: 16143294
references: EMBO J. 2011 Mar 2;30(5):797-9
references: 21364681
references: Endocrinology. 2005 May;146(5):2397-405
references: 15705778
references: J Biol Chem. 2010 Feb 5;285(6):3997-4005
references: 19959470
references: J Biol Chem. 2008 Aug 15;283(33):22612-9
references: 18522939
references: Cell. 2007 Jun 29;129(7):1401-14
references: 17604727
references: Diabetes. 2010 Feb;59(2):440-7
references: 19875615
references: J Exp Med. 2011 Mar 14;208(3):535-48
references: 21321078
references: Cell Physiol Biochem. 2010;25(6):667-74
references: 20511712
references: Cell. 2005 Jan 14;120(1):15-20
references: 15652477
references: Diabetes. 2008 Apr;57(4):938-44
references: 18171713
references: Nucleic Acids Res. 2004 Dec 22;32(22):e188
references: 15616155
references: J Biol Chem. 2012 Sep 7;287(37):31155-64
references: 22733810
references: J Biol Chem. 2009 Jun 19;284(25):16898-16905
references: 19411249
references: Diabetes. 2008 Oct;57(10):2708-17
references: 18591395
references: EMBO J. 2011 Mar 2;30(5):835-45
references: 21285947
references: Biochem Biophys Res Commun. 2011 Jan 7;404(1):16-22
references: 21094635
references: Cell. 2010 May 14;141(4):618-31
references: 20478254
references: Endocrinology. 2002 Sep;143(9):3695-8
references: 12193586
references: J Clin Oncol. 2006 Oct 10;24(29):4677-84
references: 16966691
references: Diabetes. 2011 Jul;60(7):1825-31
references: 21709277
references: FASEB J. 2008 Oct;22(10):3581-94
references: 18552236
references: Endocrinology. 2010 May;151(5):2050-9
references: 20215569
references: Endocrinology. 2002 Feb;143(2):339-42
references: 11796484