title: Transcription factor Ets1 regulates expression of thioredoxin-interacting protein and inhibits insulin secretion in pancreatic β-cells.
abstract: Long-term activation of extracellular-regulated kinase (ERK1/2) pathway has been shown to cause glucotoxicity and inhibit insulin gene expression in β-cells. Transcription factor Ets1 is activated by ERK1/2-mediated phosphorylation at the Thr38 residue. We hypothesize that Ets1 plays an important role in mediating ERK1/2 induced glucotoxicity in β-cells. We determined the role of Ets1 in Min6 cells and isolated mouse islets using overexpression and siRNA mediated knockdown of Ets1. The results show that Ets1 was localized in insulin-staining positive cells but not in glucagon-staining positive cells. Overexpression of Ets1 reduced glucose-stimulated insulin secretion in primary mouse islets. Overexpression of Ets1 in Min6 β-cells and mouse islets increased expression of thioredoxin-interacting protein (TXNIP). Conversely, knockdown of Ets1 by siRNA reduced expression of TXNIP in Min6 cells. Ets1 was associated with the txnip promoter in min6 cells and transfection of 293 cells with Ets1 and p300 synergistically increased txnip promoter reporter activity. Moreover, overexpression of Ets1 inhibited Min6 cell proliferation. Our results suggest that Ets1, by promoting TXNIP expression, negatively regulates β-cell function. Thus, over-activation of Ets1 may contribute to diet-induced β-cell dysfunction.
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: He
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Hu
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Hai
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Meifeng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yan-Shan
authors.initials: YS
authors.lastname: Dai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C494042:Ets1 protein, mouse; D007328:Insulin; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C445672:Txnip protein, mouse; D013879:Thioredoxins; D005947:Glucose