dc.contributor.author | Lv, Lixia | |
dc.contributor.author | Chen, Hewen | |
dc.contributor.author | Sun, Jiaying | |
dc.contributor.author | Lu, Di | |
dc.contributor.author | Chen, Chen | |
dc.contributor.author | Liu, Dongfang | |
dc.date.accessioned | 2019-09-10T05:27:34Z | |
dc.date.available | 2019-09-10T05:27:34Z | |
dc.date.issued | 2015 | |
dc.identifier.issn | 1355-008X | |
dc.identifier.doi | 10.1007/s12020-015-0543-8 | |
dc.identifier.uri | http://hdl.handle.net/10072/387199 | |
dc.description.abstract | Protein N-arginine methyltransferase-1 (PRMT1), the major asymmetric arginine methyltransferase, plays important roles in various cellular processes. Previous reports have demonstrated that levels and activities of PRMT1 can vary in animals with type 2 diabetes mellitus. The aim of this study was to assess the expression and mechanism of action of PRMT1 during glucose toxicity-induced β cell dysfunction. Liposome-mediated gene transfection was used to transfect INS-1 cells with siPRMT1, which inhibits PRMT1 expression, and pALTER–FOXO1, which overexpresses forkhead box protein O1 (FOXO1). The cells were then cultured in media containing 5.6 or 25 mmol/L glucose with or without the small molecule PRMT1 inhibitor AMI-1 for 48 h. The protein levels of PRMT1, the arginine methylated protein α-metR, FOXO1, Phospho-FOXO1, pancreas duodenum homeobox-1 (PDX-1), and the intracellular localization of PDX-1 and FOXO1 were then measured by western blotting. FOXO1 methylation was detected by immunoprecipitated with anti-PRMT1 antibody and were immunoblotted with α-metR. The levels of insulin mRNA were measured by real-time fluorescence quantitative PCR. Glucose-stimulated insulin secretion (GSIS) and intracellular insulin content were measured using radioimmunoassays. Intracellular Ca2+ ([Ca2+]i) was detected using Fura-2 AM. Intracellular cAMP levels were measured using ELISA. Chronic exposure to high glucose impaired insulin secretion, decreased insulin mRNA levels and insulin content, increased intracellular [Ca2+]i and cAMP levels, and abolishes their responses to glucose. Inhibiting PRMT1 expression improved insulin secretion, increased mRNA levels and insulin content by regulating the intracellular translocation of PDX-1 and FOXO1, decreasing the methylation of FOXO1, and reducing intracellular [Ca2+]i and cAMP concentrations. Transient overexpression of constitutively active FOXO1 in nuclear reversed the AMI-1-induced improvement of β cell function without changing arginine methylation. It is concluded therefore that PRMT1 regulates GSIS in INS-1 cells, through enhanced methylation-induced nuclear localization of FOXO1, which subsequently suppresses the nuclear localization of PDX-1. Our results suggest a novel mechanism that might contribute to the deficient insulin secretion observed under conditions of chronically hyperglycemia. | |
dc.description.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Springer | |
dc.relation.ispartofpagefrom | 669 | |
dc.relation.ispartofpageto | 682 | |
dc.relation.ispartofissue | 3 | |
dc.relation.ispartofjournal | Endocrine | |
dc.relation.ispartofvolume | 49 | |
dc.subject.fieldofresearch | Clinical sciences | |
dc.subject.fieldofresearchcode | 3202 | |
dc.subject.keywords | Science & Technology | |
dc.subject.keywords | Life Sciences & Biomedicine | |
dc.subject.keywords | Endocrinology & Metabolism | |
dc.subject.keywords | Protein N-arginine methyltransferase-1 | |
dc.subject.keywords | Forkhead box protein O1 | |
dc.title | PRMT1 promotes glucose toxicity-induced beta cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Lv, L; Chen, H; Sun, J; Lu, D; Chen, C; Liu, D, PRMT1 promotes glucose toxicity-induced beta cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells, Endocrine, 2015, 49 (3), pp. 669-682 | |
dcterms.dateAccepted | 2015-01-27 | |
dc.date.updated | 2019-09-10T05:26:32Z | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Chen, Chen | |