title: Induction and activation of antiviral enzyme 2',5'-oligoadenylate synthetase by in vitro transcribed insulin mRNA and other cellular RNAs.
abstract: Double-stranded RNA (dsRNA) can induce antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) expression and activate latent 2'5'AS. Our previous data have shown pancreatic β cells are sensitive to dsRNA-induced 2'5'AS expression, and constitutive high basal 2'5'AS expression is associated with susceptibility to developing type 1 diabetes (T1D), a disease due to pancreatic β cell loss. Here we report that in vitro transcribed human insulin mRNA induces the activation of human OAS gene promoter sequences, and specifically and dose-dependently induces 2'5'AS expression in murine pancreatic βTC3 cells. Over-expression of dsRNA receptor retinoic acid-inducible gene-1 enhances insulin mRNA-induced 2'5'AS expression. In vitro transcribed insulin and other mRNAs, as well as total cellular RNAs, activate latent 2'5'AS in vitro with activation ability likely associated with the sequence and length of individual mRNAs or the sample source of total cellular RNA. Insulin mRNA does not show any specificity to activate 2'5'AS, but total cellular RNA from βTC3 cells has high activation ability. Constitutive 2'5'AS expression in βTC3 cells leads to cell proliferation inhibition and apoptosis. Our study suggests the possibility of cellular RNA-regulated 2'5'AS expression and activation, and the potential risk of high insulin gene transcription in pancreatic β cells, and may help explain genetic predisposition to T1D associated with INS VNTR class I alleles.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Meixia
authors.initials: M
authors.lastname: Dan
authors.forename: Dongjun
authors.initials: D
authors.lastname: Zheng
authors.forename: L Leigh
authors.initials: LL
authors.lastname: Field
authors.forename: Vagn
authors.initials: V
authors.lastname: Bonnevie-Nielsen
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018598:Minisatellite Repeats; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis
chemical_list: D007328:Insulin; D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D015088:2',5'-Oligoadenylate Synthetase; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases