Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18.
Thioredoxin (TRX) is a key protein of the cellular redox metabolism, which expression is increased in several tumors especially gastric tumors. Even though ultraviolet (UV) and hypoxia specifically induce TRX, the mechanisms that lead to increased TRX levels are still ill defined. Here, we show that the heterogenous ribonucleoprotein A18 (hnRNP A18) RNA Binding Domain (RBD) and the arginine, glycine (RGG) rich domain can bind TRX 3'-untranslated region (3'-UTR) independently but both domains are required for maximal binding. Immunoprecipitation (IP) of hnRNP A18-mRNAs complexes and co-localization of hnRNP A18 and TRX transcripts on ribosomal fractions confirm the interaction of hnRNP A18 with TRX transcripts in cells. Moreover, down regulation of hnRNP A18 correlates with a significant reduction of TRX protein levels. In addition, hnRNP A18 increases TRX translation and interacts with the eukaryotic Initiation Factor 4G (eIF4G), a component of the general translational machinery. Furthermore, hnRNP A18 phosphorylation by the hypoxia inducible GSK3beta increases hnRNP A18 RNA binding activity in vitro and in RKO cells in response to UV radiation. These data support a regulatory role for hnRNP A18 in TRX post-transcriptional expression possibly through a kissing loop model bridging TRX 3'- and 5'-UTRs through eIF4G.
Yang
Ruiqing
R
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland Baltimore Baltimore, MD 21207, USA.
Weber
David J
DJ
Carrier
France
F
D020413:3' Untranslated Regions / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics*; D014466:Ultraviolet Rays
D020413:3' Untranslated Regions; D039603:Eukaryotic Initiation Factor-4G; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012333:RNA, Messenger; D013879:Thioredoxins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3