title: Hypoxia-inducible factor independent down-regulation of thioredoxin-interacting protein in hypoxia.
abstract: Thioredoxin-Interacting Protein (Txnip) is an important regulator of glucose metabolism and functions by inhibiting cellular glucose uptake. The expression of the Txnip gene is sensitive to glucose availability and is negatively correlated with the glycolytic rate. Here we show that hypoxia induces a rapid decrease in Txnip mRNA and protein expression in a Hypoxia-Inducible Factor independent manner. Hypoxia caused reduced binding of the glucose responsive MondoA:Mlx transcription factor to the carbohydrate response elements (ChoREs) in the Txnip promoter. Our data suggest that hypoxia decreases MondoA:Mlx activity by increasing glycolytic flux, leading to the depletion of glycolytic intermediates which normally activate MondoA:Mlx. Hypoxia dependent Txnip down-regulation may be an important compensatory mechanism through which cancer cells adapt their metabolism to low oxygen concentrations.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Tin Fan
authors.initials: TF
authors.lastname: Chai
authors.forename: Yee Chin
authors.initials: YC
authors.lastname: Leck
authors.forename: Hongpeng
authors.initials: H
authors.lastname: He
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D017930:Genes, Reporter; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D049308:Dioxygenases; D005634:Fructose-Bisphosphate Aldolase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C485496:MLXIP protein, human; C486715:TXNIP protein, human; C488894:EGLN3 protein, human; C497446:VHL protein, human