title: Mechanistic target of rapamycin (mTOR) dependent regulation of thioredoxin interacting protein (TXNIP) transcription in hypoxia.
abstract: Thioredoxin interacting protein (TXNIP), first identified as an inhibitor of thioredoxin, is also a tumor suppressor as well as an inhibitor of lipogenesis. TXNIP is known to be transcriptionally regulated in response to nutrients such as glucose and stress signals, including endoplasmic reticulum stress and lactic acidosis. In this study, we characterized the transcriptional regulation of TXNIP in response to hypoxia. Using a hepatocellular carcinoma cell line, we have found that TXNIP mRNA expression is regulated in a biphasic manner in hypoxia whereby TXNIP expression showed an initial rapid decrease, followed by an increase under prolonged hypoxia. Interestingly, we have shown that TXNIP induction in prolonged hypoxia is independent of the Hypoxia-Inducible Factor (HIF) transcription factor. The effect of hypoxia on TXNIP expression is mediated via the inhibition of the 4E-BP1/eIF4E axis of mechanistic target of rapamycin (mTORC1). Thus, we found that inhibiting mTORC1-dependent 4E-BP1 phosphorylation mimics the effect of hypoxia on TXNIP expression. Furthermore, overexpressing eIF4E prevents the induction of TXNIP in hypoxia. Our results suggest that mTORC1 may be an important regulator of hypoxia-dependent gene expression.
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
authors: Regina Wanju
authors: RW
authors: Wong
authors: Thilo
authors: T
authors: Hagen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C497396:ARNT protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D013879:Thioredoxins; D011393:Procollagen-Proline Dioxygenase; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases