A potential mechanism of metformin-mediated regulation of glucose homeostasis: Inhibition of Thioredoxin-interacting protein (Txnip) gene expression

Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

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Thioredoxin-Interacting Protein Gene Expression via MondoA Is Rapidly and Transiently Suppressed during Inflammatory Responses

PLoS ONE ◽

10.1371/journal.pone.0059026 ◽

2013 ◽

Vol 8 (3) ◽

pp. e59026 ◽

Cited By ~ 13

Author(s):

Yasuyoshi Kanari ◽

Yuki Sato ◽

Satoru Aoyama ◽

Tatsushi Muta

Keyword(s):

Gene Expression ◽

Protein Gene ◽

Inflammatory Responses ◽

Interacting Protein ◽

Thioredoxin Interacting Protein

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Thioredoxin-interacting protein: an oxidative stress-related gene is upregulated by glucose in human prostate carcinoma cells

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0033 ◽

2008 ◽

Vol 42 (3) ◽

pp. 205-214 ◽

Cited By ~ 17

Author(s):

See-Tong Pang ◽

Wen-Chi Hsieh ◽

Cheng-Keng Chuang ◽

Chun-Hsiang Chao ◽

Wen-Hui Weng ◽

...

Keyword(s):

Gene Expression ◽

Glucose Metabolism ◽

Prostate Carcinoma ◽

Promoter Activity ◽

Carcinoma Cells ◽

Human Prostate ◽

Response Element ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Human Prostate Carcinoma

Thioredoxin-interacting protein (TXNIP), also known as vitamin-D3 upregulated protein 1, interacts with reduced thioredoxin. This protein modulates the cellular redox state and plays a role in stress-induced cellular apoptosis. This study examined TXNIP gene expression in prostate cancer cells. In vitro studies by immunoblot assay have shown that elevated glucose levels (1–15 mM) upregulate TXNIP gene expression two- to fourfold in human prostate carcinoma cells (LNCaP) and hepatocellular carcinoma cells (HepG2). Transient gene expression assays reveal that the promoter activity of the TXNIP gene is upregulated by glucose, 3-O-methylglucose, and maltose, but not by mannitol. These results suggest that glucose and 3-O-methylglucose induce TXNIP expression through both glucose metabolism-dependent and -independent pathways. Cotransfection of a plasmid expression carbohydrate response element-binding protein (ChREBP) with a TXNIP reporter vector into LNCaP cells dramatically enhances reporter activity in a low glucose (1 mM) condition. The effects of glucose are apparently mediated in a region located −341 to −324 bp upstream of the translational starting point of the TXNIP gene as indicated by 5′-deletion and site-directed mutagenesis reporter assays. Mutation of the putative carbohydrate response element (ChoRE) from CACGAGGGCAGCACGAG to TTTGAGGGCAGCACGAG abolishes glucose upregulation of TXNIP promoter activity. The present study demonstrates that TXNIP is transcription induced in both LNCaP and HepG2 cells in an increased glucose metabolism-dependent or -independent response, and a putative glucose regulatory system including ChREBP and ChoRE is needed for glucose-induced TXNIP gene in human prostate carcinoma cells.

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MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

Biochemical Journal ◽

10.1042/bj20121126 ◽

2013 ◽

Vol 453 (2) ◽

pp. 209-218 ◽

Cited By ~ 7

Author(s):

Kyoung-Sim Han ◽

Donald E. Ayer

Keyword(s):

Gene Expression ◽

Feedback Inhibition ◽

Adenine Nucleotide ◽

Adenine Nucleotides ◽

Interacting Protein ◽

Kinase Activation ◽

Thioredoxin Interacting Protein ◽

Glucose Homoeostasis ◽

Independent Effects ◽

Adenine Nucleotide Pool

The MondoA–Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA–Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA–Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.

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miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

Cancer Biomarkers ◽

10.3233/cbm-203112 ◽

2021 ◽

pp. 1-12

Author(s):

Pengli Wang ◽

Dan Zheng ◽

Hongyang Qi ◽

Qi Gao

Keyword(s):

Pancreatic Cancer ◽

Hypoxia Inducible Factor ◽

Immunofluorescence Assay ◽

Luciferase Assay ◽

Interacting Protein ◽

Over Expression ◽

Thioredoxin Interacting Protein ◽

Cellular Processes ◽

And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

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