Disease relevance of TXNIP

• Melanoma metastasis suppression by chromosome 6: evidence for a pathway regulated by CRSP3 and TXNIP [1].
• Increased TXNIP expression inhibited metastasis and up-regulated KISS1 [1].
• Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein [2].
• Through gene expression profiling we discovered that the expression of thioredoxin-intereacting protein (txnip) mRNA is significantly induced by the glucocorticoid hormone dexamethasone not only in the murine T-cell lymphoma line WEHI7.2, but also in normal mouse thymocytes [3].
• In addition, it was found that VDUP1 interacted with promyelocytic leukemia zinc-finger, Fanconi anemia zinc-finger, and histone deacetylase 1, which are known to be transcriptional corepressors [4].

High impact information on TXNIP

• Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells [5].
• TXNIP/VDUP1, a thioredoxin-binding protein, was expressed more highly in neo6/C8161 and in nonmetastatic melanomas [1].
• Surprisingly, TXNIP also mapped to chromosome 1q [1].
• Depletion of myosin VI expression was also accompanied by global gene expression changes reflective of attenuated tumorigenic potential, as marked by a nearly 10-fold induction of TXNIP (VDUP1), a tumor suppressor with decreased expression in prostate cancer specimens [6].
• Thioredoxin-interacting protein (Txnip) is critical for regulation of glucose metabolism, the only currently known function of which is to bind and inhibit thioredoxin [7].

Chemical compound and disease context of TXNIP

• Overexpression of Txnip by infecting melanoma cells with adenovirus increased TEM 3-fold vs. control (P < 0.001), and this increase was blocked by N-acetylcysteine, indicating a redox-sensitive mechanism [8].
• Therefore, VDUP1 not only may be induced by stress response as a result of 5-FU cytotoxicity, but may also play a key role in 5-FU cytotoxicity in colon cancers [9].
• Hyperglycemia induced Txnip promoter activity (3.9+/-0.2-fold; P<0.001) and abolished NO effects (-37.4+/-1.0% at 5.6 mmol/L glucose versus 12.4+/-2.1% at 22.4 mmol/L glucose; P<0.05) [10].
• Vitamin D3 up-regulated protein 1 (VDUP1) expression in gastrointestinal cancer and its relation to stage of disease [11].
• The increased paclitaxel cytotoxicity is associated with an additive effect on the hyperglycemia-mediated TXNIP expression more evident in conditions of hyperglycemia than normoglycemia [12].

Biological context of TXNIP

• Thus, TXNIP is a novel proapoptotic beta-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and beta-cell apoptosis [13].
• Furthermore, we found that glucose-induced TXNIP transcription is not dependent on glucose metabolism and is mediated by a distinct carbohydrate response element (ChoRE) in the human TXNIP promoter consisting of a perfect nonpalindromic repeat of two E-boxes [13].
• Our results suggest a new potential role of TXNIP in the differentiation of epithelial cells and in mucosal immunity of the GI tract [14].
• Silencing thioredoxin by small interference RNA abrogated all angiogen-induced migration while silencing TXNIP strongly induced HMVEC migration [15].
• Stable overexpression of TXNIP in MES-13 cells increases glucose and glucosamine-mediated ECM gene expression and oxidative stress [16].

Anatomical context of TXNIP

• TXNIP is a regulator of the cellular redox state, but its role in pancreatic beta-cells and the mechanism of its regulation by glucose remain unknown [13].
• Using in situ hybridization, we demonstrated that mRNA of TXNIP was differentially expressed in the epithelium of the human GI tract [14].
• TXNIP was also highly expressed in lymphocytes in the lymphoid follicles [14].
• In cultured keratinocytes, VDUP1 and sciellin were more highly expressed in cells undergoing differentiation [17].
• By immunohistochemistry VDUP1 was localized to the basal layer of normal human epidermis and the inner and outer root sheaths but not the matrix of the hair follicle [17].

Associations of TXNIP with chemical compounds

• Reporter assays demonstrated that this glucocorticoid response element was necessary and sufficient for induction of txnip by dexamethasone [3].
• PDGF and H2O2 time-dependently suppressed VDUP-1 expression (13-fold and 30-fold reduction after 1 hour, respectively; P<0.001), and this was inhibited by the cell-permeable antioxidants N-acetylcysteine and 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) [18].
• In contrast, incubation of INS-1 beta cells with equimolar amounts (25 mM) of l-glucose or mannitol had no effect on TXNIP expression as measured by real-time RT-PCR, eliminating the possibility of an osmotic effect [19].
• We found that aside form glucose, the nonmetabolizable sugars 2-deoxyglucose, which is still converted to G-6-P as well as 3-O-methylglucose (3-MG), which cannot be phosphorylated by glucokinase, stimulate TXNIP expression [19].
• Thioredoxin binding protein-2 (TBP-2), which is identical with vitamin D3 (VD3) up-regulated protein 1 (VDUP1), plays a crucial role in the integration of glucose and lipid metabolism [20].

Physical interactions of TXNIP

• The deletion of HSE abolished transcriptional activity of VDUP1 promoter by stresses and the binding of heat shock factor (HSF) to HSE was confirmed by gel-shift and supershift assays using nuclear extracts prepared from stressed Bosc cells [21].
• These cysteines are not conserved in the broader family of arrestin domain-containing proteins, and we demonstrate that the thioredoxin-binding property of Txnip is unique [7].

Regulatory relationships of TXNIP

• Furthermore, TXNIP repression by all 3 angiogens induced thioredoxin activity [15].
• VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression [4].
• Heat shock factor regulates VDUP1 gene expression [21].
• Expression of a GFP-TXNIP fusion protein was sufficient to induce apoptosis in WEHI7.2 cells, and repression of endogenous txnip by RNA interference inhibited dexamethasone-induced apoptosis in WEHI7.2 cells [3].

Other interactions of TXNIP

• Thus, we implicated a specific gene on chromosome 6 in the etiology of melanoma metastasis and identified potential up-stream regulators of KISS1 and TXNIP [1].
• In this study we used the yeast two-hybrid system to find proteins interacting with sciellin and identified vitamin D-upregulated protein 1 (VDUP1) [17].
• The induction of txnip mRNA by dexamethasone appears to be mediated through the glucocorticoid receptor as it is blocked in the presence of RU486, a glucocorticoid receptor antagonist [3].
• Also, the enforced expression of HSF or heat shock increased the transcription of endogenous VDUP1 [21].
• The molecular interplay between thioredoxin, ASK-1, and Txnip potentially influences cell growth and survival in diverse human diseases such as cancer, diabetes, and heart disease [22].

Analytical, diagnostic and therapeutic context of TXNIP

• To analyze the levels of Txn, Txnrd, and Txnip in the uterus, we treated ovariectomized adult mice with a time course of E2 and analyzed mRNA levels by real-time PCR [23].
• METHODS: cDNA microarray technology was used to detect gene expression and the result of microarrays for genes (TIEG and VDUP1) was confirmed by Northern analysis [24].
• Northern blot analysis showed that VDUP1 cDNA hybridizes to a 2.9 kb mRNA species which is up-regulated in HL-60 cells by 1,25-dihydroxyvitamin D-3 (1,25-(OH)2D3) treatment [25].
• Immunoprecipitation experiments demonstrated that GSNO stimulation and mutation of thioredoxin at Cys69, a site of nitrosylation, had no effect on the Txnip/thioredoxin interaction [10].
• We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress [26].

References