TXN (thioredoxin)

2009-10-01   Zhe Chen , Eiji Yoshihara , Hajime Nakamura , Hiroshi Masutani , Junji Yodoi 

Department of Biological Responses, Institute for Virus Research, Kyoto University, Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, Japan

Identity

HGNC
LOCATION
9q31.3
IMAGE
Atlas Image
LEGEND
Chromosome : 9, Location : 9q31.
LEGEND
(Please visit http://www.ncbi.nlm.nih.gov for more details).
LOCUSID
ALIAS
TRDX,TRX,TRX1,Trx80
FUSION GENES

DNA/RNA

Atlas Image
5 exons of thioredoxin.
(Please visit http://www.ncbi.nlm.nih.gov for more details).

Description

5 exons, 5 part of exon 1 and 3 part of exon 5 are non-coding.

Transcription

508 bps mRNA, transcribed in a telomere to centromere direction. Alternative splicing of human thioredoxin (lacking exon 2 and 3) was reported in cancer cells.
Thioredoxin (TRX/TXN/ADF) expression is induced by a variety of physiochemical stresses, including virus infection, mitogens, UV-irradiation, hydrogen peroxide, ischemia reperfusion and so on. Natural substances including hemin, estrogen, prostaglandins, sulforaphane, and cAMP can also induce the expression and secretion of TRX. Geranylgeranylacetone (GGA), an acyclic polyisoprenoid as anti-ulcer drug, or tert-butylhydroquinone (tBHQ), a xenobiotics, can also induce TRX expression.
The 5 flanking sequence of TRX gene contains a series of stress-responsive elements, antioxidant responsive element (ARE), cAMP responsive element (CRE), xenobiotics responsive element (XRE) and Sp1.

Proteins

Note

Thioredoxin is a 12 Kda ubiquitous protein that has disulfide-reducing activity. The structural fold of thioredoxin, including redox-active site, is called "TRX-family domain", which is shared by other TRX superfamily proteins.
Atlas Image
Active site and conserved domain of thioredoxin.
(Please see http://www.ncbi.nlm.nih.gov for more details).

Description

In 1964, thioredoxin, named by one swedish group, was first identified from extracts of Escherichia coli B as hydrogen donor from NADPH to ribonucleotide reductase. Human thioredoxin was originally cloned by a Japanese group as an IL-2Ralpha (CD25) induced factor in HTLV-1 infected T-cell lines and designated as Adult T cell leukemia derived factor (ADF). It was also cloned independently by a French group as an IL-1 like growth factor produced by Epstein-Barr virus-transformed cells.
Thioredoxin is a 12 Kda multifunctional protein with a redox-active site (Cys-Gly-Pro-Cys), which is involved in dithiol/disulfide exchange reaction. Reduced TRX can reduce protein disulfide bonds and oxidized TRX is reduced by NADPH and thioredoxin reductase.

Expression

Thioredoxin is ubiquitously expressed in normal tissues or cells. Plasma levels of TRX in normal individuals vary between 10 and 80 ng/mL. The plasma TRX level is elevated in certain human diseases including HIV infection and cancer. As mentioned above, thioredoxin can also be induced by various physiochemical stress and some natural agents or drugs.

Localisation

Thioredoxin is mainly localized in the cytoplasm. Under environmental stress, such as UVB irradiation, PMA, H2O2, hypoxia, the cancer drug cisplatin, hemin and so on, it can translocate to the nucleus, possibly participating to the regulation of nuclear transcription factors, such as Ref-1. Thioredoxin can also be secreted in response to oxidative stress and function as a cytokine to alleviate inflammation. The secretion mechanism of thioredoxin remains unclear. Thioredoxin accumulation in the membrane fraction has long been implied by Holmgrens group in 1989. Later it is found to be expressed on the surface of HUVECs (human umbilical vein endothelial cells), including lipid raft which may be involved in redox signalling.

Function

Thioredoxin plays an important role in scavenging reactive oxygen intermediates (ROIs) produced in various oxidative stress. Redox-associated signal transduction inside the cell may be attributed to enhanced DNA binding ability of several transcription factors, such as Ref-1, AP-1, NF-kappaB, which have been proved to be modulated directly or indirectly by thioredoxin. Acting as an intracellular reductase, thioredoxin promotes cellular proliferation to alleviate oxidative stress. Besides reducing activity, thioredoxin inhibit apoptosis through direct binding to apoptosis signal regulating kinase-1 (ASK-1). Thioredoxin is essential for early differentiation and morphogenesis of mouse embryo. Thioredoxin-transgenic (TRX-TG) mice are more resistant to oxidative stress and survive longer than normal mice.
Extracellular thioredoxin shows cytokine or chemokine-like effects. It was reported to show mitogenic effects on leukemia cells, which is also dependent on the presence of reducing agents like 2-ME, and the intact active di-thiol site. It was also reported to show cytoprotective effects through suppressing the production of some inflammatory cytokines. Chemotactic effects of thioredoxin was also observed which may be immune cell type specific and dose dependent since TRX in higher concentration (>1 microg/ml) in circulation shows anti-chemotactic effects. How extracellular thioredoxin interacts with potential target proteins at the plasma membrane may be a key for clarifying the complicated mechanisms.
Several TRX-binding proteins have been identified so far. Reduced TRX in cytosol can bind ASK-1, which activate c-Jun N-terminal kinase (JNK) and p38 MAPK kinase pathway and is required for TNF-a-induced apoptosis. TRX also regulates transcription factor by interaction with redox factor 1 (Ref-1), which has a reducing activity and apurine/apyrimidine endonuclease repair activity. TRX was also reported to bind conserved DNA binding domain of glucocorticoid receptor under oxidative conditions to regulate nuclear receptor-mediated signal transduction. More well-known binding partner of TRX is thioredoxin binding protein-2 (TBP-2/TXNIP/VDUP-1). TBP-2 can downregulate the expression and the reducing activity of TRX. TBP-2 shows potent growth suppressive effect and until recently it was reported to be a metabolic mediator of lipid and glucose metabolisms. All these findings suggest that TRX/TBP-2 binding may regulate redox and metabolic responses in vivo.

Homology

Thioredoxin is ubiquitously expressed in different organisms. Chicken, mouse, rat and bovine TRXs have also been cloned. Human and other mammalian TRXs contain, in addition to the two cysteins in Trp-Cys32-Gly-Pro-Cys35-Lys, three other Cys redidues, Cys62, Cys69, and Cys73 (numbers are based on human TRX), which are not found in TRX of bacterial origins. The C-terminal Cys73 residue of mammalian TRX is shown to be involved in dimmer formation.
Proteins sharing the similar active sites Cys-Xxx-Yyy-Cys, are called as members of TRX superfamily. TRX-2 is one homologous protein of TRX, which also contains Cys-Gly-Pro-Cys active site. However, TRX-2 is located in mitochondrial with extra N-terminal mitochondrial translocation signal peptide. TRX2 may play an important role in the mitochondria-mediated apotosis. Other TRX superfamilly proteins consist of MIF (macrophage migration inhibitory factor), PDI (protein disulfide isomerase), TMX, glutaredoxin, nucleoredoxin, etc... These proteins have different redox-relative functions in respective cellular compartment.

Implicated in

Entity name
Various cancers
Note
Elevated expression of thioredoxin was reported in various human cancers, including hepatocellular carcinoma, pancreatic, lung, cervical, gastric, colorectal cancer, Adult T cell Leukemia, myeloma, non-Hodgkin lymphoma, and acute lymphocytic leukemia. The overexpression of TRX in cancer cells seems to be associated with the growth promotion of cancer cells, a worse prognosis for patients, and the development of resistance to anti-cancer agents.
However, there is no evidence showing that exogenously administered rhTRX promotes the growth of cancer, although exogenous rhTRX may alleviate local or systemic inflammatory disorders in these cancer patients.
Prognosis
In non-small cell lung carcinomas, intracellular TRX expression is indicative of a more aggressive tumor phenotype and worse prognosis.
Oncogenesis
Unknown
Entity name
Adult T cell leukemia (ATL), acquired immunodeficiency syndrome (AIDS), hepatitis C virus (HCV), originated from virus infection
Note
As mentioned above, human thioredoxin was first cloned as a secreted adult T cell leukemia (ATL) derived factor. Its expression is markedly enhanced in HTLV-I-infected T cells.
The elevated level of plasma thioredoxin was reported in AIDS patients with worse prognosis and inversely correlated with intracellular glutathion level.
In hepatitis C virus infection, serum levels of TRX is also elevated. The serum TRX levels of patients with HCV infection increased with their serum ferritin levels and the progression of liver fibrosis. Furthermore, serum thioredoxin and ferritin are good markers for the efficacy of interferon therapy.
Prognosis
As above, the plasma or serum level of thioredoxin is a good marker for oxidative stress associated with virus infection, so as to be possibily used in clinics.
Oncogenesis
Unknown.

Bibliography

Pubmed IDLast YearTitleAuthors
125336102003Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells.Bai J et al
113706652001Alternative splicing is associated with decreased expression of the redox proto-oncogene thioredoxin-1 in human cancers.Berggren MM et al
145971762003Thioredoxin-mediated redox control of the transcription factor Sp1 and regulation of the thioredoxin gene promoter.Bloomfield KL et al
80864741994Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3.Chen KS et al
80492541994The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors.Gasdaska PY et al
176274682007Cell-surface thioredoxin-1: possible involvement in thiol-mediated leukocyte-endothelial cell interaction through lipid rafts.Hara T et al
156235052005Identification and characterization of a novel thioredoxin-related transmembrane protein of the endoplasmic reticulum.Haugstetter J et al
91080291997AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1.Hirota K et al
104881361999Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB.Hirota K et al
120749722002Thioredoxin superfamily and thioredoxin-inducing agents.Hirota K et al
74763541995Thioredoxin and thioredoxin reductase.Holmgren A et al
26682781989Thioredoxin and glutaredoxin systems.Holmgren A et al
124466772003JPDI, a novel endoplasmic reticulum-resident protein containing both a BiP-interacting J-domain and thioredoxin-like motifs.Hosoda A et al
81440371994Genomic cloning of human thioredoxin-encoding gene: mapping of the transcription start point and analysis of the promoter.Kaghad M et al
176979312007Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome.Kaimul AM et al
115956992001Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer.Kakolyris S et al
126608212003Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response.Kim YC et al
80020311994Detection of adult T-cell leukemia-derived factor/human thioredoxin in human serum.Kitaoka Y et al
102158931999Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81Ser MIF.Kleemann R et al
169870402006Redox regulation of human thioredoxin network.Kondo N et al
91193701997Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin.Kurooka H et al
142454001964ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEOTIDES. IV. ISOLATION AND CHARACTERIZATION OF THIOREDOXIN, THE HYDROGEN DONOR FROM ESCHERICHIA COLI B.LAURENT TC et al
147133332004Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.Mahmood S et al
99158581999Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function.Makino Y et al
158183952005The thioredoxin system in retroviral infection and apoptosis.Masutani H et al
15086661992Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62.Matthews JR et al
126261252003Redox control on the cell surface: implications for HIV-1 entry.Matthias LJ et al
170952462006Extracellular thioredoxin and thioredoxin-binding protein 2 in control of cancer.Nakamura H et al
104194731999Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression.Nishiyama A et al
186365072008Thioredoxin and thioredoxin binding protein 2 in the liver.Okuyama H et al
174724352007TXNIP regulates peripheral glucose metabolism in humans.Parikh H et al
13329471992Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway.Rubartelli A et al
125691072003Characterization of human thioredoxin-like 2. A novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme.Sadek CM et al
95640421998Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.Saitoh M et al
85438311996Thioredoxin as a potent costimulus of cytokine expression.Schenk H et al
112596422001Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems.Sun QA et al
27859191989ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction.Tagaya Y et al
87590061996A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene.Taniguchi Y et al
29782231985Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression.Teshigawara K et al
21729791990Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2.Wakasugi N et al
164072242006Control of mitochondrial outer membrane permeabilization and Bcl-xL levels by thioredoxin 2 in DT40 cells.Wang D et al
128169472003Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif.Watson WH et al
111180542000Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation.Wei SJ et al
31705951988Cloning and expression of a cDNA for human thioredoxin.Wollman EE et al

Other Information

Locus ID:

NCBI: 7295
MIM: 187700
HGNC: 12435
Ensembl: ENSG00000136810

Variants:

dbSNP: 7295
ClinVar: 7295
TCGA: ENSG00000136810
COSMIC: TXN

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000136810ENST00000374515P10599
ENSG00000136810ENST00000374517P10599
ENSG00000136810ENST00000374517H9ZYJ2

Expression (GTEx)

0
500
1000
1500

Pathways

PathwaySourceExternal ID
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Metabolism of proteinsREACTOMER-HSA-392499
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
InflammasomesREACTOMER-HSA-622312
The NLRP3 inflammasomeREACTOMER-HSA-844456
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Metabolic GenesREACTOMER-HSA-5628897
MetabolismREACTOMER-HSA-1430728
Metabolism of nucleotidesREACTOMER-HSA-15869
Synthesis and interconversion of nucleotide di- and triphosphatesREACTOMER-HSA-499943
Cellular responses to stressREACTOMER-HSA-2262752
Detoxification of Reactive Oxygen SpeciesREACTOMER-HSA-3299685
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
Protein repairREACTOMER-HSA-5676934
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA33723PRDX2GenePathwayassociated23913015
PA37093TXNRD1GenePathwayassociated23913015

References

Pubmed IDYearTitleCitations
184972922008Regulated protein denitrosylation by cytosolic and mitochondrial thioredoxins.206
121892052002The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin.152
151287452004Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein.115
167667962006The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange.101
128169472003Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif.98
122443252002Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69.88
177240812007Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
121194012002Glutathionylation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems.74
195926182009Activation of the AMPK-FOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin.69

Citation

Zhe Chen ; Eiji Yoshihara ; Hajime Nakamura ; Hiroshi Masutani ; Junji Yodoi

TXN (thioredoxin)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/44354/txn