| Note | Human PRDX4 gene encodes 271 amino acids. It may present in biological system as dimeric and decameric state. The presence of dimeric or decameric state of Prx-4 may be redox regulated (Wood et al., 2002). The crystal structure of the decameric Prx-4 has been resolved. It is also noteworthy that Prx-4 forms heterodimer or multimer with other Prx isoforms. |
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| | Crystal structure of human peroxiredoxin 4 (PDB 2PN8). |
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| Description | Peroxiredoxin 4 is an antioxidant enzyme that belongs to the peroxiredoxin family. The peroxiredoxin family of proteins scavenges hydrogen peroxide and plays a critical role in cellular response to oxidative stress and intracellular signal transduction. |
| Expression | Peroxiredoxin 4 is abundantly expressed in pancreas, liver and heart. It is also expressed in blood, leukocyte and brain (Schulte, 2011). |
| Localisation | Prx-4 is mainly localized in the endoplasmic reticulum (ER), but is also present in the cytosol, lysosome, nucleus, or secreted (Leyens et al., 2003). |
| Function | The antioxidant property of Prx-4 may play an essential role in the redox balance in the ER. The Cysteine residue of Prx-4 is first oxidized to sulfenic acid form and then forms intermolecular disulfide bond with another Prx molecule, which can be reversed by the reducing activity of the thioredoxin-thioredoxin reductase system. Under oxidative stress conditions, however, the Cysteine of Prx-4 undergoes further oxidation to sulfinic/sulfonic acid forms which can only be reduced by sulfiredoxin (Jeong et al., 2012). The hyperoxidized (or overoxidized) form of Prx-4 loses its antioxidant property but may function as molecular chaperone to facilitate protein folding (Rhee and Woo, 2011; Zito et al., 2010). The Prx-4 has also been shown to mediate multiple cell signaling pathways including the phosphorylation of p38α, JNK1/JNK2, GSK3α/GSK3β, MEK1/MEK2, MSK1/MSK2, AMPKα, HSP27, Src, Fyn, etc. |
| Homology | As in other typical 2-Cys peroxiredoxins, Prdx4 also contains a peroxidatic Cysteine and a resolving Cysteine that is separated by 121 amino acids. The overall sequence homology of Prx-4 with other 2-Cys Prx is at least 56% or higher. In particular, sequences surrounding both cysteine residues are highly conserved which may indicate the importance of those motifs for the activity of Prx family of proteins. |
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| Entity | Lung cancer |
| Note | Prx-4 along with sulfiredoxin plays very important role in tumor progression and metastasis in lung cancer. The expression of Prx-4 is at least 1.5 fold higher in tumor cells compared to control and this finding applies most frequently to adenocarcinoma and to little bit modestly to squamous cell carcinoma (Lehtonen et al., 2004). Alteration in expression of Prx-4 results in alteration in rate of tumor progression and metastasis which is indicated by anchorage independent colony formation, cell migration and invasion of human lung cancer cells (Wei et al., 2011). This ability of Prx-4 to promote tumor progression and metastasis is supposed to be due to its antioxidant properties. Same study has also shown role of Srx-Prx-4 axis in activation of intracellular phosphokinase signaling including AP-1/MMP-9 axis and MAPK signaling. |
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| Entity | Leukemia |
| Note | Alteration of Prx-4 expression is proposed to play a role in development of different types of leukemia. In acute myeloid leukemia (AML) patients, the PRDX4 gene is fused with the AML1 gene between exon 5 and 6 of AML1 and exon 2 of Prdx4 (Zhang et al., 2004). This fusion of AML1 gene with the Prdx4 gene is supposed to play a role in altered expression of Prdx 4 in acute myeloid leukemia. In another study, researchers have found that the alteration in genomic sequence and expression level of Prdx4 is rare in acute myeloid leukemia but have found strong reduction in Prdx4 expression in acute promyelocytic leukemia (APL) (Palande et al., 2011). This study has suggested that due to alteration in Prdx4 expression, the signal transduction from a myeloid growth factor receptor i.e. the granulocyte colony stimulating factor receptor is affected. This study have also found the role of histone methylation in transcriptional silencing of Prdx4 in APL. |
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| Entity | Glioblastoma multiforme (GBM) |
| Note | Prx-4 is supposed to play a role in most aggressive primary brain malignancy i.e. glioblastoma multiforme (Kim et al., 2012). Kim TH et al. have found in this study that the knockdown of Prx-4 results in reduced cell growth and radiation resistance along with increase ROS level, DNA damage and apoptosis in in-vitro models. This study suggests the importance of Prx-4 in radiation resistance and tumor maintenance of GBM. It also proposes the Prx-4 as an important therapeutic target in this disorder which can be persuaded for drug discovery and may result in development of some anti-GBM chemotherapeutic drug in future. |
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| Entity | Oral cavity squamous cell carcinoma (OSCC) |
| Note | Prx-4 is also studied for its role in tumor progression, cell migration and invasiveness in oral cavity squamous cell carcinoma (Chang et al., 2011). This study proposes that the Prx-4 can act as a good tumor prognostic factor as it is highly overexpressed in OSCC. Along with the prognostic value of Prx-4 suggested in paper, the Prx-4 can also be a good therapeutic target in OSCC by virtue of its ability to mediate cell migration and/or metastasis. The attributes of Prx-4 leading to OSCC should at least be partially due its ability to manage oxidative stress. |
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| Entity | Cardiovascular diseases |
| Note | Oxidative stress is considered to play major role in the pathological remodeling of arterial wall (Martin-Ventura et al., 2012). As it is an antioxidant protein, the Prx-4 expression level increases in variety of oxidative stress conditions. Also, Prx-4 is secreted into extracellular environment; therefore, its plasma concentration may be used as a molecular indicator of various cardiovascular disease and other disorders involving oxidative stress. The increased serum Prx-4 concentration is considered as a good indicator of risk to cardiovascular disease (Abbasi et al., 2012) because cardiovascular disease have higher level of oxidative stress and Prx-4 is over-expressed in these conditions. |
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| Entity | Hepatic disease |
| Note | Prx-4 has the ability to act as a hepato-protective protein due to its ability to act as an antioxidant protein, by virtue of which Prx-4 can protect the hepatic tissue against the Hydrogen peroxide as well as other reactive oxygen species causing oxidative stress. A study in rat model of Wilson's disease has demonstrated that this disease have lower level of Prx-4 expression as compared to normal (Ito et al., 2012). The same study has proposed that Prx-4 can be used as a potential biomarker of hepatic diseases as the Prx-4 serum concentration in this model was found to be quite low. |
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| Entity | Non-canonical scurvy |
| Note | Genomic loss of Prx-4 in mice results in testicular atrophy due to elevated spermatogenic cell death (Iuchi et al., 2009). Depletion of Prx-4 along with ER specific thiol oxidases ERO1α and ERO1β lead to non-canonical scurvy in mice (Zito et al., 2012), which suggests that Prx-4 and other ER thiol oxidases may be critical for protein folding and disulfide bond formation in the ER. In this sense, Prx-4 may also be considered as an alternative to ERO1α and ERO1β in higher organisms (Zito et al., 2010). |
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| Entity | Inflammatory disease |
| Note | Prx-4 is a secretory antioxidant protein which can be detected in plasma. By virtue of its antioxidant activity, the extracellular Prx-4 can protect the vascular tissue against reactive oxygen species and hence, it has ability to inhibit the oxidative stress induced inflammation in various tissues and it can also reduce the chances of oxidative stress induced diabetes mellitus in animal models (Yamada et al., 2012). |
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| Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality. |
| Abbasi A, Corpeleijn E, Postmus D, Gansevoort RT, de Jong PE, Gans RO, Struck J, Schulte J, Hillege HL, van der Harst P, Peelen LM, Beulens JW, Stolk RP, Navis G, Bakker SJ. |
| J Am Heart Assoc. 2012 Oct;1(5):e002956. doi: 10.1161/JAHA.112.002956. Epub 2012 Oct 25. |
| PMID 23316297 |
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| Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology. |
| Chang KP, Yu JS, Chien KY, Lee CW, Liang Y, Liao CT, Yen TC, Lee LY, Huang LL, Liu SC, Chang YS, Chi LM. |
| J Proteome Res. 2011 Nov 4;10(11):4935-47. doi: 10.1021/pr200311p. Epub 2011 Sep 28. |
| PMID 21859152 |
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| Measurement of peroxiredoxin-4 serum levels in rat tissue and its use as a potential marker for hepatic disease. |
| Ito R, Takahashi M, Ihara H, Tsukamoto H, Fujii J, Ikeda Y. |
| Mol Med Rep. 2012 Aug;6(2):379-84. doi: 10.3892/mmr.2012.935. Epub 2012 Jun 6. |
| PMID 22684688 |
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| Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress. |
| Iuchi Y, Okada F, Tsunoda S, Kibe N, Shirasawa N, Ikawa M, Okabe M, Ikeda Y, Fujii J. |
| Biochem J. 2009 Apr 1;419(1):149-58. doi: 10.1042/BJ20081526. |
| PMID 19105792 |
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| Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression. |
| Jeong W, Bae SH, Toledano MB, Rhee SG. |
| Free Radic Biol Med. 2012 Aug 1;53(3):447-56. doi: 10.1016/j.freeradbiomed.2012.05.020. Epub 2012 May 24. (REVIEW) |
| PMID 22634055 |
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| Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth. |
| Kim TH, Song J, Alcantara Llaguno SR, Murnan E, Liyanarachchi S, Palanichamy K, Yi JY, Viapiano MS, Nakano I, Yoon SO, Wu H, Parada LF, Kwon CH. |
| PLoS One. 2012;7(8):e42818. doi: 10.1371/journal.pone.0042818. Epub 2012 Aug 15. |
| PMID 22916164 |
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| Peroxiredoxins, a novel protein family in lung cancer. |
| Lehtonen ST, Svensk AM, Soini Y, Paakko P, Hirvikoski P, Kang SW, Saily M, Kinnula VL. |
| Int J Cancer. 2004 Sep 10;111(4):514-21. |
| PMID 15239128 |
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| Cloning of bovine peroxiredoxins-gene expression in bovine tissues and amino acid sequence comparison with rat, mouse and primate peroxiredoxins. |
| Leyens G, Donnay I, Knoops B. |
| Comp Biochem Physiol B Biochem Mol Biol. 2003 Dec;136(4):943-55. |
| PMID 14662316 |
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| Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: detoxifying mechanisms and potential therapeutic options. |
| Martin-Ventura JL, Madrigal-Matute J, Martinez-Pinna R, Ramos-Mozo P, Blanco-Colio LM, Moreno JA, Tarin C, Burillo E, Fernandez-Garcia CE, Egido J, Meilhac O, Michel JB. |
| Thromb Haemost. 2012 Sep;108(3):435-42. doi: 10.1160/TH12-04-0248. Epub 2012 Jul 26. (REVIEW) |
| PMID 22836558 |
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| The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia. |
| Palande KK, Beekman R, van der Meeren LE, Beverloo HB, Valk PJ, Touw IP. |
| PLoS One. 2011 Jan 20;6(1):e16340. doi: 10.1371/journal.pone.0016340. |
| PMID 21283726 |
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| Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger Hv(2)Ov(2), and protein chaperones. |
| Rhee SG, Woo HA. |
| Antioxid Redox Signal. 2011 Aug 1;15(3):781-94. doi: 10.1089/ars.2010.3393. Epub 2011 Mar 31. (REVIEW) |
| PMID 20919930 |
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| Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration. |
| Schulte J. |
| BMC Med. 2011 Dec 23;9:137. doi: 10.1186/1741-7015-9-137. |
| PMID 22196027 |
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| Sulfiredoxin-Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling. |
| Wei Q, Jiang H, Xiao Z, Baker A, Young MR, Veenstra TD, Colburn NH. |
| Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7004-9. doi: 10.1073/pnas.1013012108. Epub 2011 Apr 12. |
| PMID 21487000 |
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| Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins. |
| Woo HA, Jeong W, Chang TS, Park KJ, Park SJ, Yang JS, Rhee SG. |
| J Biol Chem. 2005 Feb 4;280(5):3125-8. Epub 2004 Dec 8. |
| PMID 15590625 |
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| Dimers to doughnuts: redox-sensitive oligomerization of 2-cysteine peroxiredoxins. |
| Wood ZA, Poole LB, Hantgan RR, Karplus PA. |
| Biochemistry. 2002 Apr 30;41(17):5493-504. |
| PMID 11969410 |
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| Peroxiredoxin 4: critical roles in inflammatory diseases. |
| Yamada S, Ding Y, Sasaguri Y. |
| J UOEH. 2012 Mar 1;34(1):27-39. (REVIEW) |
| PMID 22428456 |
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| PRDX4, a member of the peroxiredoxin family, is fused to AML1 (RUNX1) in an acute myeloid leukemia patient with a t(X;21)(p22;q22). |
| Zhang Y, Emmanuel N, Kamboj G, Chen J, Shurafa M, Van Dyke DL, Wiktor A, Rowley JD. |
| Genes Chromosomes Cancer. 2004 Aug;40(4):365-70. |
| PMID 15188461 |
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| Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice. |
| Zito E, Hansen HG, Yeo GS, Fujii J, Ron D. |
| Mol Cell. 2012 Oct 12;48(1):39-51. doi: 10.1016/j.molcel.2012.08.010. Epub 2012 Sep 13. |
| PMID 22981861 |
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| Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin. |
| Zito E, Melo EP, Yang Y, Wahlander A, Neubert TA, Ron D. |
| Mol Cell. 2010 Dec 10;40(5):787-97. doi: 10.1016/j.molcel.2010.11.010. |
| PMID 21145486 |
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