G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
peroxiredoxin 2
G00000437 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000134285 (Vega human gene)
ENSG00000167815 (Ensembl human gene)
7001 (Entrez Gene)
116 (G2Cdb plasticity & disease)
PRDX2 (GeneCards)
600538 (OMIM)
Marker Symbol
HGNC:9353 (HGNC)
Protein Sequence
P32119 (UniProt)

Synonyms (6)

  • MGC4104
  • PRP
  • PRX2
  • TSA

Literature (59)

Pubmed - other

  • Low 8-oxo-7,8-dihydro-2'-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic.

    Engström KS, Vahter M, Lindh C, Teichert F, Singh R, Concha G, Nermell B, Farmer PB, Strömberg U and Broberg K

    Department of Laboratory Medicine, Lund University Hospital, Lund, Sweden. Karin.engstrom@med.lu.se

    Background: Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors.

    Objectives: To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG.

    Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied.

    Results: Median concentration of 8-oxodG was 4.7 nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7 microg/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290 microg/L (range 94-720; 380 microg/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX).

    Conclusion: Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations.

    Mutation research 2010;683;1-2;98-105

  • Chloramines and hypochlorous acid oxidize erythrocyte peroxiredoxin 2.

    Stacey MM, Peskin AV, Vissers MC and Winterbourn CC

    Department of Pathology, University of Otago at Christchurch, Christchurch 8140, New Zealand.

    Peroxiredoxin 2 (Prx2) is an abundant thiol protein that is readily oxidized in erythrocytes exposed to hydrogen peroxide. We investigated its reactivity in human erythrocytes with hypochlorous acid (HOCl) and chloramines, relevant oxidants in inflammation. Prx2 was oxidized to a disulfide-linked dimer by HOCl, glycine chloramine (GlyCl), and monochloramine (NH(2)Cl) in a dose-dependent manner. In the absence of added glucose, Prx2 and GSH showed similar sensitivities. Second-order rate constants for the reactions of Prx2 with NH(2)Cl and GlyCl were 1.5 x 10(4) and 8 M(-1) s(-1), respectively. The NH(2)Cl value is approximately 10 times higher than that for GSH, whereas Prx2 is approximately 30 times less sensitive than GSH to GlyCl. Thus, the relative sensitivity of Prx2 to GlyCl is greater in the erythrocyte. Oxidation of erythrocyte Prx2 and GSH was less in the presence of glucose, probably because of recycling. High doses of NH(2)Cl resulted in incomplete regeneration of reduced Prx2, suggesting impairment of the recycling mechanism. Our results show that, although HOCl and chloramines are less selective than H(2)O(2), they nevertheless oxidize Prx2. Exposure to these inflammatory oxidants will result in Prx2 oxidation and could compromise the erythrocyte's ability to resist damaging oxidative insult.

    Free radical biology & medicine 2009;47;10;1468-76

  • Deglutathionylation of 2-Cys peroxiredoxin is specifically catalyzed by sulfiredoxin.

    Park JW, Mieyal JJ, Rhee SG and Chock PB

    Laboratory of Biochemistry, Biochemistry and Biophysics Center, Division of Intramural Research, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-8012, USA.

    Reversible protein glutathionylation plays a key role in cellular regulation and cell signaling and protects protein thiols from hyperoxidation. Sulfiredoxin (Srx), an enzyme that catalyzes the reduction of Cys-sulfinic acid derivatives of 2-Cys peroxiredoxins (2-Cys Prxs), has been shown to catalyze the deglutathionylation of actin. We show that deglutathionylation of 2-Cys Prx, a family of peroxidases, is specifically catalyzed by Srx. Using the ubiquitously expressed member of 2-Cys Prx, Prx I, we revealed the following. (i) Among its four Cys residues, Cys(52), Cys(83), and Cys(173) can be glutathionylated in vitro. Deglutathionylation with Cys mutants showed that Cys(83) and Cys(173) were preferentially catalyzed by Srx, with glutathionylated Srx as the reaction intermediate, whereas glutaredoxin I was more favorable for deglutathionylating Cys(52). (ii) Studies using site-directed mutagenesis coupled with binding and deglutathionylation activities revealed that Pro(174) and Pro(179) of Prx I and Tyr(92) of Srx are essential for both activities. Furthermore, relative to glutaredoxin I, Srx exhibited negligible deglutathionylation activity for glutathionylated cysteine and glutathionylated BSA. These results indicate that Srx is specific for deglutathionylating Prx I due to its favorable affinity for Prx I. To assess the biological relevance of these observations, we showed that Prx I is glutathionylated in A549 and HeLa cells under modest levels of H(2)O(2). In addition, the level of glutathionylated Prx I was substantially elevated in small interfering RNA-mediated Srx-knocked down cells, whereas the reverse was observed in Srx-overexpressing cells. However, glutathionylation of Prx V, not known to bind to Srx, was not affected by the change in Srx expression levels.

    Funded by: Intramural NIH HHS; NIA NIH HHS: 2 PO1 AG 15885, P01 AG015885

    The Journal of biological chemistry 2009;284;35;23364-74

  • The malarial parasite Plasmodium falciparum imports the human protein peroxiredoxin 2 for peroxide detoxification.

    Koncarevic S, Rohrbach P, Deponte M, Krohne G, Prieto JH, Yates J, Rahlfs S and Becker K

    Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.

    Coevolution of the malarial parasite and its human host has resulted in a complex network of interactions contributing to the homeodynamics of the host-parasite unit. As a rapidly growing and multiplying organism, Plasmodium falciparum depends on an adequate antioxidant defense system that is efficient despite the absence of genuine catalase and glutathione peroxidase. Using different experimental approaches, we demonstrate that P. falciparum imports the human redox-active protein peroxiredoxin 2 (hPrx-2, hTPx1) into its cytosol. As shown by confocal microscopy and immunogold electron microscopy, hPrx-2 is also present in the Maurer's clefts, organelles that are described as being involved in parasite protein export. Enzyme kinetic analyses prove that hPrx-2 accepts Plasmodium cytosolic thioredoxin 1 as a reducing substrate. hPrx-2 accounts for roughly 50% of thioredoxin peroxidase activity in parasite extracts, thus indicating a functional role of hPrx-2 as an enzymatic scavenger of peroxides in the parasite. Under chloroquine treatment, a drug promoting oxidative stress, the abundance of hPrx-2 in the parasite increases significantly. P. falciparum has adapted to adopt the hPrx-2, thereby using the host protein for its own purposes.

    Funded by: NIAID NIH HHS: 1 R21 AI072615-01, R21 AI072615

    Proceedings of the National Academy of Sciences of the United States of America 2009;106;32;13323-8

  • Identification of a new panel of serum autoantibodies associated with the presence of in situ carcinoma of the breast in younger women.

    Desmetz C, Bascoul-Mollevi C, Rochaix P, Lamy PJ, Kramar A, Rouanet P, Maudelonde T, Mangé A and Solassol J

    Department of Cellular Biology, Hôpital Arnaud de Villeneuve, CHU Montpellier, Montpellier 34000, France.

    Purpose: We examined the feasibility of using a panel of autoantibodies to multiple tumor-associated proteins as a method for early detection of breast cancer and, more particularly, carcinoma in situ (CIS).

    PPIA, PRDX2, and FKBP52 were identified as early-stage breast cancer autoantigens by proteomic approaches. The seroreactivity of a panel of antibodies consisting of these three antigens and two previously described autoantigens, HSP60 and MUC1, was tested on 235 samples (60 from primary breast cancer patients, 82 from CIS patients, and 93 from healthy controls) with the use of specific ELISAs. FKBP52, PPIA, and PRDX2 mRNA and protein expression levels were evaluated by reverse transcription-PCR and immunohistochemistry in early-stage breast tumors.

    Results: Three of five autoantibodies, FKBP52, PPIA, and PRDX2, showed significantly increased reactivity in primary breast cancer and CIS compared with healthy controls. When combined, the five markers significantly discriminated primary breast cancer [receiver operating characteristic area under the curve, 0.73; 95% confidence interval (95% CI), 0.60-0.79] and CIS (receiver operating characteristic area under the curve, 0.80; 95% CI, 0.71-0.85) from healthy individuals. Importantly, the receiver operating characteristic-area under the curve value of the autoantibody panel was able to distinguish CIS, including high grades, from healthy controls in women under the age of 50 years (receiver operating characteristic area under the curve, 0.85; 95% CI, 0.61-0.92). Finally, only FKBP52 mRNA and protein levels were found to be increased in CIS and primary breast cancer compared with healthy breast tissue.

    Conclusions: This autoantibody assay against a panel of five antigens allows for an accurate discrimination between early-stage breast cancer, especially CIS, and healthy individuals. These results could be of interest in detecting early breast cancer as an aid to mammography, especially in women under the age of 50 years with aggressive cancers.

    Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15;14;4733-41

  • Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.

    Schläwicke Engström K, Nermell B, Concha G, Strömberg U, Vahter M and Broberg K

    Department of Laboratory Medicine, Section of Occupational and Environmental Medicine, Lund University, Lund, Sweden. Karin.engstrom@med.lu.se

    Objectives: The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism.

    Methods: We evaluated the association between urinary metabolite pattern and polymorphisms in three gene-groups related to arsenic metabolism: (1) methyltransferases, (2) other genes involved in one-carbon metabolism and (3) genes involved in reduction reactions. Forty-nine polymorphisms were successfully genotyped in indigenous women (N=104) from northern Argentina, exposed to approximately 200 microg/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA).

    Results: Genetic factors affecting arsenic metabolite pattern included two polymorphisms in arsenic (+III) methyltransferase (AS3MT) (rs3740400, rs7085104), where carriers had lower %MMA and higher %DMA. These single nucleotide polymorphisms (SNPs) were in strong linkage disequilibrium (LD) with three intronic AS3MT SNPs, previously reported to be associated with arsenic metabolism, indicating the existence of a strongly methylating, population-specific haplotype. The CYP17A1 rs743572, 27kilobasepairs (kbs) upstream of AS3MT, was in strong LD with the AS3MT SNPs and thus had similar effects on the metabolite profile. Smaller effects were also seen for one-carbon metabolism genes choline dehydrogenase (CHDH) (rs9001, rs7626693) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) (rs1801394) and genes involved in reduction reactions, glutaredoxin (GLRX) (rs3822751) and peroxiredoxin 2 (PRDX2) (rs10427027, rs12151144). Genotypes associated with more beneficial arsenic metabolite profile (low %MMA and/or high %DMA in urine) were more common in this population, which has been exposed to arsenic in drinking water for thousands of years.

    Conclusions: Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism.

    Mutation research 2009;667;1-2;4-14

  • Expression of human peroxiredoxin isoforms in response to cervical carcinogenesis.

    Kim K, Yu M, Han S, Oh I, Choi YJ, Kim S, Yoon K, Jung M and Choe W

    Department of Biochemistry and Molecular biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyunghee University School of Medicine, Seoul 130-701, Korea.

    Despite considerable progress in understanding the function of peroxiredoxin (Prx) in cancer, its expression patterns have not been extensively studied in response to cervical carcinogenesis. We evaluated the expression of Prx isoforms in normal tissue, cervical intraepithelial neoplasia (CIN1, CIN2, and CIN3), and cervical cancer. We found strong pattern of increased Prx II and III immunostaining with increasing severity of the lesion. No difference in staining intensity by grade of lesion was observed for Prx I, and IV. Therefore, we conclude that Prx II and III are upregulated in response to the development of cervical cancer.

    Oncology reports 2009;21;6;1391-6

  • Nipradilol and timolol induce Foxo3a and peroxiredoxin 2 expression and protect trabecular meshwork cells from oxidative stress.

    Miyamoto N, Izumi H, Miyamoto R, Kubota T, Tawara A, Sasaguri Y and Kohno K

    Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.

    Purpose: Oxidative stress plays an important role in pathogenesis of glaucoma. The purpose of this study is to investigate the novel effect of antiglaucoma drugs on the expression of antioxidant peroxiredoxins of trabecular meshwork (TM) cells.

    Methods: The expression of the peroxiredoxin family was investigated using immortalized TM cell lines. Cells were treated with antiglaucoma drugs and analyzed for the expression of peroxiredoxin, and cellular sensitivity to oxidative stress. Furthermore, the effect of antiglaucoma drugs on the molecular regulation of the expression of peroxiredoxin was examined using a reporter assay and siRNA strategy.

    Results: Glaucomatous TM cells highly express peroxiredoxin 2 when compared with normal TM cells. Nipradilol and timolol, but not latanoprost, induce the expression of peroxiredoxin 2 through the activation of the Foxo3a transcription factor. TM cells showed reduced sensitivity to H(2)O(2) when cells were treated with either nipradilol or timolol, but not with latanoprost. In addition, both Foxo3a and PRDX2 expression were enhanced by drug-induced signal transduction through its receptor.

    Conclusions: These results indicate that both nipradilol and timolol possess a novel mechanism of action and function as potent protective agents against oxidative stress.

    Investigative ophthalmology & visual science 2009;50;6;2777-84

  • Novel protective mechanism against irreversible hyperoxidation of peroxiredoxin: Nalpha-terminal acetylation of human peroxiredoxin II.

    Seo JH, Lim JC, Lee DY, Kim KS, Piszczek G, Nam HW, Kim YS, Ahn T, Yun CH, Kim K, Chock PB and Chae HZ

    School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea.

    Peroxiredoxins (Prxs) are a group of peroxidases containing a cysteine thiol at their catalytic site. During peroxidase catalysis, the catalytic cysteine, referred to as the peroxidatic cysteine (C(P)), cycles between thiol (C(P)-SH) and disulfide (-S-S-) states via a sulfenic (C(P)-SOH) intermediate. Hyperoxidation of the C(P) thiol to its sulfinic (C(P)-SO(2)H) derivative has been shown to be reversible, but its sulfonic (C(P)-SO(3)H) derivative is irreversible. Our comparative study of hyperoxidation and regeneration of Prx I and Prx II in HeLa cells revealed that Prx II is more susceptible than Prx I to hyperoxidation and that the majority of the hyperoxidized Prx II formation is reversible. However, the hyperoxidized Prx I showed much less reversibility because of the formation of its irreversible sulfonic derivative, as verified with C(P)-SO(3)H-specific antiserum. In an attempt to identify the multiple hyperoxidized spots of the Prx I on two-dimensional PAGE analysis, an N-acetylated Prx I was identified as part of the total Prx I using anti-acetylated Lys antibody. Using peptidyl-Asp metalloendopeptidase (EC peptide fingerprints, we found that N(alpha)-terminal acetylation (N(alpha)-Ac) occurred exclusively on Prx II after demethionylation. N(alpha)-Ac of Prx II blocks Prx II from irreversible hyperoxidation without altering its affinity for hydrogen peroxide. A comparative study of non-N(alpha)-acetylated and N(alpha)-terminal acetylated Prx II revealed that N(alpha)-Ac of Prx II induces a significant shift in the circular dichroism spectrum and elevation of T(m) from 59.6 to 70.9 degrees C. These findings suggest that the structural maintenance of Prx II by N(alpha)-Ac may be responsible for preventing its hyperoxidation to form C(P)-SO(3)H.

    The Journal of biological chemistry 2009;284;20;13455-65

  • The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2.

    Manta B, Hugo M, Ortiz C, Ferrer-Sueta G, Trujillo M and Denicola A

    Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.

    Peroxiredoxin 2 (Prx2) is a 2-Cys peroxiredoxin extremely abundant in the erythrocyte. The peroxidase activity was studied in a steady-state approach yielding an apparent K(M) of 2.4 microM for human thioredoxin and a very low K(M) for H2O2 (0.7 microM). Rate constants for the reaction of peroxidatic cysteine with the peroxide substrate, H2O2 or peroxynitrite, were determined by competition kinetics, k(2) = 1.0 x 10(8) and 1.4 x 10(7) M(-1) s(-1) at 25 degrees C and pH 7.4, respectively. Excess of both oxidants inactivated the enzyme by overoxidation and also tyrosine nitration and dityrosine were observed with peroxynitrite treatment. Prx2 associates into decamers (5 homodimers) and we estimated a dissociation constant K(d) < 10(-23) M(4) which confirms the enzyme exists as a decamer in vivo. Our kinetic results indicate Prx2 is a key antioxidant enzyme for the erythrocyte and reveal red blood cells as active oxidant scrubbers in the bloodstream.

    Archives of biochemistry and biophysics 2009;484;2;146-54

  • Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.

    Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Maccarrone G, Dias-Neto E and Turck CW

    Laboratório de Neurociências, Instituto de Psiquiatria, Universidade de São Paulo, Rua. Dr. Ovidio Pires de Campos, no 785, Consolação, São Paulo, SP 05403-010, Brazil.

    Schizophrenia is a complex disease, likely to be caused by a combination of serial alterations in a number of genes and environmental factors. The dorsolateral prefrontal cortex (Brodmann's Area 46) is involved in schizophrenia and executes high-level functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts and attitudes, correct social behavior and personality expression. Global proteomic analysis of post-mortem dorsolateral prefrontal cortex samples from schizophrenia patients and non-schizophrenic individuals was performed using stable isotope labeling and shotgun proteomics. The analysis resulted in the identification of 1,261 proteins, 84 of which showed statistically significant differential expression, reinforcing previous data supporting the involvement of the immune system, calcium homeostasis, cytoskeleton assembly, and energy metabolism in schizophrenia. In addition a number of new potential markers were found that may contribute to the understanding of the pathogenesis of this complex disease.

    European archives of psychiatry and clinical neuroscience 2009;259;3;151-63

  • Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey.

    Starr JM, Shiels PG, Harris SE, Pattie A, Pearce MS, Relton CL and Deary IJ

    MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Royal Victoria Hospital, Edinburgh EH4 2DN, UK. jstarr@staffmail.ed.ac.uk

    Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans. Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes (GSTZ1, MSRA, NDUFA3, NDUFA8, VIM) had robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs (MSRA rs4841322, p=0.008; NDUFA8 rs6822, p=0.048) on telomere length. These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.

    Funded by: Biotechnology and Biological Sciences Research Council: S18386; Chief Scientist Office: CZB/4/505, ETM/55; Medical Research Council; Wellcome Trust

    Mechanisms of ageing and development 2008;129;12;745-51

  • Decreasing peroxiredoxin II expression decreases glutathione, alters cell cycle distribution, and sensitizes glioma cells to ionizing radiation and H(2)O(2).

    Smith-Pearson PS, Kooshki M, Spitz DR, Poole LB, Zhao W and Robbins ME

    Department of Radiation Oncology and Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

    Glioblastomas are notorious for their resistance to ionizing radiation and chemotherapy. We hypothesize that this resistance to ionizing radiation is due, in part, to alterations in antioxidant enzymes. Here, we show that rat and human glioma cells overexpress the antioxidant enzyme peroxiredoxin II (Prx II). Glioma cells in which Prx II is decreased using shRNA exhibit increased hyperoxidation of the remaining cellular Prxs, suggesting that the redox environment is more oxidizing. Of interest, decreasing Prx II does not alter other antioxidant enzymes (i.e., catalase, GPx, Prx I, Prx III, CuZnSOD, and MnSOD). Analysis of the redox environment revealed that decreasing Prx II increased intracellular reactive oxygen species in 36B10 cells; extracellular levels of H(2)O(2) were also increased in both C6 and 36B10 cells. Treatment with H(2)O(2) led to a further elevation in intracellular reactive oxygen species in cells where Prx II was decreased. Decreasing Prx II expression in glioma cells also reduced clonogenic cell survival following exposure to ionizing radiation and H(2)O(2). Furthermore, lowering Prx II expression decreased intracellular glutathione and resulted in a significant decline in glutathione reductase activity, suggesting a possible mechanism for the observed increased sensitivity to oxidative insults. Additionally, decreasing Prx II expression increased cell cycle doubling times, with fewer cells distributed to S phase in C6 glioma cells and more cells redistributed to the most radiosensitive phase of the cell cycle, G2/M, in 36B10 glioma cells. These findings support the hypothesis that inhibiting Prx II sensitizes glioma cells to oxidative stress, presenting Prxs as potential therapeutic targets.

    Funded by: NCI NIH HHS: CA086862, CA100045, CA110274, CA112593, F31 CA110274, F31 CA110274-01, P30 CA086862, R01 CA100045, R01 CA112593, R01 CA112593-01; NIGMS NIH HHS: GM050389, R01 GM050389

    Free radical biology & medicine 2008;45;8;1178-89

  • Peroxiredoxin II expression and its association with oxidative stress and cell proliferation in human idiopathic pulmonary fibrosis.

    Vuorinen K, Ohlmeier S, Leppäranta O, Salmenkivi K, Myllärniemi M and Kinnula VL

    Pulmonary Division, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    Oxidant burden has been suggested to be a contributor to the pathogenesis of idiopathic pulmonary fibrosis (IPF). The study focused on peroxiredoxin (Prx) II, an antioxidant that has been associated with platelet-derived growth factor (PDGF) signaling and consequent cell proliferation. Localization and expression of Prx II, PDGF receptors (PDGFRalpha, PDGFRbeta), Ki67, and nitrotyrosine were assessed in control (n=10) and IPF/usual interstitial pneumonia (UIP) (n=10) lung biopsies by immunohistochemistry and morphometry. Prx II oxidation was determined by standard and non-reducing Western blots, two-dimensional gel electrophoresis, and mass spectrometry. Prx II localized in the IPF/UIP epithelium and alveolar macrophages. Prx II-positive area in the fibroblastic foci (FF) was smaller than in other parenchymal areas (p=0.03) or in the hyperplastic epithelium (p=0.01). There was no major Prx II oxidation in IPF/UIP compared with the normal lung. The FF showed only minor immunoreactivity to the PDGFRs; Ki67, a marker of cell proliferation; and nitrotyrosine, a marker of oxidative/nitrosative stress. The results suggest that Prx II oxidation does not relate to the pathogenesis of IPF/UIP and that Prx II, PDGFRs, and proliferating cells colocalize in the IPF/UIP lung. Unexpectedly, FF represented areas of low cell proliferation.

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2008;56;10;951-9

  • Identification of intact protein thiosulfinate intermediate in the reduction of cysteine sulfinic acid in peroxiredoxin by human sulfiredoxin.

    Jönsson TJ, Tsang AW, Lowther WT and Furdui CM

    Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

    The reversible oxidation of the active site cysteine in typical 2-Cys peroxiredoxins (Prx) to sulfinic acid during oxidative stress plays an important role in peroxide-mediated cell signaling. The catalytic retroreduction of Prx-SO(2)(-) by sulfiredoxin (Srx) has been proposed to proceed through two novel reaction intermediates, a sulfinic phosphoryl ester and protein-based thiosulfinate. Two scenarios for the repair mechanism have been suggested that differ in the second step of the reaction. The attack of Srx or GSH on the Prx-SO(2)PO(3)(2-) intermediate would result in either the formation of Prx-Cys-S(=O)-S-Cys-Srx or the formation of Prx-Cys-S(=O)-S-G thiosulfinates, respectively. To elucidate the mechanism of Prx repair, we monitored the reduction of human PrxII-SO(2)(-) using rapid chemical quench methodology and electrospray ionization time-of-flight mass spectrometry. An (18)O exchange study revealed that the Prx sulfinic acid phosphoryl ester is rapidly formed and hydrolyzed (k = 0.35 min(-1)). Furthermore, we observed the exclusive formation of a thiosulfinate linkage between Prx and Srx (k = 1.4 min(-1)) that collapses to the disulfide-bonded Srx-Prx species (k = 0.14 min(-1)). Thus, the kinetic and chemical competences of the first two steps in the Srx reaction have been demonstrated. It is clear, however, that GSH may influence thiosulfinate formation and that GSH and Srx may play additional roles in the resolution of the thiosulfinate intermediate.

    Funded by: NCI NIH HHS: R01 CA136810; NIGMS NIH HHS: R01 GM072866, R01GM072866

    The Journal of biological chemistry 2008;283;34;22890-4

  • HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation.

    Parmigiani RB, Xu WS, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P and Marks PA

    Cell Biology and Molecular Biology Programs, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

    Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1-11) and NAD(+)-dependent enzymes (sirtuins 1-7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases alpha-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H(2)O(2) reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to high-molecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.

    Funded by: NCI NIH HHS: P30 CA008748, P30CA08748-41

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;28;9633-8

  • Thermodynamics of the dimer-decamer transition of reduced human and plant 2-cys peroxiredoxin.

    Barranco-Medina S, Kakorin S, Lázaro JJ and Dietz KJ

    Biochemistry and Physiology of Plants, Faculty of Biology-W5, Bielefeld University, 33501 Bielefeld, Germany.

    Isothermal titration calorimetry (ITC) is a powerful technique for investigating self-association processes of protein complexes and was expected to reveal quantitative data on peroxiredoxin oligomerization by directly measuring the thermodynamic parameters of dimer-dimer interaction. Recombinant classical 2-cysteine peroxoredoxins from Homo sapiens, Arabidopsis thaliana, and Pisum sativum as well as a carboxy-terminally truncated variant were subjected to ITC analysis by stepwise injection into the reaction vessel under various redox conditions. The direct measurement of the decamer-dimer equilibrium of reduced peroxiredoxin revealed a critical concentration in the very low micromolar range. The data suggest a cooperative assembly above this critical transition concentration where a nucleus facilitates assembly. The rather abrupt transition indicates that assembly processes do not occur below the critical transition concentration while oligomerization is efficiently triggered above it. The magnitude of the measured enthalpy confirmed the endothermic nature of the peroxiredoxin oligomerization. Heterocomplexes between peroxiredoxin polypeptides from different species were not formed. We conclude that a functional constraint conserved the dimer-decamer transition with highly similar critical transition concentrations despite emerging sequence variation during evolution.

    Biochemistry 2008;47;27;7196-204

  • Decreased expression of peroxiredoxins in Fuchs' endothelial dystrophy.

    Jurkunas UV, Rawe I, Bitar MS, Zhu C, Harris DL, Colby K and Joyce NC

    Schepens Eye Research Institute, Boston, Massachusetts, USA. ula_jurkunas@meei.harvard.edu

    Purpose: To compare the relative expression of peroxiredoxin (Prx) proteins in normal human corneal endothelium with endothelium in corneas affected by Fuchs' endothelial dystrophy (FED) and between normal human endothelium and epithelial/stromal tissue.

    Methods: Human corneal endothelial cell-Descemet's membrane (HCEC-DM) complexes from normal and FED corneal buttons were dissected from the epithelium/stroma. For proteomic analysis, HCEC-DM protein extracts were separated by using two-dimensional gel electrophoresis. Relative differences in protein spot density was analyzed. Proteins of interest, including Prx isoforms, were identified by MALDI-TOF (matrix-assisted desorption ionization-time of flight) mass spectrometry. Western blot analysis compared the relative expression of Prx isoforms in normal and FED endothelium and between normal endothelium and normal epithelium/stroma. Expression of Prx-2 mRNA was compared by using real-time PCR.

    Results: Proteomic analysis identified differences in the relative expression of Prx isoforms between normal and FED endothelium. Western blot analysis confirmed that expression of Prx-2, -3, and -5 was significantly decreased (P < 0.05) in FED cells. Normal HCECs expressed significantly (P < 0.05) higher levels of Prx-2 and -3 than did the epithelium/stroma. Expression of Prx-5 was not significantly different (P > 0.05) in the endothelium versus the epithelium/stroma. Real-time PCR analysis revealed that Prx-2 mRNA was significantly decreased (P = 0.027) in FED samples.

    Conclusions: Prx proteins were identified in human corneal endothelium. The fact that Prx-2 and -3 were expressed at significantly higher levels in HCEC-DM compared with the epithelium/stroma reflects the different physiologic activities of individual corneal cell types. Significantly decreased expression of Prx-2, -3, and -5 in FED may suggest an alteration in the ability of endothelial cells to withstand oxidant-induced damage and may be closely related to the pathogenesis of this disease.

    Funded by: NEI NIH HHS: K12 EY016335, K12 EY016335-02

    Investigative ophthalmology & visual science 2008;49;7;2956-63

  • Presence of cytosolic peroxiredoxin 2 in the erythrocyte membrane of patients with hereditary spherocytosis.

    Rocha S, Vitorino RM, Lemos-Amado FM, Castro EB, Rocha-Pereira P, Barbot J, Cleto E, Ferreira F, Quintanilha A, Belo L and Santos-Silva A

    Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal. susaroc@hotmail.com

    We studied 82 Portuguese individuals, 57 with hereditary spherocytosis (HS) and 25 unaffected controls. We performed standardized diagnosis tests, including electrophoretic membrane protein analysis to identify and quantify protein deficiencies underlying HS. Membrane bound hemoglobin (MBH) and band 3 profiles were determined as oxidative stress and aging markers. A protein of about 22 kDa, present in 21 of 57 HS patients, but not in controls, was identified as peroxiredoxin 2 (Prx2), by mass-spectroscopy and by immunoblotting. Human erythrocyte Prx2 is a peroxiredoxin with thiol-specific antioxidant activity. The presence of Prx2 in erythrocyte membranes was linked to higher levels of oxidative stress, as reflected by significantly increased MBH in those HS patients. No relation with HS clinical severity was observed and Prx2 was detected in all types of membrane protein abnormalities. Prx2 membrane linkage is associated with a higher oxidative stress susceptibility of HS erythrocytes.

    Blood cells, molecules & diseases 2008;41;1;5-9

  • S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's disease.

    Fang J, Nakamura T, Cho DH, Gu Z and Lipton SA

    Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

    Peroxiredoxins (Prx), a family of peroxidases that reduce intracellular peroxides with the thioredoxin system as the electron donor, are highly expressed in various cellular compartments. Among the antioxidant Prx enzymes, Prx2 is the most abundant in mammalian neurons, making it a prime candidate to defend against oxidative stress. Here we report that Prx2 is S-nitrosylated (forming SNO-Prx2) by reaction with nitric oxide at two critical cysteine residues (C51 and C172), preventing its reaction with peroxides. We observed increased SNO-Prx2 in human Parkinson's disease (PD) brains, and S-nitrosylation of Prx2 inhibited both its enzymatic activity and protective function from oxidative stress. Dopaminergic neurons, which are lost in PD, become particularly vulnerable. Thus, our data provide a direct link between nitrosative/oxidative stress and neurodegenerative disorders such as PD.

    Funded by: NEI NIH HHS: R01 EY005477, R01 EY009024, R01 EY05477, R01 EY09024; NICHD NIH HHS: P01 HD029587, P01 HD29587; NINDS NIH HHS: P30 NS057096, R01 NS041207, R01 NS41207

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;47;18742-7

  • Bronchoalveolar lavage fluid proteome in bronchiolitis obliterans syndrome: possible role for surfactant protein A in disease onset.

    Meloni F, Salvini R, Bardoni AM, Passadore I, Solari N, Vitulo P, Oggionni T, Viganò M, Pozzi E and Fietta AM

    Department of Haematological, Pneumological and Cardiovascular Sciences, Section of Pneumology, University of Pavia, Pavia, Italy. f.meloni@smatteo.pv.it

    Background: Bronchiolitis obliterans syndrome (BOS) affects long-term survival of lung transplant (Tx) recipients (LTRs), with no consistently effective treatment strategy. Identifying early markers of BOS is of paramount importance for improving graft survival.

    Methods: We used 2-dimensional gel electrophoresis and protein identification by mass spectrometry to compare the protein profile of bronchoalveolar lavage fluid (BALf) in two groups of LTRs: one composed of patients with BOS and the other composed of patients with good graft function at >5 years post-surgery (stable LTRs). Based on the hypothesis that only proteins of lung origin could represent reliable BOS markers, we also evaluated paired plasma samples. Proteins of interest were also assessed in the BALf of control subjects and results confirmed by dot- blot analysis.

    Results: Among 11 differentially expressed proteins, we identified 2 locally produced factors: peroxiredoxin II (PRXII), exclusively expressed in BOS; and surfactant protein A (SP-A), expressed consistently less in BOS patients than in stable LTRs. PRXII expression was never observed in BALf from control subjects, whereas SP-A was present in higher amounts compared with stable LTRs and BOS patients. Finally, the time course of SP-A was studied in 5 LTRs who subsequently developed BOS. A reduction in BALf SP-A content was detectable early after Tx, preceding BOS onset in 4 of 5 patients.

    Conclusions: Our results suggest that testing SP-A levels in BALf could predict LTR patients who are at higher risk of BOS development.

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2007;26;11;1135-43

  • Human peroxiredoxin 1 and 2 are not duplicate proteins: the unique presence of CYS83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2.

    Lee W, Choi KS, Riddell J, Ip C, Ghosh D, Park JH and Park YM

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

    Human peroxiredoxins 1 and 2, also known as Prx1 and Prx2, are more than 90% homologous in their amino acid sequences. Prx1 and Prx2 are elevated in various cancers and are shown to influence diverse cellular processes. Although their growth regulatory role has traditionally been attributed to the peroxidase activity, the physiological significance of this function is unclear because the proteins are highly susceptible to inactivation by H(2)O(2). A chaperone activity appears to emerge when their peroxidase activity is lost. Structural studies suggest that they may form a homodimer or doughnut-shaped homodecamer. However, little information is available whether human Prx1 and Prx2 are duplicative in structure and function. We noted that Prx1 contains a cysteine (Cys(83)) at the putative dimer-dimer interface, which is absent in Prx2. We studied the role of Cys(83) in regulating the peroxidase and chaperone activities of Prx1, because the redox status of Cys(83) might influence the oligomeric structure and consequently the functions of Prx1. We show that Prx1 is more efficient as a molecular chaperone, whereas Prx2 is better suited as a peroxidase enzyme. Substituting Cys(83) with Ser(83) (Prx1C83S) results in dramatic changes in the structural and functional characteristics of Prx1 in a direction similar to those of Prx2. Here we also report the first crystal structure of human Prx1 and the presence of the Cys(83)-Cys(83) bond at the dimer-dimer interface of decameric Prx1. These findings are consistent with the hypothesis that human Prx1 and Prx2 possess unique functions and regulatory mechanisms and that Cys(83) bestows a distinctive identity to Prx1.

    Funded by: NCI NIH HHS: CA105500, CA109480, CA111846, CA16056; NEI NIH HHS: EY09412; NIGMS NIH HHS: GM62794

    The Journal of biological chemistry 2007;282;30;22011-22

  • A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition.

    Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ and Deary IJ

    Department of Psychology, University of Edinburgh, Edinburgh, UK. Sarah.Harris@hgu.mrc.ac.uk <Sarah.Harris@hgu.mrc.ac.uk&gt;

    Background: Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.

    Results: Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone.

    Conclusion: This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.

    Funded by: Medical Research Council: MC_U127561128

    BMC genetics 2007;8;43

  • The tumor suppressor PP2A Abeta regulates the RalA GTPase.

    Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, DeCaprio JA and Hahn WC

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

    The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme family that regulates numerous signaling pathways. Biallelic mutations of the structural PP2A Abeta subunit occur in several types of human tumors; however, the functional consequences of these cancer-associated PP2A Abeta mutations in cell transformation remain undefined. Here we show that suppression of PP2A Abeta expression permits immortalized human cells to achieve a tumorigenic state. Cancer-associated Abeta mutants fail to reverse tumorigenic phenotype induced by PP2A Abeta suppression, indicating that these mutants function as null alleles. Wild-type PP2A Abeta but not cancer-derived Abeta mutants form a complex with the small GTPase RalA. PP2A Abeta-containing complexes dephosphorylate RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. These observations identify PP2A Abeta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA.

    Funded by: NCI NIH HHS: P01 CA050661, P01 CA050661-190009, P01 CA50661

    Cell 2007;129;5;969-82

  • The high reactivity of peroxiredoxin 2 with H(2)O(2) is not reflected in its reaction with other oxidants and thiol reagents.

    Peskin AV, Low FM, Paton LN, Maghzal GJ, Hampton MB and Winterbourn CC

    Free Radical Research Group, Department of Pathology, University of Otago, P. O. Box 4345, Christchurch, New Zealand. alexander.peskin@chmeds.ac.nz

    Peroxiredoxin 2 is a member of the mammalian peroxiredoxin family of thiol proteins that is important in antioxidant defense and redox signaling. We have examined its reactivity with various biological oxidants, in order to assess its ability to act as a direct physiological target for these species. Human erythrocyte peroxiredoxin 2 was oxidized stoichiometrically to its disulfide-bonded homodimer by hydrogen peroxide, as monitored electrophoretically under nonreducing conditions. The protein was highly susceptible to oxidation by adventitious peroxide, which could be prevented by treating buffers with low concentrations of catalase. However, this did not protect peroxiredoxin 2 against oxidation by added H(2)O(2). Experiments measuring inhibition of dimerization indicated that at pH 7.4 catalase and peroxiredoxin 2 react with hydrogen peroxide at comparable rates. A rate constant of 1.3 x 10(7) M(-1) s(-1) for the peroxiredoxin reaction was obtained from competition kinetic studies with horseradish peroxidase. This is 100-fold faster than is generally assumed. It is sufficiently high for peroxiredoxin to be a favored cellular target for hydrogen peroxide, even in competition with catalase or glutathione peroxidase. Reactions of t-butyl and cumene hydroperoxides with peroxiredoxin were also fast, but amino acid chloramines reacted much more slowly. This contrasts with other thiol compounds that react many times faster with chloramines than with hydrogen peroxide. The alkylating agent iodoacetamide also reacted extremely slowly with peroxiredoxin 2. These results demonstrate that peroxiredoxin 2 has a tertiary structure that facilitates reaction of the active site thiol with hydrogen peroxide while restricting its reactivity with other thiol reagents.

    The Journal of biological chemistry 2007;282;16;11885-92

  • Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte.

    Low FM, Hampton MB, Peskin AV and Winterbourn CC

    Free Radical Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand.

    Peroxiredoxin 2 (Prx2), a thiol-dependent peroxidase, is the third most abundant protein in the erythrocyte, and its absence in knock-out mice gives rise to hemolytic anemia. We have found that in human erythrocytes, Prx2 was extremely sensitive to oxidation by H(2)O(2), as dimerization was observed after exposure of 5 x 10(6) cells/mL to 0.5 muM H(2)O(2). In contrast to Prx2 in Jurkat T lymphocytes, Prx2 was resistant to overoxidation (oxidation of the cysteine thiol to a sulfinic/sulfonic acid) in erythrocytes. Reduction of dimerized Prx2 in the erythrocyte occurred very slowly, with reversal occurring gradually over a 20-minute period. Very low thioredoxin reductase activity was detected in hemolysates. We postulate that this limits the rate of Prx2 regeneration, and this inefficiency in recycling prevents the overoxidation of Prx2. We also found that Prx2 was oxidized by endogenously generated H(2)O(2), which was mainly derived from hemoglobin autoxidation. Our results demonstrate that in the erythrocyte Prx2 is extremely efficient at scavenging H(2)O(2) noncatalytically. Although it does not act as a classical antioxidant enzyme, its high concentration and substrate sensitivity enable it to handle low H(2)O(2) concentrations efficiently. These unique redox properties may account for its nonredundant role in erythrocyte defense against oxidative stress.

    Blood 2007;109;6;2611-7

  • Oxidation state governs structural transitions in peroxiredoxin II that correlate with cell cycle arrest and recovery.

    Phalen TJ, Weirather K, Deming PB, Anathy V, Howe AK, van der Vliet A, Jönsson TJ, Poole LB and Heintz NH

    Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA.

    Inactivation of eukaryotic 2-Cys peroxiredoxins (Prxs) by hyperoxidation has been proposed to promote accumulation of hydrogen peroxide (H2O2) for redox-dependent signaling events. We examined the oxidation and oligomeric states of PrxI and -II in epithelial cells during mitogenic signaling and in response to fluxes of H2O2. During normal mitogenic signaling, hyperoxidation of PrxI and -II was not detected. In contrast, H2O2-dependent cell cycle arrest was correlated with hyperoxidation of PrxII, which resulted in quantitative recruitment of approximately 66- and approximately 140-kD PrxII complexes into large filamentous oligomers. Expression of cyclin D1 and cell proliferation did not resume until PrxII-SO2H was reduced and native PrxII complexes were regenerated. Ectopic expression of PrxI or -II increased Prx-SO2H levels in response to oxidant exposure and failed to protect cells from arrest. We propose a model in which Prxs function as peroxide dosimeters in subcellular processes that involve redox cycling, with hyperoxidation controlling structural transitions that alert cells of perturbations in peroxide homeostasis.

    Funded by: NHLBI NIH HHS: P01 HL067004, P01 HL67004; NIEHS NIH HHS: T32 ES007122; NIGMS NIH HHS: R01 GM050389, R01 GM050389-13, R01 GM074204, R01 GM74204

    The Journal of cell biology 2006;175;5;779-89

  • Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress.

    Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, Eizirik DL, She JX and Wang CY

    Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, GA 30912, USA.

    The substrates of SUMO4, a novel member for the SUMO gene family, were characterized in HEK293 cells cultured under serum starvation by proteomic analysis. We identified 90 SUMO4 substrates including anti-stress proteins such as antioxidant enzymes and molecular chaperones or co-chaperones. The substrates also include proteins involved in the regulation of DNA repair and synthesis, RNA processing, protein degradation, and glucose metabolism. Several SUMO4-associated transcription factors were characterized by Western blot analyses. AP-1 was selected for in vitro conjugation assays to confirm SUMO4 sumoylation of these transcription factors. Further functional analyses of the transcription factors suggested that SUMO4 sumoylation represses AP-1 and AP-2alpha transcriptional activity, but enhances GR DNA binding capacity. These results demonstrate that SUMO4 sumoylation may play an important role in the regulation of intracellular stress.

    Biochemical and biophysical research communications 2005;337;4;1308-18

  • Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

    Bruneel A, Labas V, Mailloux A, Sharma S, Royer N, Vinh J, Pernet P, Vaubourdolle M and Baudin B

    Service de Biochimie A, Hôpital Saint-Antoine, AP-HP, Paris, France. arnaud.bruneel@sat.ap-hop-paris.fr

    We have undertaken to continue the proteomic study of human umbilical vein endothelial cells (HUVECs) using the combination of 2-DE, automated trypsin digestion, and PMF analysis after MALDI-TOF MS and peptide sequencing using nano LC-ESI-MS/MS. The overall functional characterization of the 162 identified proteins from primary cultures of HUVECs confirms the metabolic capabilities of endothelium and illustrates various cellular functions more related to cell motility and angiogenesis, protein folding, anti-oxidant defenses, signal transduction, proteasome pathway and resistance to apoptosis. In comparison with controls cells, the differential proteomic analysis of HUVECs treated by the pro-apoptotic topoisomerase inhibitor etoposide further revealed the variation of eight proteins, namely, GRP78, GRP94, valosin-containing protein, proteinase inhibitor 9, cofilin, 37-kDa laminin receptor protein, bovine apolipoprotein, and tropomyosin. These data suggest that etoposide-induced apoptosis of human vascular endothelial cells results from the intricate involvement of multiple apoptosis processes including at least the mitochondrial and the ER stress pathways. The presented 2-D pattern and protein database, as well as the data related to apoptosis of HUVECs, are available at http://www.huvec.com.

    Proteomics 2005;5;15;3876-84

  • Peroxiredoxin I and II are up-regulated during differentiation of epidermal keratinocytes.

    Yun SJ, Seo JJ, Chae JY and Lee SC

    Department of Dermatology, Chonnam National University Medical School, 8 Hak-dong, Gwangju, 501-757, Korea (South).

    Peroxiredoxins (Prxs) are expressed in the epidermis, and the accentuated expression of the Prx I and Prx II isotypes (Prx I/II) in the suprabasal layers suggests the potential role of Prx I/II in epidermal differentiation. To evaluate the novel function of Prx I/II, we checked the modulation of Prx I/II in differentiating keratinocytes. To induce differentiation in vitro, normal human epidermal keratinocytes (NHEK) were cultured for up to 10 days after the confluent state (post-confluency). In Western blot analysis, the marked induction of Prx I was observed from the second day, but the marked induction of Prx II was observed later from the sixth day of post-confluency, when loricrin and transglutaminase 1 were induced (sixth day of post-confluency). When NHEK cells were treated with INF-gamma and TGF-beta1, Prx I/II were up-regulated by INF-gamma, but Prx I/II were down-regulated by TGF-beta1. In summary, Prx I and Prx II are induced at the early and late stage of differentiation of NHEK cells, respectively.

    Archives of dermatological research 2005;296;12;555-9

  • Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II.

    Choi MH, Lee IK, Kim GW, Kim BU, Han YH, Yu DY, Park HS, Kim KY, Lee JS, Choi C, Bae YS, Lee BI, Rhee SG and Kang SW

    Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea.

    Platelet-derived growth factor (PDGF) is a potent mitogenic and migratory factor that regulates the tyrosine phosphorylation of a variety of signalling proteins via intracellular production of H2O2 (refs 1, 2-3). Mammalian 2-Cys peroxiredoxin type II (Prx II; gene symbol Prdx2) is a cellular peroxidase that eliminates endogenous H2O2 produced in response to growth factors such as PDGF and epidermal growth factor; however, its involvement in growth factor signalling is largely unknown. Here we show that Prx II is a negative regulator of PDGF signalling. Prx II deficiency results in increased production of H2O2, enhanced activation of PDGF receptor (PDGFR) and phospholipase Cgamma1, and subsequently increased cell proliferation and migration in response to PDGF. These responses are suppressed by expression of wild-type Prx II, but not an inactive mutant. Notably, Prx II is recruited to PDGFR upon PDGF stimulation, and suppresses protein tyrosine phosphatase inactivation. Prx II also leads to the suppression of PDGFR activation in primary culture and a murine restenosis model, including PDGF-dependent neointimal thickening of vascular smooth muscle cells. These results demonstrate a localized role for endogenous H2O2 in PDGF signalling, and indicate a biological function of Prx II in cardiovascular disease.

    Nature 2005;435;7040;347-53

  • Identification of differentially expressed proteins during human urinary bladder cancer progression.

    Memon AA, Chang JW, Oh BR and Yoo YJ

    Department of Life Science, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea. amemo@akh.aaa.dk

    Comparative proteome analysis was performed between RT4 (grade-1) and T24 (grade-3) bladder cancer cell lines, in an attempt to identify differentially expressed proteins during bladder cancer progression. Among those relatively abundant proteins, seven spots changed more than two-fold reproducibly and identified by peptide mass fingerprinting using mass spectrometry and database search. We found most extensive and reproducible down-regulation of NADP dependent isocitrate dehydrogenase cytoplasmic (IDPc) and peroxiredoxin-II (Prx-II), in poorly differentiated T24 compared to well-differentiated RT4 bladder cancer cell line. Subsequent Western blotting analysis of human biopsy samples from bladder cancer patient revealed significant loss of IDPc and Prx-II in more advance tumor samples, in agreement with data on cell lines. These results suggest that loss of IDPc and Prx-II during tumor development may involve in tumor progression and metastasis. However, additional investigations are needed on large number of human samples to further verify these findings.

    Cancer detection and prevention 2005;29;3;249-55

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD.

    Budanov AV, Sablina AA, Feinstein E, Koonin EV and Chumakov PM

    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

    Acting as a signal, hydrogen peroxide circumvents antioxidant defense by overoxidizing peroxiredoxins (Prxs), the enzymes that metabolize peroxides. We show that sestrins, a family of proteins whose expression is modulated by p53, are required for regeneration of Prxs containing Cys-SO(2)H, thus reestablishing the antioxidant firewall. Sestrins contain a predicted redox-active domain homologous to AhpD, the enzyme catalyzing the reduction of a bacterial Prx, AhpC. Purified Hi95 (sestrin 2) protein supports adenosine triphosphate-dependent reduction of overoxidized PrxI in vitro, indicating that unlike AhpD, which is a disulfide reductase, sestrins are cysteine sulfinyl reductases. As modulators of peroxide signaling and antioxidant defense, sestrins constitute potential therapeutic targets.

    Science (New York, N.Y.) 2004;304;5670;596-600

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • Regeneration of peroxiredoxins during recovery after oxidative stress: only some overoxidized peroxiredoxins can be reduced during recovery after oxidative stress.

    Chevallet M, Wagner E, Luche S, van Dorsselaer A, Leize-Wagner E and Rabilloud T

    Commissariat à l'Energie Atomique-Laboratoire de Bioénergétique Cellulaire et Pathologique, EA 2943, Département Réponses et Dynamique Cellulaire/BioEnergétique Cellulaire et Pathologique-Grenoble, 17 rue des martyrs, F-38054 Grenoble Cedex 9, France.

    Peroxiredoxins (prx) are redox enzymes using an activated cysteine as their active site. This activated cysteine can be easily overoxidized to cysteine sulfinic acid or cysteine sulfonic acid, especially under oxidative stress conditions. The regeneration of peroxiredoxins after a short, intense oxidative stress was studied, using a proteomics approach. Important differences in regeneration speed were found, prx2 being the fastest regenerated protein, followed by prx1, whereas prx3 and prx6 were regenerated very slowly. Further study of the mechanism of this regeneration by pulse-chase experiments using stable isotope labeling and cycloheximide demonstrated that the fast-regenerating peroxiredoxins are regenerated at least in part by a retroreduction mechanism. This demonstrates that the overoxidation can be reversible under certain conditions. The pathway of this retroreduction and the reasons explaining the various regeneration speeds of the peroxiredoxins remain to be elucidated.

    The Journal of biological chemistry 2003;278;39;37146-53

  • Expression of peroxiredoxin II in vascular tumors of the skin: a novel vascular marker of endothelial cells.

    Lee SC, Na YP and Lee JB

    Department of Dermatology, Chonnam National University Medical School, Gwangju, South Korea. schul@chonnam.ac.kr

    Background: The peroxiredoxin (Prx) family consists of peroxidases to remove H(2)O(2) by using the thioredoxin system. In a previous study, Prx II was ubiquitously expressed in the epidermis and dermis including dermal vessels.

    Objective: This study aims to elucidate expression patterns of Prx II in benign and malignant vascular tumors.

    Methods: Immunohistochemical staining for Prx II, factor VIII-related antigen, and CD34 was performed in formalin-fixed specimens.

    Results: Prx II was strongly expressed in mature endothelial cells of benign vascular tumors, whereas it was expressed weakly or not expressed in immature endothelial cells in malignant tumors of Kaposi's sarcoma and angiosarcoma. The expression patterns of Prx II were similar to those of factor VIII-related antigen, rather than CD34.

    Conclusions: Prx II can be used as a novel marker of endothelial cells and indicates that reactive oxygen may play a role in the pathogenesis of vascular tumors.

    Journal of the American Academy of Dermatology 2003;49;3;487-91

  • Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, is under-expressed in Down syndrome fetal brains.

    Sánchez-Font MF, Sebastià J, Sanfeliu C, Cristòfol R, Marfany G and Gonzàlez-Duarte R

    Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain.

    Suppression subtractive hybridization performed on Down syndrome (DS) versus control fetal brains revealed differential expression of peroxiredoxin 2 (PRDX2), mapped at 13q12. Peroxiredoxins are antioxidant enzymes involved in protein and lipid protection against oxidative injury and in cellular signalling pathways regulating apoptosis. The under-expression of PRDX2 observed in DS samples was confirmed by real-time PCR (0.73-fold). To test whether decreased expression is associated with enhanced sensitivity of DS neurons to reactive oxygen species, we down-regulated PRDX2 through stable transfections of SH-SY5Y neuroblastoma cells with antisense contructs of the complete PRDX2 coding sequence. In addition, we over-expressed SOD1 and compared the effects of the two genes on cell viability. Cells transfected with either construct showed similar sensitivity to oxidative stress in addition to increased apoptosis under basal conditions and after treatment with oxidative cytotoxic agents. This suggests that the decreased expression of PRDX2 may contribute to the altered redox state in DS at levels comparable to that of the increased expression of SOD1.

    Cellular and molecular life sciences : CMLS 2003;60;7;1513-23

  • Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders.

    Krapfenbauer K, Engidawork E, Cairns N, Fountoulakis M and Lubec G

    F. Hoffman-La Roche, Basel, Switzerland.

    An increasing body of evidence indicates that oxidative stress and damage play a role in the pathogenesis of a number of diseases associated with neurodegeneration, including Down syndrome (DS), Alzheimer's disease (AD) and Pick's disease (PD). Although oxidative stress is a common element in these diseases, specific clinico-pathological phenotypes have been described for each disorder. Development of these phenotypes might be linked, among others, to differences in antioxidant response. The present study is designed to investigate expression of peroxiredoxins (Prxs), the newly characterized family of highly conserved antioxidant enzymes, and other antioxidant enzymes in frontal cortex and cerebellum of DS, AD and PD patients using the technique of proteomics. Levels of Prx I, Mn superoxide dismutase (SOD2) and glutathione-S-transferase omega1 in DS, AD and PD were not significantly different from that of controls in both brain regions investigated. In contrast, Prx II was significantly increased (P<0.05) in frontal cortex of DS, AD and PD, whereas Prx III was decreased in frontal cortex of DS (P<0.01) and PD (P<0.001). Interestingly, Prx VI displayed a significant increase (P<0.05) only in PD frontal cortex. The present data indicate that differential regulation of antioxidant enzymes exist in DS, AD and PD, suggestive of the diversity as well as distinct functional roles of these proteins. Moreover, while up-regulation of Prx II appears to provide evidence for the existence of compensatory response in increased cell loss, up-regulation of Prx VI may be used to discriminate PD from AD as well as DS.

    Brain research 2003;967;1-2;152-60

  • HIV-1 antiviral activity of recombinant natural killer cell enhancing factors, NKEF-A and NKEF-B, members of the peroxiredoxin family.

    Geiben-Lynn R, Kursar M, Brown NV, Addo MM, Shau H, Lieberman J, Luster AD and Walker BD

    Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA. acceleration@rcn.com

    CD8(+) T-cells are a major source for the production of non-cytolytic factors that inhibit HIV-1 replication. In order to characterize further these factors, we analyzed gene expression profiles of activated CD8(+) T-cells using a human cDNA expression array containing 588 human cDNAs. mRNA for the chemokine I-309 (CCL1), the cytokines granulocyte-macrophage colony-stimulating factor and interleukin-13, and natural killer cell enhancing factors (NKEF) -A and -B were up-regulated in bulk CD8(+) T-cells from HIV-1 seropositive individuals compared with seronegative individuals. Recombinant NKEF-A and NKEF-B inhibited HIV-1 replication when exogenously added to acutely infected T-cells at an ID(50) (dose inhibiting HIV-1 replication by 50%) of approximately 130 nm (3 microg/ml). Additionally, inhibition against dual-tropic simian immunodeficiency virus and dual-tropic simian-human immunodeficiency virus was found. T-cells transfected with NKEF-A or NKEF-B cDNA were able to inhibit 80-98% HIV-1 replication in vitro. Elevated plasma levels of both NKEF-A and NKEF-B proteins were detected in 23% of HIV-infected non-treated individuals but not in persons treated with highly active antiviral therapy or uninfected persons. These results indicate that the peroxiredoxin family members NKEF-A and NKEF-B are up-regulated in activated CD8(+) T-cells in HIV infection, and suggest that these antioxidant proteins contribute to the antiviral activity of CD8(+) T-cells.

    Funded by: NIAID NIH HHS: AI28568, AI30914, AI46999

    The Journal of biological chemistry 2003;278;3;1569-74

  • Proteomics analysis of cellular response to oxidative stress. Evidence for in vivo overoxidation of peroxiredoxins at their active site.

    Rabilloud T, Heller M, Gasnier F, Luche S, Rey C, Aebersold R, Benahmed M, Louisot P and Lunardi J

    CEA-Laboratoire de Bioénergétique Cellulaire et Pathologique, EA UJF 2943, DRDC/BECP, CEA-Grenoble, 17 rue des martyrs, F-38054 Grenoble Cedex 9, France.

    The proteomics analysis reported here shows that a major cellular response to oxidative stress is the modification of several peroxiredoxins. An acidic form of the peroxiredoxins appeared to be systematically increased under oxidative stress conditions. Peroxiredoxins are enzymes catalyzing the destruction of peroxides. In doing so, a reactive cysteine in the peroxiredoxin active site is weakly oxidized (disulfide or sulfenic acid) by the destroyed peroxides. Cellular thiols (e.g. thioredoxin) are used to regenerate the peroxiredoxins to their active state. Tandem mass spectrometry was carried out to characterize the modified form of the protein produced in vivo by oxidative stress. The cysteine present in the active site was shown to be oxidized into cysteic acid, leading to an inactivated form of peroxiredoxin. This strongly suggested that peroxiredoxins behave as a dam upon oxidative stress, being both important peroxide-destroying enzymes and peroxide targets. Results obtained in a primary culture of Leydig cells challenged with tumor necrosis factor alpha suggested that this oxidized/native balance of peroxiredoxin 2 may play an active role in resistance or susceptibility to tumor necrosis factor alpha-induced apoptosis.

    The Journal of biological chemistry 2002;277;22;19396-401

  • Identification of new proteins in follicular fluid of mature human follicles.

    Anahory T, Dechaud H, Bennes R, Marin P, Lamb NJ and Laoudj D

    Cell Biology Unit, Institut de Génétique Humaine, Centre National de la Recherche Scientifique, Montpellier, France.

    Proteins present in human follicular fluid (HFF) have been poorly characterized to date. The purpose of our study was to analyse the protein content and identify new proteins originating from fluid of mature human follicles. A total of six females from infertile couples referred for in vitro fertilization (IVF) were stimulated and 44 follicular fluid samples from mature follicles yielding an oocyte were collected 34-36 h after human chorionic gonadotropin administration. HFF samples were processed for high-resolution two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Comparative analysis of the 2-D gels revealed up to 600 spots, of which four were selected because of variations in their expression level. Using direct sequencing procedures (Edman degradation) or matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS), these four spots were identified as three new proteins: thioredoxin peroxydase 1 (TDPX1), transthyretin (TTR) and retinol-binding protein (RBP). The proteins identified here may emerge as potential candidates for specific functions during folliculogenesis and may prove useful as biomedical markers for follicle and/or oocyte maturation.

    Electrophoresis 2002;23;7-8;1197-202

  • Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

    Shen C and Nathan C

    Department of Microbiology & Immunology, Weill Medical College, Cornell University, New York, New York 10021, USA. cnathan@med.cornell.edu

    Background: Peroxiredoxins (Prxs) are antioxidant enzymes expressed by most free-living organisms, often in multiple isoforms. Because mammalian Prxs have not been experimentally deleted or inhibited, it is not known how much they contribute to antioxidant defense, nor whether the multiple isoforms afford redundant or additive protection.

    Expression of the four members of the 2-Cys family of human Prxs was tested in human tumor cell lines. Monospecific antibodies were developed and used to monitor the extent and specificity of inhibition of expression of each isoform in prostate cancer cells stably transfected with antisense constructs.

    Results: Seventeen tumor lines transcribed genes for all four human Prxs. Prostate cancer cells coexpressed each isoform at the protein level. Stable transfection with antisense allowed partial, selective suppression of Prx 1, 2, 3, or 4. Prostate cancer cells were rendered more sensitive to hydrogen peroxide or an organic hydroperoxide when Prx 1, 2, or 3 but not 4 was partially suppressed, bringing them into the range of sensitivity of mouse cells. The effect of partially suppressing a single Prx was comparable to that of depleting glutathione. In contrast, sensitization to adriamycin, an antitumor agent with a redox-active quinone, followed the partial suppression of Prxs 1, 2, or 4 but not 3. Individual suppression of Prxs 1-4 had no effect on sensitivity of the cells to reactive nitrogen intermediates, tumor necrosis factor (TNF), paclitaxel (Taxol), or etoposide.

    Conclusions: The 2-Cys Prxs act in a mutually nonredundant and sometimes stress-specific fashion to protect human cells from oxidant injury. The substantial resistance of human cells to hydroperoxides may result in part from the additive action of multiple Prxs.

    Molecular medicine (Cambridge, Mass.) 2002;8;2;95-102

  • Comparison of the decameric structure of peroxiredoxin-II by transmission electron microscopy and X-ray crystallography.

    Harris JR, Schröder E, Isupov MN, Scheffler D, Kristensen P, Littlechild JA, Vagin AA and Meissner U

    Institute of Zoology, University of Mainz, Germany. rharris@web.de

    The decameric human erythrocyte protein torin is identical to the thiol-specific antioxidant protein-II (TSA-II), also termed peroxiredoxin-II (Prx-II). Single particle analysis from electron micrographs of Prx-II molecules homogeneously orientated across holes in the presence of a thin film of ammonium molybdate and trehalose has facilitated the production of a >/=20 A 3-D reconstruction by angular reconstitution that emphasises the D5 symmetry of the ring-like decamer. The X-ray structure for Prx-II was fitted into the transmission electron microscopic reconstruction by molecular replacement. The surface-rendered transmission electron microscopy (TEM) reconstruction correlates well with the solvent-excluded surface of the X-ray structure of the Prx-II molecule. This provides confirmation that transmission electron microscopy of negatively stained specimens, despite limited resolution, has the potential to reveal a valid representation of surface features of protein molecules. 2-D crystallisation of the Prx-II protein on mica as part of a TEM study resulted in the formation of a p2 crystal form with parallel linear arrays of stacked rings. This latter 2-D form correlates well with that observed from the 2.7 A X-ray structure of Prx-II solved from a new orthorhombic 3-D crystal form.

    Biochimica et biophysica acta 2001;1547;2;221-34

  • Overexpression of peroxiredoxin in human breast cancer.

    Noh DY, Ahn SJ, Lee RA, Kim SW, Park IA and Chae HZ

    Department of Surgery, College of Medicine, Seoul National University, Jongno-Ku, Korea. dynoh@plaza.snu.ac.kr

    The peroxiredoxins (Prx) are a family of 25 kDa peroxidases that can reduce H2O2 using an electron from thioredoxin (Trx) or other substances. The mammalian Prx family is divided into six groups (Prx I-VI) on the basis of homology of amino acid sequences. They are located in the cytosol and play a role in the cell signaling system. Previous reports have shown that Prx II has proliferative and anti-apoptotic properties and thus may induce carcinogenic changes. We conducted this study to reveal the change in expression of Prx in human breast cancer in comparison to normal tissues. Western immunoblotting using Prx type I, II and III antibodies was undertaken on 24 human breast cancer tissues and normal counterparts. We used antibodies against purified recombinant NKEF-A/PAG, NKEF-B and MER 5 which are the Prx isoforms. Type I Prx was overexpressed in the cancer tissues of 21 patients (87.5%), type II in 18 patients (75%) and type III in 19 patients (79.2%) in relation to normal tissue. However, no significant relationship was found between Prx overexpression and clinicopathological parameters of breast cancer such as tumor size, lymphatic invasiveness, hormone receptor status or nuclear and histologic grade. In conclusion, Prx is overexpressed in breast cancer tissues to a great extent suggesting that Prx has a proliferative effect and may be related to cancer development or progression.

    Anticancer research 2001;21;3B;2085-90

  • Protein levels of human peroxiredoxin subtypes in brains of patients with Alzheimer's disease and Down syndrome.

    Kim SH, Fountoulakis M, Cairns N and Lubec G

    Department of Pediatrics, University of Vienna, Austria.

    Human peroxiredoxin (Prx) play important roles in eliminating hydrogen peroxide generated during cellular mechanisms using electrons from thioredoxin (Trx). Oxidative stress induced by reactive oxygen species (ROS) such as hydrogen peroxide has been implicated in the pathogenesis of several neurodegenerative diseases. We applied the proteomic approach to study protein levels of three subtypes of human Prx in brain regions from patients with Alzheimer's disease (AD) and Down Syndrome (DS). Protein levels of Prx-I and Prx-II were significantly increased in AD and DS. Protein levels of Prx-III, a mitochondrial protein, however, were significantly decreased. We conclude that increased protein levels of Prx-I and Prx-II could provide protection against neuronal cell death induced by hydrogen peroxide. Decreased protein levels of Prx-III could be caused by mitochondrial damage shown in AD and DS. Showing upregulated Prx protein levels provides evidence for the involvement of ROS in the pathogenesis of AD and DS.

    Journal of neural transmission. Supplementum 2001;61;223-35

  • Chemokines are the main proinflammatory mediators in human monocytes activated by Staphylococcus aureus, peptidoglycan, and endotoxin.

    Wang ZM, Liu C and Dziarski R

    Northwest Center for Medical Education, Indiana University School of Medicine, Gary, Indiana 46408, USA.

    It is widely believed that the cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 are the main proinflammatory mediators induced in the host by bacteria and their cell wall components. To test this hypothesis, we compared the level of expression of 600 genes activated in human monocytes by Staphylococcus aureus, peptidoglycan, endotoxin, and interferon-gamma. These stimulants induced expression of over 120 genes, as identified by cDNA arrays. The highest activated genes for proinflammatory mediators induced by all three bacterial stimulants were chemokine genes (IL-8 and macrophage inflammatory protein (MIP)-1alpha), whereas cytokine genes (TNF-alpha, IL-1, and IL-6) were induced to a lower extent. Genes for other chemokines (MIP-2alpha, MIP-1beta, and monocyte chemoattractant protein-1) were also induced higher than the cytokine genes by peptidoglycan, and as high or higher than the cytokine genes by S. aureus and endotoxin. This high induction of chemokine genes was confirmed by quantitative RNase protection assay, and high secretion of chemokines was confirmed by enzyme-linked immunosorbent assays. Although genes for chemokines were the highest and genes for cytokines were the second highest induced genes by all three bacterial stimulants, each stimulus induced a unique pattern of gene expression. By contrast, expression of a completely different gene pattern was induced by a nonbacterial stimulus, interferon-gamma. These results establish chemokines as the main mediators induced by both Gram-positive and Gram-negative bacteria and are consistent with the highly inflammatory nature of bacterial infections.

    Funded by: NIAID NIH HHS: AI2879

    The Journal of biological chemistry 2000;275;27;20260-7

  • Crystal structure of decameric 2-Cys peroxiredoxin from human erythrocytes at 1.7 A resolution.

    Schröder E, Littlechild JA, Lebedev AA, Errington N, Vagin AA and Isupov MN

    Schools of Chemistry and Biological Sciences, University of Exeter, Exeter, EX4 4QD, UK. eschrode@ex.ac.uk

    Background: The peroxiredoxins (Prxs) are an emerging family of multifunctional enzymes that exhibit peroxidase activity in vitro, and in vivo participate in a range of cellular processes known to be sensitive to reactive oxygen species. Thioredoxin peroxidase B (TPx-B), a 2-Cys type II Prx from erythrocytes, promotes potassium efflux and down-regulates apoptosis and the recruitment of monocytes by endothelial tissue.

    Results: The crystal structure of human decameric TPx-B purified from erythrocytes has been determined to 1.7 [corrected)] A resolution. The structure is a toroid comprising five dimers linked end-on through predominantly hydrophobic interactions, and is proposed to represent an intermediate in the in vivo reaction cycle. In the crystal structure, Cys51, the site of peroxide reduction, is oxidised to cysteine sulphinic acid. The residue Cys172, lies approximately 10 A away from Cys51 [corrected].

    Conclusions: The oxidation of Cys51 appears to have trapped the structure into a stable decamer, as confirmed by sedimentation analysis. A comparison with two previously reported dimeric Prx structures reveals that the catalytic cycle of 2-Cys Prx requires significant conformational changes that include the unwinding of the active-site helix and the movement of four loops. It is proposed that the stable decamer forms in vivo under conditions of oxidative stress. Similar decameric structures of TPx-B have been observed by electron microscopy, which show the protein associated with the erythrocyte membrane.

    Structure (London, England : 1993) 2000;8;6;605-15

  • Interaction of human thiol-specific antioxidant protein 1 with erythrocyte plasma membrane.

    Cha MK, Yun CH and Kim IH

    National Creative Research Initiatives Center for Antioxidant Proteins, Department of Biochemistry, Paichai University, Taejon 302-735, Korea.

    During the purification from human erythrocytes, human thiol-specific antioxidant protein 1 (hTSA1), one human member of the TSA/alkyl hydroperoxide reductase subunit C (AhpC) family, was fragmented to a molecular mass of 20 323.9300. The fragmented form, in contrast to the intact form, did not bind to the C-terminal peptide (Gln-185-Gln-197) antibody. On the basis of the molecular mass of the fragmented form, the cleavage site was calculated to be between Val-186 and Asp-187. The C-terminal region of hTSA1 appeared to be unnecessary for the antioxidant reaction. In addition to hTSA1, two isoenzymes (hORF06 and hTSA2) were detected in the soluble fraction, whereas only hTSA1 was detected in the membrane fraction. A membrane binding study shows that the intact form binds to erythrocyte plasma membrane but the fragment does not, which suggests that the deleted C-terminal legion (Asp-187-Gln-197) is required for the membrane binding. A model membrane study using phospholipid vesicle showed a strong association of hTSA1 with the phospholipid. Human TSA1 exhibited high catalytic activity for the reduction of the fatty acid hydroperoxide as indicated by K(m) and V(max) (89.9 microM for linoleic acid hydroperoxide, 28.64 micromol(-1) min(-1) mg(-1), respectively). In this paper, we are making the first report of the involvement of the C-terminal region of hTSA1 in membrane binding as evidence supporting the existence of the membrane-associated forms in the erythrocyte. On the basis of our observations, we suggest that hTSA1 can act as a very effective antioxidant to remove oxidative stresses not only in matrix as a free form but also in the membrane surface of red blood cells (RBC) as a membrane-associated form.

    Biochemistry 2000;39;23;6944-50

  • A two-dimensional gel database of human colon carcinoma proteins.

    Ji H, Reid GE, Moritz RL, Eddes JS, Burgess AW and Simpson RJ

    Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research (Melbourne Branch), Parkville, Victoria, Australia.

    The master two-dimensional gel database of human colon carcinoma cells currently lists cellular proteins from normal crypts and the colorectal cancer cell lines LIM 1863, LIM 1215 and LIM 1899 (Ward et al., Electrophoresis 1990, 11, 883-891; Ji et al., Electrophoresis 1994, 15, 391-405). Updated two-dimensional electrophoretic (2-DE) maps of cellular proteins from LIM 1215 cells, acquired under both nonreducing and reducing conditions, are presented. Fifteen cellular proteins are identified in the reducing 2-DE gel map, and seven in the nonreducing gel map, along with a tabular listing of their M(r)/pI loci and mode of identification. We also include our mass spectrometric based procedures for identifying 2-DE resolved proteins. This procedure relies on a combination of capillary column (0.10-0.32 mm internal diameter) reversed-phase HPLC peptide mapping of in-gel digested proteins, peptide mass fingerprinting, sequence analysis by either collision-induced dissociation or post-source-decay fragmentation, and protein identification using available database search algorithms. These data, and descriptions of the micro-techniques employed in this laboratory for identifying 2-DE resolved proteins can be accessed via the internet URL: http:(/)/www.ludwig.edu.au.

    Electrophoresis 1997;18;3-4;605-13

  • Glutathione-linked thiol peroxidase activity of human serum albumin: a possible antioxidant role of serum albumin in blood plasma.

    Cha MK and Kim IH

    Department of Biochemistry, Pai-Chai University, Taejon, Korea.

    A 65-kDa molecular mass of thiol-specific antioxidant protein was purified from human plasma and identified as human serum albumin (HSA) by the analysis of amino-terminal amino acid sequence. This protein exhibited the preventive effects against the inactivation of glutamine synthetase activity and the peroxidation of lipid by a metal-catalyzed oxidation system. These antioxidant activities were supported by a thiol-reducing equivalent such as DTT and reduced glutathione. The thiol-specific antioxidant activity of HSA was greatly activated by halide ion, especially by chloride ion. HSA showed a significant capability to destroy H2O2 in the presence of reduced glutathione, resulting in the production of oxidized glutathione. Both the preventive activity against the glutamine synthetase inactivation and the peroxidase activity were completely abolished by the reactions of HSA with N-ethylmaleimide and iodoacetate, chemical modification agents for sulfhydryl of protein, only in the presence of thiol-reducing equivalent such as DTT. These results suggest that serum albumin acts as a major and predominate antioxidant exerting a glutathione-linked thiol peroxidase activity which removes reactive oxygen species such as H2O2 within blood plasma.

    Biochemical and biophysical research communications 1996;222;2;619-25

  • Localization of TDPX1, a human homologue of the yeast thioredoxin-dependent peroxide reductase gene (TPX), to chromosome 13q12.

    Pahl P, Berger R, Hart I, Chae HZ, Rhee SG and Patterson D

    Eleanor Roosevelt Institute for Cancer Research, Denver, Colorado 80206, USA.

    Reactive oxygen species and free radicals that are produced during normal metabolism can potentially damage cellular macromolecules. Defenses against such damage include a number of antioxidant enzymes that specifically target the removal or dismutation of the reactive agent. We report here the isolation and regional mapping of a human gene, TDPX1, that encodes an enzyme homologous to a yeast thioredoxin-dependent peroxide reductase (thioredoxin peroxidase, TPX). The human TDPX1 coding sequence was determined from the product of a polymerase chain reaction (PCR) amplification of human cDNA. Based on PCR analysis of DNA from a human/rodent somatic cell hybrid panel, the TDPX1 locus was assigned to chromosome 13. Further localization of the locus to 13q12 was accomplished by fluorescence in situ hybridization analysis, using as a probe DNA from a yeast artificial chromosome (YAC) that contains the TDPX1 gene. It was also determined by PCR analysis of various YACs that the TDPX1 locus is in the region of the dinucleotide repeat markers D13S289 and D13S290. This regional mapping localizes the TDPX1 gene to a genomic region recently shown to contain the breast cancer susceptibility gene BRCA2 and a gene associated with a form of muscular dystrophy. Oxygen radical metabolism has been hypothesized to be important for cancer, muscular dystrophy, and other disorders, so TDPX1 should be considered a candidate gene for these diseases.

    Funded by: NIA NIH HHS: AG00029; NICHD NIH HHS: HD07197

    Genomics 1995;26;3;602-6

  • Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes.

    Chae HZ, Robison K, Poole LB, Church G, Storz G and Rhee SG

    Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

    A cDNA corresponding to a thiol-specific antioxidant enzyme (TSA) was isolated from a rat brain cDNA library with the use of antibodies to bovine TSA. The cDNA clone encoded an open reading frame capable of encoding a 198-residue polypeptide. The rat and yeast TSA proteins show significant sequence homology to the 21-kDa component (AhpC) of Salmonella typhimurium alkyl hydroperoxide reductase, and we have found that AhpC exhibits TSA activity. AhpC and TSA define a family of > 25 different proteins present in organisms from all kingdoms. The similarity among the family members extends over the entire sequence and ranges between 23% and 98% identity. A majority of the members of the AhpC/TSA family contain two conserved cysteines. At least eight of the genes encoding AhpC/TSA-like polypeptides are found in proximity to genes encoding other oxidoreductase activities, and the expression of several of the homologs has been correlated with pathogenicity. We suggest that the AhpC/TSA family represents a widely distributed class of antioxidant enzymes. We also report that a second family of proteins, defined by the 57-kDa component (AhpF) of alkyl hydroperoxide reductase and by thioredoxin reductase, has expanded to include six additional members.

    Funded by: NIGMS NIH HHS: R01 GM050389

    Proceedings of the National Academy of Sciences of the United States of America 1994;91;15;7017-21

  • The thiol-specific antioxidant protein from human brain: gene cloning and analysis of conserved cysteine regions.

    Lim YS, Cha MK, Kim HK and Kim IH

    Department of Biochemistry, Pai-Chai University, Taejon, South Korea.

    The complete cDNA encoding human thiol-specific antioxidant protein (PRP) was isolated from a human brain cDNA library in the lambda Zap expression vector. An open reading frame (ORF) was identified and found to encode a polypeptide of 197 aa with a M(r) of 21,729. The cDNA contained 98 bp of 5'-untranslated sequence (UTR) and 259 bp of 3'-UTR containing a poly(A) signal, AATAAA. Expression of the human PRP cDNA in Escherichia coli yielded a functionally active protein. The observed local sequence homologies between human PRP and other homologous proteins whose functions have not yet been defined give important insight into elucidating the biochemical function of a new protein family which has highly conserved regions containing cysteine.

    Gene 1994;140;2;279-84

  • Purification and characterization of thiol-specific antioxidant protein from human red blood cell: a new type of antioxidant protein.

    Lim YS, Cha MK, Yun CH, Kim HK, Kim K and Kim IH

    Department of Biochemistry, Pai-Chai University, Taejon, Republic of Korea.

    A thiol-specific antioxidant protein (Protector Protein, PRP) was purified from human red blood cells (RBC). The PRP exists as a predominant protein in human RBC, which showed distinct thiol-specific antioxidant activities in the presence of dithiothreitol (DTT) as a reducing equivalent. The human RBC PRP (HRPRP) completely inhibited visible absorption spectral changes of oxyhemoglobin, DNA cleavage, and the peroxidation of RBC membrane by a nonenzymatic Fe3+/O2/thiol mixed-function oxidation system capable of generating hydroxyl radical. These observations suggest that HRPRP could act as a new type of antioxidant protein to maintain the RBC integrity by scavenging reactive oxygen species.

    Biochemical and biophysical research communications 1994;199;1;199-206

  • Cloning and sequence analysis of candidate human natural killer-enhancing factor genes.

    Shau H, Butterfield LH, Chiu R and Kim A

    Division of Surgical Oncology, UCLA School of Medicine 90024-1782.

    A cytosol factor from human red blood cells enhances natural killer (NK) activity. This factor, termed NK-enhancing factor (NKEF), is a protein of 44,000 M(r) consisting of two subunits of equal size linked by disulfide bonds. NKEF is expressed in the NK-sensitive erythroleukemic cell line K562. Using an antibody specific for NKEF as a probe for immunoblot screening, we isolated several clones from a lambda gt11 cDNA library of K562. Additional subcloning and sequencing revealed that the candidate NKEF cDNAs fell into one of two catagories of closely related but non-identical genes, referred to as NKEF A and B. They are 88% identical in amino acid sequence and 71% identical in nucleotide sequence. Southern blot analysis suggests that there are two to three NKEF family members in the genome. Analysis of predicted amino acid sequences indicates that both NKEF A and B are cytosol proteins with several phosphorylation sites each, but that they have no glycosylation sites. They are significantly homologous to several other proteins from a wide variety of organisms ranging from prokaryotes to mammals, especially with regard to several well-conserved motifs within the amino acid sequences. The biological functions of these proteins in other species are mostly unknown, but some of them were reported to be induced by oxidative stress. Therefore, as well as for immunoregulation of NK activity, NKEF may be important for cells in coping with oxidative insults.

    Funded by: NCI NIH HHS: NCI CA-9120-19

    Immunogenetics 1994;40;2;129-34

  • Plasma and red blood cell protein maps: update 1993.

    Golaz O, Hughes GJ, Frutiger S, Paquet N, Bairoch A, Pasquali C, Sanchez JC, Tissot JD, Appel RD, Walzer C et al.

    Medicine Department, Geneva University.

    This publication updates the reference plasma and red blood cell protein maps obtained with immobilized pH gradients. Seventeen polypeptide spots or chains were partially characterized by direct N-terminal sequencing or by sequencing of peptides obtained from enzymatic digestion. Additional new polypeptides and previously known proteins are listed in a table and/or labeled on the protein maps, thus providing the 1993 update of the human plasma and red blood cell two-dimensional gel SWISS-2DPAGE database. SWISS-2DPAGE and the SWISS-PROT protein sequence databases are closely linked together through the use of common accession numbers.

    Electrophoresis 1993;14;11;1223-31

  • Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes.

    Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE and Vandekerckhove J

    Institute of Medical Biochemistry, Aarhus University, Denmark.

    Microsequencing of proteins recovered from two-dimensional (2-D) gels is being used systematically to identify proteins in the master human keratinocyte 2-D gel database. To date, about 250 protein spots recorded in human 2-D gel databases have been microsequenced and, of these, 145 are recorded in the keratinocyte database under the entry partial amino acid sequence. Coomassie Brilliant Blue-stained protein spots cut from several (up to 40) dry gels were concentrated by elution-concentration gel electrophoresis, electroblotted onto PVDF membranes and digested in situ with trypsin. Eluting peptides were separated by reversed-phase HPLC, collected individually and sequenced. Computer search using the FASTA and TFASTA programs from Genetics Computer Group indicated that 110 of the microsequenced polypeptides shared significant similarity with proteins contained in the PIR, Mipsx or GenEMBL databases. Only 35 polypeptides corresponded to hitherto unknown proteins. Peptide sequences of all 145 proteins are listed together with their coordinates (apparent molecular weight and pI) in the keratinocyte database.

    Electrophoresis 1992;13;12;960-9

Gene lists (10)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000011 G2C Homo sapiens Human clathrin Human orthologues of mouse clathrin coated vesicle genes adapted from Collins et al (2006) 150
L00000012 G2C Homo sapiens Human Synaptosome Human orthologues of mouse synaptosome adapted from Collins et al (2006) 152
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000049 G2C Homo sapiens TAP-PSD-95-CORE TAP-PSD-95 pull-down core list (ortho) 120
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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