Oxidative Stress-dependent Structural and Functional Switching of a Human 2-Cys Peroxiredoxin Isotype II That Enhances HeLa Cell Resistance to H2O2-induced Cell Death

Abstract

Although biochemical properties of 2-Cys peroxiredoxins (Prxs) have been extensively studied, their real physiological functions in higher eukaryotic cells remain obscure and certainly warrant further study. Here we demonstrated that human (h) PrxII, a cytosolic isotype of human 2-Cys Prx, has dual functions as a peroxidase and a molecular chaperone, and that these different functions are closely associated with its adoption of distinct protein structures. Upon exposure to oxidative stress, hPrxII assumes a high molecular weight complex structure that has a highly efficient chaperone function. However, the subsequent removal of stressors induces the dissociation of this protein structure into low molecular weight proteins and triggers a chaperone-to-peroxidase functional switch. The formation of a high molecular weight hPrxII complex depends on the hyperoxidation of its N-terminal peroxidatic Cys residue as well as on its C-terminal domain, which contains a “YF motif” that is exclusively found in eukaryotic 2-Cys Prxs. A C-terminally truncated hPrxII exists as low and oligomeric protein species and does not respond to oxidative stress. Moreover, this C-terminal deletion of hPrxII converted it from an oxidation-sensitive to a hyperoxidation-resistant form of peroxidase. When functioning as a chaperone, hPrxII protects HeLa cells from H2O2-induced cell death, as measured by a terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and fluorescence-activated cell sorting analysis. Although biochemical properties of 2-Cys peroxiredoxins (Prxs) have been extensively studied, their real physiological functions in higher eukaryotic cells remain obscure and certainly warrant further study. Here we demonstrated that human (h) PrxII, a cytosolic isotype of human 2-Cys Prx, has dual functions as a peroxidase and a molecular chaperone, and that these different functions are closely associated with its adoption of distinct protein structures. Upon exposure to oxidative stress, hPrxII assumes a high molecular weight complex structure that has a highly efficient chaperone function. However, the subsequent removal of stressors induces the dissociation of this protein structure into low molecular weight proteins and triggers a chaperone-to-peroxidase functional switch. The formation of a high molecular weight hPrxII complex depends on the hyperoxidation of its N-terminal peroxidatic Cys residue as well as on its C-terminal domain, which contains a “YF motif” that is exclusively found in eukaryotic 2-Cys Prxs. A C-terminally truncated hPrxII exists as low and oligomeric protein species and does not respond to oxidative stress. Moreover, this C-terminal deletion of hPrxII converted it from an oxidation-sensitive to a hyperoxidation-resistant form of peroxidase. When functioning as a chaperone, hPrxII protects HeLa cells from H2O2-induced cell death, as measured by a terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and fluorescence-activated cell sorting analysis. Because of their distinct catalytic mechanism, ubiquitous localization, and wide range of novel properties, 2-Cys peroxiredoxins (Prxs) 1The abbreviations used are: Prx, peroxiredoxin; hPrx, human Prx; DMEM, Dulbecco's modified Eagle's medium; FACS, fluorescence-activated cell sorting; FBS, fetal bovine serum; PI, propidium iodide; ROS, reactive oxygen species; SEC, size exclusion chromatography; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling; CHAPS, 3-[(3-chlolamidopropyl)dimethylammonio]-1-propane sulfonate; CS, citrate synthase; Trx, thioredoxin; BSA, bovine serum albumin; PBS, phosphate-buffered saline; FITC, fluorescein isothiocyanate; DM, double mutant. have recently received considerable attention as a new type of antioxidant enzyme (1.Ritz D. Lim J. Reynolds C.M. Poole L.B. Beckwith J. Science. 2001; 294: 158-160Crossref PubMed Scopus (104) Google Scholar, 2.Woo H.A. Chae H.Z. Hwang S.C. Yang K.-S. Kang S.W. Kim K. Rhee S.G. Science. 2003; 300: 653-656Crossref PubMed Scopus (470) Google Scholar). In addition to functioning in hydrogen peroxide catalysis, 2-Cys Prxs have been shown to regulate mitogen-activated protein kinase activity (3.Veal E.A. Findlay V.J. Day A.M. Bozonet S.M. Evans J.M. Quinn J. Morgan B.A. Mol. Cell. 2004; 15: 129-139Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar) and to modulate the activity of NF-κB, a master transcription factor (4.Kang S.W. Chang T.-S. Lee T.-H. Kim E.S. Yu D.Y. Rhee S.G. J. Biol. Chem. 2004; 279: 2535-2543Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 5.Barford D. Curr. Opin. Struct. Biol. 2004; 14: 679-686Crossref PubMed Scopus (275) Google Scholar). These observations suggest that the proteins may function as peroxidases and serve as components of peroxide-mediated signaling cascades (5.Barford D. Curr. Opin. Struct. Biol. 2004; 14: 679-686Crossref PubMed Scopus (275) Google Scholar, 6.Neumann C.A. Krause D.S. Carman C.V. Das S. Dubey D.P. Abraham J.L. Bronson R.T. Fugiwara Y. Orkin S. Van Etten R.A. Nature. 2003; 424: 561-565Crossref PubMed Scopus (637) Google Scholar, 7.Delaunay A. Pflieger D. Barrault M.B. Vinh J. Toledano M.B. Cell. 2002; 111: 471-481Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar). Furthermore, numerous 2-Cys Prxs have been associated with various cellular phenomena, including cell proliferation and growth control, differentiation, immune responses, tumorigenesis, and apoptosis (8.Hirotsu S. Abe Y. Okada K. Nagahara N. Nishino T. Hakoshima T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12333-12338Crossref PubMed Scopus (235) Google Scholar). Specifically, it was reported that 2-Cys Prxs were overexpressed in several cancers (9.Noh D.Y. Ahn S.J. Lee R.A. Kim S.W. Chae H.Z. Anticancer Res. 2001; 21: 2085-2090PubMed Google Scholar, 10.Yanagawa T. Ishikawa T. Ishii T. Tabuchi K. Iwasa S. Bannai S. Omura K. Suzuki H. Yoshida H. Cancer Lett. 1999; 145: 127-135Crossref PubMed Scopus (112) Google Scholar, 11.Kinnula V.L. Lehtonen S. Kaarteenaho-wilk R. Kang S.W. Rhee S.G. Soini Y. J. Pathol. 2002; 196: PubMed Scopus Google Scholar, Lee Kim Res. 2001; PubMed Scopus Google Scholar) and in as and T. A. D. K. PubMed Scopus Google Scholar, K. N. Res. 2003; PubMed Scopus Google Scholar). In their was found to with the of to apoptosis by J. H. J. Res. 2002; PubMed Scopus Google Scholar) the Mol. Cancer Res. 2003; Google Scholar). to it is well that the of reactive oxygen species is in the of J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Lee E.S. J.M. S.J. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was that antioxidant including 2-Cys are in these in an by the to the cells from oxidative stress. However, that 2-Cys Prxs have catalytic peroxidases and that a to the catalytic Kang S.W. H.A. Hwang S.C. Chae H.Z. Kim K. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google it is not that their high in human their peroxidase function. we recently a novel molecular chaperone function of the cytosolic form of the 2-Cys Prxs and in Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). found that these proteins dual as peroxidases and molecular and that these distinct functions are by oxidative stress. the of the 2-Cys Prxs to their in a in J. Toledano M.B. Nature. 2003; PubMed Scopus Google Scholar). These with the high of human and 2-Cys Prxs and their catalytic properties, to human Prxs this chaperone function and to their functional in human the of on cytosolic 2-Cys Prxs Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google we hPrxII from the human as the of was of the human have Cys and to the 2-Cys and of these and to the (4.Kang S.W. Chang T.-S. Lee T.-H. Kim E.S. Yu D.Y. Rhee S.G. J. Biol. Chem. 2004; 279: 2535-2543Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Moreover, as the antioxidant enzyme in the physiological of is as by the that and Kim Yu Kim D.S. H. Lee J. S. Kang S.W. Lee Rhee S.G. Yu D.Y. 2003; PubMed Scopus Google Scholar). In we hPrxII proteins have been reported to with the protein J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google which have the of in in to the functional of hPrxII in we hPrxII in HeLa In on the of the that the C-terminal of 2-Cys Prxs in their activity Poole L.B. Science. 2003; 300: PubMed Scopus Google we the of the C-terminal of hPrxII in its dual of the protein contains a “YF motif” that is to eukaryotic 2-Cys Prxs J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Here we that in addition to its peroxidase hPrxII chaperone that these dual functions are by the N-terminal peroxidatic Cys residue and the C-terminal “YF of the we that the chaperone function of hPrxII a in as it oxidative in HeLa and cells were to growth in Dulbecco's modified Eagle's fetal bovine serum The cells were to a of and by with bovine serum and were from and and an it were by Kang A terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling was from Science. were from was from and the and hPrxII were from and of the and of the in hPrxII was from a human by A hPrxII protein a C-terminally truncated hPrxII from its including the and a double form of hPrxII the and the were by as Kang S.W. H.A. Hwang S.C. Chae H.Z. Kim K. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). hPrxII was in the The hPrxII a was by and the hPrxII was as Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and molecular of hPrxII were by size exclusion on a and as Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of and peroxidase activity of hPrxII to was by the in as Kang S.W. H.A. Hwang S.C. Chae H.Z. Kim K. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). activity of the protein was measured CS, and as Kang Kang Biol. 2002; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). to was in a with a cell and and HeLa cells were with phosphate-buffered and by and by the were and their protein was measured by PubMed Scopus Google Scholar). of the proteins were to the cell with of CHAPS, was as Kang S.W. H.A. Hwang S.C. Chae H.Z. Kim K. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of proteins were to a and the was with and of hPrxII in of hPrxII in the was into type the of the as a The cells were in to and in to the cells to the the cells were with properties of hPrxII in the cell were by on a of hPrxII into HeLa and of cells were an of in with cells were by a and in a of of various hPrxII with the and of the cell were in an was by of a which the cells were to with cells the various of hPrxII proteins were in the hPrxII were in in the of the in the hPrxII were on a and their cellular was of by and of HeLa cells was by and to the HeLa cells with various of hPrxII were on The were with and with The were with PBS, and the cells were by with in with were by terminal and fluorescein dUTP was by an with of cells were in by and propidium a as H. J. PubMed Scopus Google Scholar). fluorescein by an and were and a was used were of hPrxII has a high of and biochemical properties Poole L.B. Science. 2003; 300: PubMed Scopus Google Scholar) with and which were shown to as peroxidases and molecular Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). we the chaperone activity of hPrxII by its to the of that hPrxII of to which was used as a of was was used of of with of hPrxII a in and a of hPrxII to of was that hPrxII as an efficient molecular demonstrated that hPrxII protects the from In addition to these we the chaperone activity of hPrxII which is a of in and and is by oxidative Kang Kang Biol. 2002; PubMed Scopus Google Scholar, T. A. A. K. Y. Y. Res. 2004; PubMed Scopus Google Scholar). that by and of in with Kang Kang Biol. 2002; PubMed Scopus Google Scholar). However, the and of were by hPrxII that the chaperone function of hPrxII is in of a cytosolic protein in these it in addition to its well peroxidase hPrxII highly efficient molecular chaperone as was the and proteins Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The of hPrxII with and complex and we found that their dual peroxidase and chaperone functions were closely associated with the of in their protein Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Because hPrxII chaperone activity and high molecular weight molecular complex formation of a protein is a of a molecular chaperone J. J. Mol. Biol. PubMed Scopus Google we the molecular of hPrxII by that hPrxII of high molecular weight protein that have molecular from to When we further the molecular of protein in by with an on a of protein were in The protein of hPrxII in were to by However, the from a protein with a molecular of was of the protein that hPrxII exists as a complex of of its we that the dual functions of and are by their protein Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google we to this is the the human protein the by The molecular in of the were to of their biochemical properties in not The molecular weight hPrxII protein complex chaperone activity with a of peroxidase the the molecular weight proteins peroxidase activity and chaperone In the protein complex demonstrated peroxidase and chaperone as the These observations suggest that the peroxidase and chaperone of hPrxII are by the of in its protein structures. of the N-terminal Cys and the C-terminal of hPrxII on and in to the catalytic the peroxidatic Cys of 2-Cys Prxs is to which with a to form an H.Z. S.J. Rhee S.G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). However, exposure of cells to of the peroxidatic Cys is to H.A. Chae H.Z. Hwang S.C. Yang K.-S. Kang S.W. Kim K. Rhee S.G. Science. 2003; 300: 653-656Crossref PubMed Scopus (470) Google Scholar, Kang S.W. H.A. Hwang S.C. Chae H.Z. Kim K. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). induces in the protein structure of 2-Cys Prxs and the of their functions from peroxidases to molecular Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The of 2-Cys Prxs is by and Yu S. Kang S.W. Rhee S.G. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee S. Kim Kim K. K. Chae H.Z. 2002; PubMed Scopus Google Scholar). 2-Cys Prxs have been from of which is to hyperoxidation by the is to hyperoxidation J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). In that the that the of the to oxidative was of the of a C-terminal the the of these we proteins of a C-terminally truncated protein that the and the double form the proteins in we the of their protein structure and functions in the of various of the form of the and of hPrxII not form higher with in the of a Trx, and Furthermore, the peroxidase activity of was not by high of that the C-terminal converted the oxidation-sensitive form of hPrxII into an the not peroxidase in the of a the chaperone activity of hPrxII exposure to of the chaperone functions of the and were not by These suggest that the catalytic Cys of hPrxII as an efficient to of the protein structure and functions and that the in its protein structure by the C-terminal is to oxidative in is with has been with as its chaperone activity to by different that are and Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the 2-Cys Prxs that C-terminal oxidative Poole L.B. Science. 2003; 300: PubMed Scopus Google Scholar). have oxidative 2-Cys Prxs an C-terminal that the of the proteins the of eukaryotic of hPrxII in that the protein and functions of and are to oxidative in Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google we hPrxII is this we HeLa cells with various of cell and to and by an The hPrxII proteins from HeLa cells in of low and oligomeric protein in exposure to in the of the proteins converted into high molecular weight in a a we that the H2O2-induced high molecular weight complex from the hyperoxidation of the Cys of hPrxII H.A. Kang S.W. Kim Yang K.-S. Chae H.Z. Rhee S.G. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of we HeLa cell protein on and to with hPrxII and of the hPrxII in a form in the of of hPrxII were by exposure to and this was associated with a in the form of the protein The H2O2-induced hyperoxidation of hPrxII was by the When we from the to the in of the high molecular weight of hPrxII were to their in the it is that the protein of hPrxII are by oxidative in a Moreover, of hPrxII are by functional it is that the of its peroxidase function does not the of its catalytic as a its molecular chaperone function. of hPrxII in the of hPrxII protein structure in we hPrxII the of in The protein of hPrxII were different from in HeLa cells as by on a with an of the hPrxII protein structure were in When the cells hPrxII were to to the in of low molecular weight proteins were converted into high molecular weight However, in with which as a Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) hPrxII was by the to form high molecular weight In in to the of protein the high molecular weight of hPrxII in the cells to to their the the These suggest that used the high molecular weight complex formation of and the in J. Toledano M.B. Nature. 2003; PubMed Scopus Google Scholar) the function of its as H.A. Lee S.M. S. Rhee S.G. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) Science. 2004; PubMed Scopus Google in the dissociation of the high molecular weight in of hPrxII HeLa from H2O2-induced low of that are not to cells the of the hPrxII structure and function in the physiological of the functional of hPrxII from a peroxidase to a molecular chaperone, hPrxII and a their were and into the The were into HeLa and cell that overexpressed the hPrxII proteins were of cell that the of hPrxII in the HeLa cells was higher the in cells with the not In the and of hPrxII were to the hPrxII as by on an an of the proteins the was by the with an the protein of hPrxII the HeLa cells to and the of the cells by and with an that in HeLa hPrxII from low and oligomeric to high molecular weight of with these high molecular weight in not However, the low molecular weight protein of the and were not by that the catalytic Cys and the C-terminal of hPrxII the are high molecular weight complex formation in and in to cell HeLa cells with the were to with of cells and In cells hPrxII to H2O2-induced cell the and may the chaperone function of hPrxII protects the of by oxidative stress. it may the high molecular weight of signaling cascades that cell These are with that a function of and in H. Lee E.S. J.M. S.J. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and cell J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google in the was not to the chaperone function of these The of HeLa cells and hPrxII proteins were higher of cells of cells hPrxII and that the chaperone activity of the hPrxII proteins that is on an Cys residue to to a to cells from oxidative stress. The of cells in the of oxidative was associated with apoptosis we the H2O2-induced apoptosis of HeLa cells the various of hPrxII by and which and has been shown that and to the of the are of a in cell H. J. PubMed Scopus Google Scholar). In cells are found in the cells are in the and cells are in the with it was that the exposure of type HeLa cells to the of and cells However, of hPrxII in HeLa cells this apoptosis as shown in In the cells hPrxII of cell In observations suggest that the chaperone function of hPrxII protects human cells from Although various have that the 2-Cys a of peroxidase are associated with cellular A. Pflieger D. Barrault M.B. Vinh J. Toledano M.B. Cell. 2002; 111: 471-481Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar, J. Y. 2002; PubMed Scopus Google their functions in cells remain Although as these low activity and are to the catalytic low of H.A. Chae H.Z. Hwang S.C. Yang K.-S. Kang S.W. Kim K. Rhee S.G. Science. 2003; 300: 653-656Crossref PubMed Scopus (470) Google Scholar, Poole L.B. Science. 2003; 300: PubMed Scopus Google Scholar). that may the A of of 2-Cys Prxs by and (5.Barford D. Curr. Opin. Struct. Biol. 2004; 14: 679-686Crossref PubMed Scopus (275) Google Scholar, A. N. A. J.M. PubMed Scopus Google Scholar) that the functional of 2-Cys Prxs in were closely to their protein structures. The were in from to in a highly in to a of including and as found that the in structure of hPrxII in HeLa cells was by and the protein structure from low molecular weight species to high molecular weight oxidative In the of hPrxII was closely associated with a in its These in well with has been the cytosolic of 2-Cys Prxs Lee Lee Lee Kim Kang Rhee S.G. Lee Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). in the we that the of 2-Cys Prxs in its protein structure and functions is from as to including chaperone activity is by the of the is in a as the and human 2-Cys Prxs. Although is as a molecular chaperone in a the protein its structure from a to an oligomeric species oxidative and its chaperone activity T. T. K. K. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). it that the activity of several chaperone proteins is by and that this may an that signaling in cells 2003; PubMed Scopus Google Scholar). In to the 2-Cys Prxs and exists as oligomeric with a of chaperone Upon stress, these into that a higher chaperone the N-terminal of a in these and functional A. H. S. T. J. J. Mol. Biol. 2004; PubMed Scopus Google Scholar). The of eukaryotic 2-Cys Prxs on the N-terminal catalytic Cys and the C-terminal the is found in eukaryotic to the of eukaryotic 2-Cys J. Poole L.B. Sci. 2003; Full Text Full Text PDF PubMed Scopus Google the protein in a with the of of a and the to the catalysis, the peroxidatic Cys in the to Cys induces a in the eukaryotic 2-Cys protein structure that the to the C-terminal of 2-Cys The proteins form a is by that to a this catalytic the C-terminal to the peroxidatic Cys of 2-Cys is and in a well In this the form of 2-Cys with to 2-Cys hPrxII was shown to to with not hPrxII with (4.Kang S.W. Chang T.-S. Lee T.-H. Kim E.S. Yu D.Y. Rhee S.G. J. Biol. Chem. 2004; 279: 2535-2543Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). However, the formation of the is a the Cys of the 2-Cys Prxs are the form of eukaryotic 2-Cys to in that on the of The is the the with the C-terminal of the to form a In the which in the of high of and a the further into is with that the C-terminal of hPrxII the oxidation-sensitive protein into an in the to form high molecular weight in the of oxidative and this is that the eukaryotic 2-Cys the 2-Cys which and not the C-terminal are their C-terminal higher the formation of the and the hyperoxidation of the to oxidative Kim Yu Kim D.S. H. Lee J. S. Kang S.W. Lee Rhee S.G. Yu D.Y. 2003; PubMed Scopus Google Scholar, Poole L.B. Science. 2003; 300: PubMed Scopus Google Scholar, J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). in eukaryotic 2-Cys Prxs that the molecular of their these to by hyperoxidation Lee S. Kim Kim K. K. Chae H.Z. 2002; PubMed Scopus Google Scholar). The of the C-terminal of 2-Cys Prxs in oxidative is shown in S. which 2-Cys of these which the C-terminal is highly to by oxidative stress, the a C-terminal and is to hyperoxidation J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). it has been that a truncated form of C-terminal was by was in PubMed Scopus Google Scholar). with that of the 2-Cys Prxs their may regulate their protein and functions in hPrxII has a chaperone function may of the cellular functions of 2-Cys Prxs. The that this chaperone function is to is shown by 2-Cys which a of several and the of proteins C.A. Krause D.S. Carman C.V. Das S. Dubey D.P. Abraham J.L. Bronson R.T. Fugiwara Y. Orkin S. Van Etten R.A. Nature. 2003; 424: 561-565Crossref PubMed Scopus (637) Google Scholar). that the chaperone function of and oxidative further the in of the chaperone function of 2-Cys Prxs S. J. 2004; PubMed Scopus Google Scholar). Moreover, it that the chaperone function of the 2-Cys Prxs protects cells from Although the by which triggers apoptosis is not well S. Nature. 1999; PubMed Scopus Google Scholar, R. R. 1999; PubMed Scopus Google it is well that ROS, including apoptosis in various cell H. Lee E.S. J.M. S.J. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.J. J. Biol. 1999; 145: PubMed Scopus Google Scholar). Here we demonstrated that H2O2-induced of HeLa cells is by the chaperone function of hPrxII and which is with of an of and Kang S.W. Rhee S.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is to that 2-Cys are overexpressed in a of human including several of and (9.Noh D.Y. Ahn S.J. Lee R.A. Kim S.W. Chae H.Z. Anticancer Res. 2001; 21: 2085-2090PubMed Google Scholar, 10.Yanagawa T. Ishikawa T. Ishii T. Tabuchi K. Iwasa S. Bannai S. Omura K. Suzuki H. Yoshida H. Cancer Lett. 1999; 145: 127-135Crossref PubMed Scopus (112) Google Scholar, 11.Kinnula V.L. Lehtonen S. Kaarteenaho-wilk R. Kang S.W. Rhee S.G. Soini Y. J. Pathol. 2002; 196: PubMed Scopus Google Scholar, K. N. Res. 2003; PubMed Scopus Google Scholar, J. H. J. Res. 2002; PubMed Scopus Google Scholar). new to the of the molecular chaperone function of 2-Cys Prxs in these their is that a oxidative stress. is that to the of that are closely associated with a reported that 2-Cys in was associated with an and of T. Iwasa S. Ishii T. K. H. K. Omura K. H. Suzuki H. H. Cancer Lett. PubMed Scopus (104) Google Scholar). that hPrxII oxygen and of that this enzyme may to human In hPrxII functions as an antioxidant protein low its function from a peroxidase to a molecular chaperone high this functional with the of its C-terminal domain, its protein structure hyperoxidation of its peroxidatic The oxidative chaperone function of hPrxII not of it may to the of human A. Pflieger D. Barrault M.B. Vinh J. Toledano M.B. Cell. 2002; 111: 471-481Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar, D. 2002; PubMed Scopus Google Scholar).