Key points are not available for this paper at this time.
The GSH/glutaredoxin (GRX) system is involved in the redox regulation of certain enzyme activities, and this system protects cells from H2O2-induced apoptosis by regulating the redox state of Akt (Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., and Kondo, T. (2003) J. Biol. Chem. 278, 50226–50233). Estrogens, such as 17β-estradiol (E2), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor α (ERα). However, the role of the ERβ-mediated pathway in this cytoprotection and the involvement of E2 in the redox regulation are not well understood. In the present study, we demonstrated that E2 protected cardiac H9c2 cells, expressing ERβ from H2O2-induced apoptosis concomitant with an increase in the activity of Akt. E2 induced the expression of glutaredoxin (GRX) as well as γ-glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both γ-glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E2 on cell survival as well as the activity of Akt, suggesting that ERβ is involved in the cytoprotection and redox regulation by E2. Transcription of the GRX gene was enhanced by E2. The promoter activity of GRX was up-regulated by an ERβ-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E2 on the redox state of Akt, a pathway that is mediated, at least in part, by ERβ. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy. The GSH/glutaredoxin (GRX) system is involved in the redox regulation of certain enzyme activities, and this system protects cells from H2O2-induced apoptosis by regulating the redox state of Akt (Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., and Kondo, T. (2003) J. Biol. Chem. 278, 50226–50233). Estrogens, such as 17β-estradiol (E2), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor α (ERα). However, the role of the ERβ-mediated pathway in this cytoprotection and the involvement of E2 in the redox regulation are not well understood. In the present study, we demonstrated that E2 protected cardiac H9c2 cells, expressing ERβ from H2O2-induced apoptosis concomitant with an increase in the activity of Akt. E2 induced the expression of glutaredoxin (GRX) as well as γ-glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both γ-glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E2 on cell survival as well as the activity of Akt, suggesting that ERβ is involved in the cytoprotection and redox regulation by E2. Transcription of the GRX gene was enhanced by E2. The promoter activity of GRX was up-regulated by an ERβ-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E2 on the redox state of Akt, a pathway that is mediated, at least in part, by ERβ. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy. Oxidative stress is a principle cause of the development of aging and diseases such as inflammation, infection, cancer, and cardiovascular disorders (1Berlett S.B. Stadtman E.R. J. Biol. Chem. 1997; 272: 20313-20316Abstract Full Text Full Text PDF PubMed Scopus (2789) Google Scholar, 2Finkel T. Holbrook N.J. Nature. 2000; 408: 239-247Crossref PubMed Scopus (7346) Google Scholar). Exogenous or endogenous sources of oxidative stress and weakened antioxidative defenses can damage macromolecules such as DNA, lipids, and proteins. Estrogens play an important role in development, growth, and the differentiation of both female and male secondary sex characteristics (3Yang S.H. Liu R. Perez E.J. Wen Y. Stevens S.M. Jr-Valencia T. Brun-Zinkernagel A.M. Prokai L. Will Y. Dykens J. Koulen P. Simpkins J.W. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4130-4135Crossref PubMed Scopus (411) Google Scholar). Protective effects of estrogen, such as 17β-estradiol (E2), 3The abbreviations used are: E2, 17β-estradiol; ER, estrogen receptor; ERE, estrogen-response element; GRX, glutaredoxin; γ-GCS, γ-glutamylcysteine synthetase; PP2A, protein phosphatase 2A; MTT, 3-(4,5-dimethyl-thiazole-2-yl)-2,5-diphenyltetrazolium bromide; HRP, horseradish peroxidase; PPT, propylpyrazoletriol; TBS, Tris-buffered saline; PDK1, 3-phosphoinositide-dependent protein kinase-1; TRX, thioredoxin; AMS, 4-acetamido-4′-maleimidylstilbene-2,2′-disulfonic acid; PBS, phosphate-buffered saline; RT, reverse transcription; BSO, buthionine sulfoximine; EpRE, electrophoretic response element. on oxidative stress have been indicated (4Baba T. Shimizu T. Suzuki Y. Ogawara M. Isono K. Koseki H. Kurosawa H. Shirakawa T. J. Biol. Chem. 2005; 280: 16417-16426Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). E2 regulates longevity signals to enhance resistance to oxidative stress in mice. Inhibitory effects of E2 on atherosclerosis are mediated by COX-2-derived prostacyclin (5Egan K.M. Lawson J.A. Fries S. Koller B. Rader D.J. Smyth E.M. Fitzgerald G.A. Science. 2004; 306: 1954-1957Crossref PubMed Scopus (388) Google Scholar). E2 induces production of antioxidative enzymes, such as superoxide dismutase (6Strehlow K. Rotter S. Wassmann S. Adam O. Grohe C. Laufs K. Bohm M. Nickenig G. Circ. Res. 2003; 93: 170-177Crossref PubMed Scopus (384) Google Scholar), γ-glutamylcysteine synthetase (γ-GCS), and glutathione S-transferase (7Montano M.M. Deng H. Liu M. Sun X. Singal R. Oncogene. 2004; 23: 2442-2453Crossref PubMed Scopus (61) Google Scholar). The effects of E2 are mediated mostly through ERα, which functions as a ligand-induced transcription factor and belongs to the nuclear receptor superfamily (8Beato M. Herrlich P. Schutz G. Cell. 1995; 83: 851-857Abstract Full Text PDF PubMed Scopus (1637) Google Scholar). ERα binds to a variety of ligands and displays tissue-specific effects through estrogen-response element (ERE). When estrogen-responsive genes do not contain EREs, ERα can up-regulate gene expression through AP-1 and Sp1 sites (9Schultz J.R. Petz L.N. Nardulli A.M. J. Biol. Chem. 2005; 280: 347-354Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Another ER, ERβ, is expressed in cells targeted by E2, including cardiomyocytes (10Foster C. Keitz S. Hultenby K. Warner M. Gustafsson J.A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 14234-14239Crossref PubMed Scopus (61) Google Scholar). However, the role of ERβ in protection against oxidative stress has not been well studied. Protein thiols act as redox-sensitive switches and are believed to be a key element in maintaining the cellular redox balance. The redox state of protein thiols is regulated by oxidative stress and redox signaling and important to cellular functions. To maintain the cellular thiol-disulfide redox status, living cells possess two major systems, the thioredoxin (TRX)/TRX reductase system and the glutathione (γ-glutamylcysteinyl glycine, GSH)/glutaredoxin (GRX) system (11Holmgren A. J. Biol. Chem. 1989; 264: 13963-13966Abstract Full Text PDF PubMed Google Scholar). GSH is synthesized in two sequential enzymatic reactions that are each catalyzed by a rate-limiting enzyme, γ-GCS, and GSH synthetase (12Meister A. Science. 1973; 180: 33-39Crossref PubMed Scopus (471) Google Scholar). GRX, also known as thioltransferase, was first discovered as a GSH-dependent hydrogen donor for ribonucleotide reductase in Escherichia coli mutants lacking TRX (13Holmgren A. Proc. Natl. Acad. Sci. U. S. A. 1976; 73: 2275-2279Crossref PubMed Scopus (363) Google Scholar). Oxidized GRX is recycled to the reduced by GSH with the of glutathione and of GSH by with and glutathione reductase J. Biol. Chem. Full Text PDF PubMed Google Scholar). GRX functions a by the which and the of PubMed Scopus Google Scholar). GRX also as a redox with TRX M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2003; PubMed Scopus Google Scholar). we have that GRX protects against oxidative cell from apoptosis by regulating the redox state of Akt H. Y. H. J. K. T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). is a and a of an signaling pathway that effects on survival and apoptosis X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Akt has been to be to signaling oxidative and and stress Sci. Full Text Full Text PDF PubMed Scopus Google Scholar). Akt can and transcription to an of apoptosis L. G.A. C. Oncogene. 2003; PubMed Scopus Google Scholar). The of Akt is and at and of Akt also of the two sites by protein phosphatase S. G. Biol. Cell. PubMed Scopus Google Scholar, M. T. P. J.W. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar). The of Akt to the survival of cells A. Circ. Res. 2000; PubMed Scopus Google Scholar). has been that the of activity is regulated by redox S. K. Y. H. J. H. Res. 1997; PubMed Scopus Google Scholar). However, the of redox regulation in the have not been we a mechanism for the antiapoptotic effect of E2 through the regulation of the redox state of Akt oxidative of cardiac H9c2 cells with E2 for protected against H2O2-induced E2 induced the expression of GRX at least in part, through ERβ-mediated GSH and GRX the redox of Akt on the of cells to was from against ERα and ERβ from was from was from and from and from was from 3-(4,5-dimethyl-thiazole-2-yl)-2,5-diphenyltetrazolium was from was from and from and from cells, a from and cancer cells, and cells, from the cancer cells from The for of and H9c2 cells in or and cells in The cells with in a of and at M. T. P. J.W. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar). was by a as S. K. Y. Y. T. J. Res. 93: PubMed Scopus Google Scholar). cells in of well in with of the cells for at with and with of in each an at the at was cells as the cells in a with cells with for to the of nuclear with was an and the a and to the expression of ERα and ERβ was as Y. K. S. M. T. T. 2004; PubMed Scopus Google Scholar). cells with in and with for at ERβ and in and for ERα of and in the with the and with in with or for at and with in sites with and or and in the of and a and used of the The results of for as or with the with or of a or cells and for at in as J. 2003; PubMed Scopus Google Scholar). The by of the at for used in Protein a Protein on or for protein The in the The in Tris-buffered and and and with in with at with the with horseradish in the the enhanced to the Akt activity was an Akt to the with protein as a of was by a specific Akt was from cell the and the at for in an by and to to an Protein activity was a phosphatase to the The and used as phosphatase of redox of by with T. S. M. H. T. K. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). with or cell or with at a of to and the as well as to redox The protein by at for at The in and and in a and by and to in the by as of was by with T. H. Y. S. Y. M. S. T. PubMed Scopus Google Scholar). The with a The of and as by J. T. Scholar). on a to a and with a specific system for the of was also an by a of of and each of of and of of from the cells was The for GRX GRX as a as an The for and The for and The for ERα ERα and for ERβ ERβ and and and the and for the for ERα and for ERβ and The was as at for the reverse for at and a of for as at at for and at at of GSH and a glutathione to the and GSH to The of GSH in the was by at of cell with and to the of GSH. in the was reduced to GSH a reductase and and the of as for GSH. Protein protein activity was an to the protein was first with for at and with for at the activity was by the with as a for at in the of of of the GRX gene promoter to S. J. A. PubMed Scopus Google was by The used as a and a reverse The was to was with and the the promoter from to was the of the to To a of the was with and for was with to as a by a The used as electrophoretic response element and reverse The was by with an system was H9c2 cells by to the of cells for and with E2 or for activity was with cellular by a system electrophoretic for the and element was as C. Y. S. Y. T. S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). to and with specific for the and element to the of the GRX promoter used as reactions in of and of nuclear and of the specific to the during the for as by of was of expression of in H9c2 cells was and the results of the cells, which are known to both ERα and ERβ H9c2 cells expressed ERβ not ERα the results of the ERβ not ERα was in H9c2 the both in of E2 on Oxidative the cytoprotective effect of E2 on oxidative apoptosis in H9c2 induces apoptosis or in cardiac H9c2 cells C. Y. S. Y. T. S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. K. P. Perez E.J. Liu R. Simpkins J.W. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). for maintaining cells, oxidative stress of cells, in to the effect of E2 on H2O2-induced oxidative the of in the was from to in the that in the cell by as with the The cell with for was of the of the cells with and E2 for the cell damage by and of the The increase in cell by E2 in and H2O2-induced was E2 protected against ICI182,780, an abolished the protective effect of E2 a specific inhibitor of ERα, on the protective effect of E2 These results suggest that the protective effect against oxidative stress on of the cells with E2 for regulation mediated by ERβ through a genomic pathway in this cell on the effect of E2 by the cells with E2 for nuclear was from the with E2 for with or a specific inhibitor of ERs, or and with for E2 and E2 and cells with E2 and E2 and E2 the of Akt in to Akt is known to the survival The Akt is involved in both the genomic L. J. J. 2004; PubMed Scopus Google and the pathway of E2 J. Biol. Cell. 2004; PubMed Scopus Google Scholar). the involvement of Akt in the cytoprotective effect of E2 in H9c2 of Akt was by in by and the was in and with E2 for in a increase in the H2O2-induced of Akt in by and the and and abolished the effect of E2 and The H2O2-induced of Akt activity as a was by E2 and and concomitant with the increase in the of Akt. The activity of PDK1, of Akt, was by E2 effect on the activity of The of Akt is regulated by H. Y. H. J. K. T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The activity of and as was not by and E2 The suggest that the in the activity of is not involved in the of the of Akt by E2. has been that Akt a redox-sensitive to H. Y. H. J. K. T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), and we that the redox state of Akt is by X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the redox state of Akt by with In cells, Akt mostly in an of cells with in a increase in an of Akt and In the cells with E2 for Akt in a reduced The reduced of Akt, by for was in and The that E2 Akt in a reduced oxidative The redox state of Akt is regulated by the and this system protects cells against H2O2-induced apoptosis by the of Akt with X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). we the effect of E2 on the of Akt in the of buthionine a specific inhibitor of γ-GCS, or an inhibitor of is a rate-limiting enzyme of GSH The effect of E2 on the was abolished both by and by These results suggest that E2 the of to cells against oxidative E2 the of and E2 the of GSH and E2 the of GSH The of GSH was cells in cells and cells in cells with E2 for The of in the cells was cells and was not by E2 not The expression of was up-regulated by E2 by in and E2 the expression of GRX by in and abolished the of GSH synthesis as well as GRX synthesis is that the redox state of Akt is regulated by an of the GRX/GSH The of GRX by E2 an by (7Montano M.M. Deng H. Liu M. Sun X. Singal R. Oncogene. 2004; 23: 2442-2453Crossref PubMed Scopus (61) Google Scholar), the expression of the is up-regulated by E2 an not by an To the mechanism of the regulation of GRX by E2, we used a genomic the promoter of GRX a The promoter or two sites to and to and Sp1 to The activity of the cells with E2 for was the was or of or Sp1 effect on the of the E2 the the of the in the expression of GRX, an electrophoretic was with nuclear from the cells with E2 for for in a of by E2 and in the of an of or with the for The of the the to the involvement of ERβ as a transcription factor that to the The of GRX not with or from the of the (7Montano M.M. Deng H. Liu M. Sun X. Singal R. Oncogene. 2004; 23: 2442-2453Crossref PubMed Scopus (61) Google Scholar). the the Sp1 was by E2 not of ERβ in the role of ERβ in protection against oxidative stress through redox regulation of Akt, we cancer cells, and in an that cells expressed ERβ effect of E2 on the activity of Akt was in cells and However, abolished the protective effect of E2 and E2 induced the expression of GRX and The results that the cytoprotective effect of E2 is mediated through redox regulation of Akt activity in ERβ-mediated against Oxidative are for the and differentiation of female to male and play a role in maintaining and cell functions (9Schultz J.R. Petz L.N. Nardulli A.M. J. Biol. Chem. 2005; 280: 347-354Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). has been used to and the and of The the first of the nuclear receptor to be ERα has been well and a major role in genomic in both and cytoprotection against oxidative cell damage has been in cells L. K. P. Perez E.J. Liu R. Simpkins J.W. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, L. J. J. 2004; PubMed Scopus Google and cancer cells J. Biol. Cell. 2004; PubMed Scopus Google Scholar). the the role of ERβ is not well understood. that of the genes regulated by ERβ are from regulated by ERα in response to E2 and estrogen receptor C. A. J. Biol. Cell. 2004; Scholar). ERβ regulates in cells, and a of ERβ was as a or factor of resistance in cancer H. J.W. M. M. Circ. Res. 2004; PubMed Scopus Google Scholar). These results suggest a role for ERβ in the regulation of cellular the of ERβ and mechanism are (3Yang S.H. Liu R. Perez E.J. Wen Y. Stevens S.M. Jr-Valencia T. Brun-Zinkernagel A.M. Prokai L. Will Y. Dykens J. Koulen P. Simpkins J.W. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4130-4135Crossref PubMed Scopus (411) Google Scholar). this is the first at the role of ERβ-mediated signals of E2 in redox regulation in response to oxidative of Akt in the of E2 by of Akt has been in the cytoprotective effect of E2 against oxidative This effect of E2 was and in cells X. X. S. X. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), cells Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar), and cancer cells S. M. A. Y. K. Y. 2004; PubMed Scopus Google Scholar). the M. S. R. A. A. Oncogene. 2003; PubMed Scopus Google that signals up-regulated the expression of Akt in cancer also demonstrated that signals up-regulated the expression of ERα in cells, suggesting that Akt a role in the and survival of cancer the mechanism by which Akt is by E2 was not In the present study, we in the involvement of Akt signals in the ERβ-mediated effect against oxidative H9c2 cells that ERβ that H2O2-induced apoptosis was the cells with E2 for the effect of E2 was mediated by a genomic pathway through and E2 the of Akt in response to the of the in ERβ-mediated Akt a role for the GRX/GSH system in the regulation of Akt X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Akt is a protein with and Akt is through a factor of the pathway L. G.A. C. Oncogene. 2003; PubMed Scopus Google Scholar). The of Akt is and at and of Akt also of the two sites by M. T. P. J.W. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar, A. Circ. Res. 2000; PubMed Scopus Google Scholar). The of Akt to the survival of cells S. K. Y. H. J. H. Res. 1997; PubMed Scopus Google Scholar). induces of Akt at and and the of Akt can be by X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). is a major phosphatase in the regulation of cellular including the regulation of cell gene and protein J. C. 2005; PubMed Scopus Google Scholar). have that Akt is also by at in cells T. H. H. J.A. M. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). we that the of Akt is by C. Y. S. Y. T. S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). induced the expression of the mediated by the element. In the present study, the activity and the expression of the not with E2 in H9c2 cells suggesting that the of may not be by of protein such as phosphatase A. J.A. Nature. 2003; PubMed Scopus Google Scholar), protein H. S. S. L. H. M. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), and Res. PubMed Scopus Google Scholar), has been In the present study, the activity of was not by suggesting that of by is not The redox state of Akt is regulated by X. M. Y. P. H. X. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). of Akt at and the of PP2A, to the of Akt. However, the activity of Akt is not by the In the present study, of Akt was in the with in the of and the with the of Akt for In such E2 Akt in the reduced This that E2 the functions of the The system regulates such as protein and protein 2005; PubMed Scopus Google Scholar). The present for the first that ERβ-mediated signaling E2 the activity of the system to Akt and protects cells against oxidative of and GRX by expression of in response to oxidative stress has been effects on the expression of (4Baba T. Shimizu T. Suzuki Y. Ogawara M. Isono K. Koseki H. Kurosawa H. Shirakawa T. J. Biol. Chem. 2005; 280: 16417-16426Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, K. Rotter S. Wassmann S. Adam O. Grohe C. Laufs K. Bohm M. Nickenig G. Circ. Res. 2003; 93: 170-177Crossref PubMed Scopus (384) Google Scholar), (6Strehlow K. Rotter S. Wassmann S. Adam O. Grohe C. Laufs K. Bohm M. Nickenig G. Circ. Res. 2003; 93: 170-177Crossref PubMed Scopus (384) Google Scholar), L. S. Circ. Res. 2005; PubMed Scopus Google Scholar), and (5Egan K.M. Lawson J.A. Fries S. Koller B. Rader D.J. Smyth E.M. Fitzgerald G.A. Science. 2004; 306: 1954-1957Crossref PubMed Scopus (388) Google Scholar). of GRX expression by E2 was in cells K. H. M. K. M. M. J. PubMed Scopus Google and in female L. J. J. 2004; PubMed Scopus Google Scholar). These a of TRX and GRX to the protection of cells against oxidative to ERβ, the expression of induced by E2 was to be mediated by ERβ (7Montano M.M. Deng H. Liu M. Sun X. Singal R. Oncogene. 2004; 23: 2442-2453Crossref PubMed Scopus (61) Google in cell In the present study, we that the expression of both GRX and is up-regulated by E2 in on the of the and with an increase in the of GSH is with such a E2 up-regulated the expression of GRX and of both GSH and GRX to the reduced of Akt. abolished the effect of E2 on the of Akt and also abolished the effect of E2 The of as well as GRX expression by E2 was abolished by suggesting involvement of the ERβ-mediated genomic effect of E2. The role of ERβ in the cytoprotection against oxidative stress was by the results cells involvement of ERα in the cytoprotective effect of E2 be in cells, is that the GRX/GSH system is involved in the cytoprotective and genomic effects of E2 on the redox state of Akt, a pathway that is mediated, at least in part, by ERβ. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy. in the of ERα and ERβ was (3Yang S.H. Liu R. Perez E.J. Wen Y. Stevens S.M. Jr-Valencia T. Brun-Zinkernagel A.M. Prokai L. Will Y. Dykens J. Koulen P. Simpkins J.W. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4130-4135Crossref PubMed Scopus (411) Google Scholar, Y. K. S. M. T. T. 2004; PubMed Scopus Google Scholar, J.A. Oncogene. 2005; PubMed Scopus Google Scholar, J. 2005; PubMed Scopus Google Scholar). ERα and ERβ in the in cells and cell and which may the tissue-specific functions and the two The role of the redox system in the antiapoptotic effect of E2 was In the present study, we that the of GRX expression by E2 is mediated by an element and The GRX promoter or two of to ERβ and the activity of Transcription of the GRX gene was by E2 by However, not to or This element may be a of In E2 has a cytoprotective effect against oxidative stress in H9c2 cells expressing ERβ. The genomic effect of E2 on the redox system Akt a mechanism that may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy. are to for
Urata et al. (2006) studied this question.
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