Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1997 Oct 15;25(20):4035–4040. doi: 10.1093/nar/25.20.4035

Functional modulation of estrogen receptor by redox state with reference to thioredoxin as a mediator.

S Hayashi 1, K Hajiro-Nakanishi 1, Y Makino 1, H Eguchi 1, J Yodoi 1, H Tanaka 1
PMCID: PMC146993  PMID: 9321654

Abstract

Redox regulation of transcription factors has recently been demonstrated for AP-1, NF-kappaB, Sp-1 and glucocorticoid receptor in vitro and in vivo. The redox state in estrogen-dependent cells possibly influences the function of estrogen receptor (ER), and the regulation of the function of ER is essential for understanding of growth and differentiation of these cells, as well as promotion and progression of estrogen-associated cancer. In this paper, we first analyzed the effects of redox state on transcriptional activity of ER in terms of pS2 mRNA expression and transfection of ERE-CAT plasmid in human breast cancer cells. Addition of H2O2 at low concentrations lowered levels of pS2 mRNA and also down-regulated ERE-CAT activity, which was recovered by transfection of thioredoxin (TRX) expression vector. Next, the transfection of antisense TRX plasmid diminished ERE-CAT activity, and the activity was recovered by co-transfected sense TRX. Furthermore, specific DNA binding activity of recombinant ER was inhibited by sulfhydryl-modifying reagents and restored by the addition of recombinant TRX protein in electrophoretic mobility shift assay. These results in vitro and in vivo revealed that the transcription activity of ER is strongly influenced by its redox state, which is reversibly modulated by endogenous redox effector protein, TRX.

Full Text

The Full Text of this article is available as a PDF (549.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abate C., Patel L., Rauscher F. J., 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990 Sep 7;249(4973):1157–1161. doi: 10.1126/science.2118682. [DOI] [PubMed] [Google Scholar]
  2. Arnold S. F., Vorojeikina D. P., Notides A. C. Phosphorylation of tyrosine 537 on the human estrogen receptor is required for binding to an estrogen response element. J Biol Chem. 1995 Dec 15;270(50):30205–30212. doi: 10.1074/jbc.270.50.30205. [DOI] [PubMed] [Google Scholar]
  3. Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
  4. Benner S. E., Clark G. M., McGuire W. L. Steroid receptors, cellular kinetics, and lymph node status as prognostic factors in breast cancer. Am J Med Sci. 1988 Jul;296(1):59–66. doi: 10.1097/00000441-198807000-00011. [DOI] [PubMed] [Google Scholar]
  5. Berggren M., Gallegos A., Gasdaska J. R., Gasdaska P. Y., Warneke J., Powis G. Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res. 1996 Nov-Dec;16(6B):3459–3466. [PubMed] [Google Scholar]
  6. Brown A. M., Jeltsch J. M., Roberts M., Chambon P. Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. Proc Natl Acad Sci U S A. 1984 Oct;81(20):6344–6348. doi: 10.1073/pnas.81.20.6344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bunone G., Briand P. A., Miksicek R. J., Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996 May 1;15(9):2174–2183. [PMC free article] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Ercolani L., Florence B., Denaro M., Alexander M. Isolation and complete sequence of a functional human glyceraldehyde-3-phosphate dehydrogenase gene. J Biol Chem. 1988 Oct 25;263(30):15335–15341. [PubMed] [Google Scholar]
  10. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fujii S., Nanbu Y., Nonogaki H., Konishi I., Mori T., Masutani H., Yodoi J. Coexpression of adult T-cell leukemia-derived factor, a human thioredoxin homologue, and human papillomavirus DNA in neoplastic cervical squamous epithelium. Cancer. 1991 Oct 1;68(7):1583–1591. doi: 10.1002/1097-0142(19911001)68:7<1583::aid-cncr2820680720>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  12. Gallegos A., Gasdaska J. R., Taylor C. W., Paine-Murrieta G. D., Goodman D., Gasdaska P. Y., Berggren M., Briehl M. M., Powis G. Transfection with human thioredoxin increases cell proliferation and a dominant-negative mutant thioredoxin reverses the transformed phenotype of human breast cancer cells. Cancer Res. 1996 Dec 15;56(24):5765–5770. [PubMed] [Google Scholar]
  13. Gasdaska J. R., Berggren M., Powis G. Cell growth stimulation by the redox protein thioredoxin occurs by a novel helper mechanism. Cell Growth Differ. 1995 Dec;6(12):1643–1650. [PubMed] [Google Scholar]
  14. Green S., Walter P., Kumar V., Krust A., Bornert J. M., Argos P., Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986 Mar 13;320(6058):134–139. doi: 10.1038/320134a0. [DOI] [PubMed] [Google Scholar]
  15. Grippo J. F., Holmgren A., Pratt W. B. Proof that the endogenous, heat-stable glucocorticoid receptor-activating factor is thioredoxin. J Biol Chem. 1985 Jan 10;260(1):93–97. [PubMed] [Google Scholar]
  16. Hayashi S., Imai K., Suga K., Kurihara T., Higashi Y., Nakachi K. Two promoters in expression of estrogen receptor messenger RNA in human breast cancer. Carcinogenesis. 1997 Mar;18(3):459–464. doi: 10.1093/carcin/18.3.459. [DOI] [PubMed] [Google Scholar]
  17. Hayashi S., Watanabe J., Kawajiri K. Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem. 1991 Oct;110(4):559–565. doi: 10.1093/oxfordjournals.jbchem.a123619. [DOI] [PubMed] [Google Scholar]
  18. Hayashi S., Watanabe J., Nakachi K., Eguchi H., Gotoh O., Kawajiri K. Interindividual difference in expression of human Ah receptor and related P450 genes. Carcinogenesis. 1994 May;15(5):801–806. doi: 10.1093/carcin/15.5.801. [DOI] [PubMed] [Google Scholar]
  19. Hayashi T., Ueno Y., Okamoto T. Oxidoreductive regulation of nuclear factor kappa B. Involvement of a cellular reducing catalyst thioredoxin. J Biol Chem. 1993 May 25;268(15):11380–11388. [PubMed] [Google Scholar]
  20. Holmgren A. Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide. Structure. 1995 Mar 15;3(3):239–243. doi: 10.1016/s0969-2126(01)00153-8. [DOI] [PubMed] [Google Scholar]
  21. Holmgren A. Thioredoxin. Annu Rev Biochem. 1985;54:237–271. doi: 10.1146/annurev.bi.54.070185.001321. [DOI] [PubMed] [Google Scholar]
  22. Hoskins K., Weber B. L. The biology of breast cancer. Curr Opin Oncol. 1994 Nov;6(6):554–559. doi: 10.1097/00001622-199411000-00004. [DOI] [PubMed] [Google Scholar]
  23. Hulka B. S., Chambless L. E., Wilkinson W. E., Deubner D. C., McCarty K. S., Sr, McCarty K. S., Jr Hormonal and personal effects on estrogen receptors in breast cancer. Am J Epidemiol. 1984 May;119(5):692–704. doi: 10.1093/oxfordjournals.aje.a113790. [DOI] [PubMed] [Google Scholar]
  24. Jakowlew S. B., Breathnach R., Jeltsch J. M., Masiakowski P., Chambon P. Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7. Nucleic Acids Res. 1984 Mar 26;12(6):2861–2878. doi: 10.1093/nar/12.6.2861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kato S., Endoh H., Masuhiro Y., Kitamoto T., Uchiyama S., Sasaki H., Masushige S., Gotoh Y., Nishida E., Kawashima H. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995 Dec 1;270(5241):1491–1494. doi: 10.1126/science.270.5241.1491. [DOI] [PubMed] [Google Scholar]
  26. Makino Y., Okamoto K., Yoshikawa N., Aoshima M., Hirota K., Yodoi J., Umesono K., Makino I., Tanaka H. Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system. J Clin Invest. 1996 Dec 1;98(11):2469–2477. doi: 10.1172/JCI119065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Masiakowski P., Breathnach R., Bloch J., Gannon F., Krust A., Chambon P. Cloning of cDNA sequences of hormone-regulated genes from the MCF-7 human breast cancer cell line. Nucleic Acids Res. 1982 Dec 20;10(24):7895–7903. doi: 10.1093/nar/10.24.7895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meyer M., Schreck R., Baeuerle P. A. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nakamura H., Matsuda M., Furuke K., Kitaoka Y., Iwata S., Toda K., Inamoto T., Yamaoka Y., Ozawa K., Yodoi J. Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. Immunol Lett. 1994 Sep;42(1-2):75–80. doi: 10.1016/0165-2478(94)90038-8. [DOI] [PubMed] [Google Scholar]
  30. Nomura Y., Miura S., Koyama H., Enomoto K., Kasumi F., Yamamoto H., Kimura M., Tominaga T., Iino H., Morimoto T. Relative effect of steroid hormone receptors on the prognosis of patients with operable breast cancer. A univariate and multivariate analysis of 3089 Japanese patients with breast cancer from the Study Group for the Japanese Breast Cancer Society on Hormone Receptors and Prognosis in Breast Cancer. Cancer. 1992 Jan 1;69(1):153–164. doi: 10.1002/1097-0142(19920101)69:1<153::aid-cncr2820690127>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  31. Oblong J. E., Berggren M., Gasdaska P. Y., Powis G. Site-directed mutagenesis of active site cysteines in human thioredoxin produces competitive inhibitors of human thioredoxin reductase and elimination of mitogenic properties of thioredoxin. J Biol Chem. 1994 Apr 22;269(16):11714–11720. [PubMed] [Google Scholar]
  32. Oshima H., Simons S. S., Jr Sequence-selective interactions of transcription factor elements with tandem glucocorticoid-responsive elements at physiological steroid concentrations. J Biol Chem. 1993 Dec 25;268(36):26858–26865. [PubMed] [Google Scholar]
  33. Reese J. C., Katzenellenbogen B. S. Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. Nucleic Acids Res. 1991 Dec 11;19(23):6595–6602. doi: 10.1093/nar/19.23.6595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schenk H., Klein M., Erdbrügger W., Dröge W., Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1672–1676. doi: 10.1073/pnas.91.5.1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Spector A., Yan G. Z., Huang R. R., McDermott M. J., Gascoyne P. R., Pigiet V. The effect of H2O2 upon thioredoxin-enriched lens epithelial cells. J Biol Chem. 1988 Apr 5;263(10):4984–4990. [PubMed] [Google Scholar]
  36. Tagaya Y., Maeda Y., Mitsui A., Kondo N., Matsui H., Hamuro J., Brown N., Arai K., Yokota T., Wakasugi H. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989 Mar;8(3):757–764. doi: 10.1002/j.1460-2075.1989.tb03436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tagaya Y., Wakasugi H., Masutani H., Nakamura H., Iwata S., Mitsui A., Fujii S., Wakasugi N., Tursz T., Yodoi J. Role of ATL-derived factor (ADF) in the normal and abnormal cellular activation: involvement of dithiol related reduction. Mol Immunol. 1990 Dec;27(12):1279–1289. doi: 10.1016/0161-5890(90)90032-u. [DOI] [PubMed] [Google Scholar]
  38. Taniguchi Y., Taniguchi-Ueda Y., Mori K., Yodoi J. A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene. Nucleic Acids Res. 1996 Jul 15;24(14):2746–2752. doi: 10.1093/nar/24.14.2746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wakasugi N., Tagaya Y., Wakasugi H., Mitsui A., Maeda M., Yodoi J., Tursz T. Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8282–8286. doi: 10.1073/pnas.87.21.8282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wu X., Bishopric N. H., Discher D. J., Murphy B. J., Webster K. A. Physical and functional sensitivity of zinc finger transcription factors to redox change. Mol Cell Biol. 1996 Mar;16(3):1035–1046. doi: 10.1128/mcb.16.3.1035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Xanthoudakis S., Miao G., Wang F., Pan Y. C., Curran T. Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. EMBO J. 1992 Sep;11(9):3323–3335. doi: 10.1002/j.1460-2075.1992.tb05411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yodoi J., Tursz T. ADF, a growth-promoting factor derived from adult T cell leukemia and homologous to thioredoxin: involvement in lymphocyte immortalization by HTLV-I and EBV. Adv Cancer Res. 1991;57:381–411. doi: 10.1016/s0065-230x(08)61004-0. [DOI] [PubMed] [Google Scholar]
  43. Yokomizo A., Ono M., Nanri H., Makino Y., Ohga T., Wada M., Okamoto T., Yodoi J., Kuwano M., Kohno K. Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Res. 1995 Oct 1;55(19):4293–4296. [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES