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Involvement of Erks activation in cadmium‐induced AP‐1 transactivation in vitro and in vivo

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Abstract

Cadmium is a potent and effective carcinogen in rodents and has recently been accepted by IARC (International Agency for Research on Cancer) as a category 1 carcinogen. Cadmium-induced up‐regulation of intracellular signaling pathways leading to increased mitogenesis is thought to be a major mechanism for the carcinogenic activity following chronic cadmium exposure. In the present study, we found that exposure of cells to cadmium induced significant activation of AP‐1 and all three members of the MAP kinase family in mouse epidermal JB6 cells. The induction of AP‐1 activity by cadmium appears to involve activation of Erks, since the induction of AP‐1 activity by cadmium was blocked by pretreatment of cells with PD98058. Interestingly, the induction of AP‐1 by cadmium was greatly enhanced by the chemical tumor promoter, TPA and the growth factor EGF, but not by ultraviolet C radiation. In vivo studies demonstrated that cadmium could also induce transactivation of AP‐1 in AP‐1‐luciferase report transgenic mice. Considering the role of AP‐1 activation in tumor promotion, the results presented in this study provide a possible molecular mechanism for cadmium‐induced carcinogenesis.

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References

  1. International Agency for Research on Cancer: Beryllium, cadmium, mercury and exposures in the glass manufacturing industry. IARC Monographs on the evaluation of carcinogenesis. Risks to Humans 58: 41–117, 1993

    Google Scholar 

  2. Degraeve N: Carcinogenic, tertogenic, and mutagenic effects of cadmium. Mutat Res 86: 115–135, 1981

    Google Scholar 

  3. Beyersmann D, Hechtenberg S: Cadmium, gene regulation and cellular signaling in mammalian cells. Toxicol Appl Pharmacol 144: 247–261, 1997

    Google Scholar 

  4. Buzard GS, Kasprzak KS: Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: A review. J Environ Pathol Toxicol Oncol 19: 179–199, 2000

    Google Scholar 

  5. Rossman TG, Roy NK, Lin W-C: Is cadmium genotoxic? In: G.F. Nordberg, R.F.M. Herber, L. Alessio (eds). Cadmium in the Human Environment: Toxicity and Carcinogenicity. International Agency for Research on Cancer, Lyon 22, pp 367–375

  6. Meplan C, Mann K, Hainaut P: Cadmium induced conformational modifications of wide-type p53 and suppresses p53 response to DNA damage in culture cells. J Biol Chem 274: 31663–31670, 1999

    Google Scholar 

  7. Ishikawa T, Igarashi T, Hata K, Fujita T: C-fos induction by heat, arsenite, and cadmium is mediated by a heat shock element in its promoter. Biochem Biophys Res Commun 254: 566–571, 1999

    Google Scholar 

  8. Waalkees MP, Rehm S: Cadmium and prostate cancer. J Toxicol Environ Health 43: 251–269, 1994

    Google Scholar 

  9. Achanzar WE, Achanzar KB, Lewis JG, Webber MM, Waalkees MP: Cadmium induced c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis. Toxicol Appl Pharmacol 164: 291–300, 2000

    Google Scholar 

  10. Abshire MK, Buzard GS, Shiraishi N, Waalkes MP: Induction c-myc and c-jun proto-oncogene expression in rat L6 myoblasts by cadmium in inhibited by zinc preinduction of the metallothionein gene. J Toxicol Environ Health 48: 359–377, 1996

    Google Scholar 

  11. Zheng H, Liu J, Choo KHA, Michalska AE, Klaassen CD: Metallothionein-I and-II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53. Toxicol Appl Pharmacol 136: 229–235, 1996

    Google Scholar 

  12. Ding W, Templeton DM: Stress-activated protein kinase-dependent induction of c-fos by Cd2+ is mediated by MKK7. Biochem Biophys Res Commun 273: 718–722, 2000

    Google Scholar 

  13. Coogan TP, Shiraishi N, Wallkes MP: Minimal basal activity and lack of metal-induced activation of the metallothionein gene correlates with lobe-specific sensitivity to the carcinogenic effects of cadmium in the rat prostate. Toxicol Appl Pharmacol 132: 164–173, 1995

    Google Scholar 

  14. Chuang S-M, Wang I-C, Yang J-L: Role of JNK, p38 and ERK mitogenactivated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis 7: 1423–1432, 2000

    Google Scholar 

  15. Elbirt KK, Whitmarch AJ, Davis RJ, Bonkovsky HL: Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells: Role of mitogen-activated protein kinases. J Biol Chem 273: 8922–8931, 2000

    Google Scholar 

  16. Matsuoka M, Igisu H: Activation of c-jun NH2-terminal kinase (JNK/ SAPK) in LLC-PK1cells by cadmium. Biochem Biophys Res Commun 251: 527–532, 1998

    Google Scholar 

  17. Huang C, Ma W-Y, Boden GT, Dong Z: Ultraviolet B-induced activated AP-1 activation does not require epidermal growth factor receptor but is blocked by a dominant negative PKC. J Biol Chem 49: 31262–31268, 1996

    Google Scholar 

  18. Rincon M, Flavell RA: AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J 13: 4370–4381, 1994

    Google Scholar 

  19. Huang C, Ma W-Y, Dawson MI, Rincon M, Flavell RA, Dong Z: Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid. Proc Natl Acad Sci USA 94: 5826–5830, 1997

    Google Scholar 

  20. Huang C, Ma W-Y, Hanenberger D, Cleary MP, Bowden GT, Dong Z: Inhibition of ultraviolet B-induced activator-protein-1 (AP-1) activity by aspirin in AP-1-luciferase transgenic mice. J Biol Chem 272: 26325–26331, 1997

    Google Scholar 

  21. Huang C, Ma W-Y, Young MR, Colburn N, Dong Z: Shortage of mitogen-activation protein kinase in responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Proc Natl Acad Sci USA 95: 156–161, 1998

    Google Scholar 

  22. Snow ET: Metal carcinogenesis: mechanistic implications. Pharmacol Therapeut 53: 31–65, 1992

    Google Scholar 

  23. Piscator M: Role of cadmium in carcinogenesis with special reference to cancer of the prostate. Environ Health Perspect 40: 107–120, 1981

    Google Scholar 

  24. Waalkes MP, Oberdorster G: Cadmium carcinogenesis. In: E.C. Foulkes (ed). Biological Effects of Heavy Metals, vol. 2. CRC Press, Boca Raton, FL, pp 129–158

  25. Angel P, Karin M: The role of Jun, Fos, and the AP-1 complex in cell-proliferation and transformation. Biochim Biophy Acta 1072: 129–157, 1991

    Google Scholar 

  26. Dong Z, Watts RG, Sun Y, Colburn NH: Progressive elevation of AP-1 activity during preneoplastic-to-neoplastic progression as modeled in mouse JB6 cell variants. Int J Oncol 7: 359–364, 1995

    Google Scholar 

  27. Dong, Z, Birrer MJ, Watts RG, Matrisian LM, Colburn NH: Blocking tumor promoter induced AP-1 activity inhibits induced transformation in JB6 cells. Proc Natl Acad Sci USA 91: 609–613, 1994

    Google Scholar 

  28. Huang C, Ma W-Y, Dong Z: Inhibitory effects of ascorbic acid on AP-1 activity and transformation in JB6 cells. Int J Oncol 8: 389–393, 1996

    Google Scholar 

  29. Huang C, Ma W-Y, Hecht SS, Dong Z: Inositol hexaphosphate inhibits cell transformation and AP-1 activation by targeting phosphatidylinositol-3 kinase. Cancer Res 57: 2873–2878

  30. Huang, C, Ma W-Y, Dong Z: Requirement of phosphatidylinositol-3 kinase in epidermal growth factor-induced AP-1 transactivation and transformation in JB6 P+ cells. Mol Cell Biol 16: 6427–6435, 1996

    Google Scholar 

  31. Huang C, Li J, Ma W-Y, Dong Z: JNKs activation is required for JB6 cell transformation induced by TNF-α but not by TPA. J Biol Chem 274: 29672–29676, 1999

    Google Scholar 

  32. Bernstein LR, Colburn NH: AP-1/jun function is differentially induced in promotion-sensitive and resistant JB6 cells. Science 244: 566–569, 1989

    Google Scholar 

  33. Watts RG, Huang C, Young MR, Li JJ, Dong Z, Pennie WD, Colburn NH: Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation. Oncogene 17: 3493–3498, 1998

    Google Scholar 

  34. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M: Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49: 729–739, 1987

    Google Scholar 

  35. Cohen DR, Curran T: Fra-1: A serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Mol Cell Biol 8: 2063–2069, 1988

    Google Scholar 

  36. Wilson CL, Heppner KJ, Labosky PA, Hogan BL, Matrisian LM: Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci USA 94: 1402–1407, 1997

    Google Scholar 

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Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, New York University School of Medicine, NY, 10016, USA

    Chuanshu Huang, Qunwei Zhang, Jingxia Li & Max Costa

  2. Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA

    Xianglin Shi & Vincent Castranova

  3. The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA

    Gong Ju

  4. The Institute of Neuroscience, The Fourth Military Medical University, Xi'an, 710032, P.R. China

    Zigang Dong

Authors
  1. Chuanshu Huang
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  2. Qunwei Zhang
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  3. Jingxia Li
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  4. Xianglin Shi
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  7. Max Costa
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Correspondence to Chuanshu Huang.

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Huang, C., Zhang, Q., Li, J. et al. Involvement of Erks activation in cadmium‐induced AP‐1 transactivation in vitro and in vivo. Mol Cell Biochem 222, 141–147 (2001). https://doi.org/10.1023/A:1017953927347

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