Requirement of Erk, but Not JNK, for Arsenite-induced Cell Transformation

Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associated with cancers of skin, lung, liver, and bladder. However, the mechanism by which arsenite causes cancer is not well understood. In this study, we found that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 μm) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 μm, while higher doses (more than 50 μm) are required for activation of JNK. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant negative Erk2 into cells, while expression of dominant negative Erk2 did not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2. In contrast, overexpression of dominant negative JNK1 was shown to increase cell transformation even though it inhibits arsenite-induced JNK activation. Our results not only show that arsenite induces Erk activation, but also for the first time demonstrates that activation of Erk, but not JNK, by arsenite is required for its effects on cell transformation. Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associated with cancers of skin, lung, liver, and bladder. However, the mechanism by which arsenite causes cancer is not well understood. In this study, we found that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 μm) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 μm, while higher doses (more than 50 μm) are required for activation of JNK. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant negative Erk2 into cells, while expression of dominant negative Erk2 did not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2. In contrast, overexpression of dominant negative JNK1 was shown to increase cell transformation even though it inhibits arsenite-induced JNK activation. Our results not only show that arsenite induces Erk activation, but also for the first time demonstrates that activation of Erk, but not JNK, by arsenite is required for its effects on cell transformation. Arsenite is introduced into the environment during energy production based on coal, oil shale, and geothermal sources. Once in the environment, arsenite represents a potential health hazard of unknown magnitude. Arsenite is associated with increased risks of human cancer of the skin, respiratory tract, hematopoietic system, and urinary bladder (1Bettley L.R. O'Shea J. Br. J. Dermatol. 1975; 92: 563-568Crossref PubMed Scopus (70) Google Scholar, 2Evans S. Br. J. Dermatol. 1977; 97: 13-16Crossref Scopus (18) Google Scholar, 3Landolph J.R. Environ. Health Perspect. 1994; 102: 119-125Crossref PubMed Scopus (71) Google Scholar, 4Waalkes M.P. Goyer R.A. Klaassen C.D. Waalkes M.P. Metal Toxicology. Academic Press, New York1995: 54-56Google Scholar). Epidemiological investigations indicated that long-term arsenic exposure results in promotion of carcinogenesis, especially in lung and skin via inhalation and ingestion (5International Agency for Research on Cancer IARC Monogr. Eval. Carcinog. Risk Hum. 1980; 23: 37-141Google Scholar). Many cases of skin cancer have been documented in people exposed to arsenite through medical or other occupational exposures. It has been reported that high arsenic levels in drinking water (0.35–1.14 mg/liter) increased risks of cancer of skin, bladder, kidney, lung, and colon (1Bettley L.R. O'Shea J. Br. J. Dermatol. 1975; 92: 563-568Crossref PubMed Scopus (70) Google Scholar,2Evans S. Br. J. Dermatol. 1977; 97: 13-16Crossref Scopus (18) Google Scholar, 5International Agency for Research on Cancer IARC Monogr. Eval. Carcinog. Risk Hum. 1980; 23: 37-141Google Scholar, 6Tseng W.P. Chu M.M. How S.W. J. Natl. Cancer Inst. 1968; 40: 453PubMed Google Scholar). Hence, arsenite is a well documented human carcinogen (5International Agency for Research on Cancer IARC Monogr. Eval. Carcinog. Risk Hum. 1980; 23: 37-141Google Scholar,7Lansdown A.B.G. Crit. Rev. Toxicol. 1995; 25: 397-462Crossref PubMed Scopus (121) Google Scholar). Previously, several hypotheses have been proposed to describe the mechanism of arsenite-induced carcinogenesis (8Cobo J.M. Valdez J.G. Gurley L.R. Toxic. In Vitro. 1995; 9: 459-465Crossref PubMed Scopus (7) Google Scholar, 9Liu Y. Guyton K.Z. Gorospe M. Xu Q. Lee J.C. Holbrook N.J. Free Rad. Biol. Med. 1996; 21: 771-781Crossref PubMed Scopus (190) Google Scholar, 10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar, 11Jha A.N. Noditi M. Nilsson R. Natarajan A.T. Mutat. Res. 1992; 284: 215-221Crossref PubMed Scopus (157) Google Scholar, 12Nakamuro K. Sayato Y. Mutat. Res. 1981; 88: 73-80Crossref PubMed Scopus (34) Google Scholar, 13Zhao C.Q. Young M.R. Diwan B.A. Coogan T.P. Waalkes M.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10907-10912Crossref PubMed Scopus (479) Google Scholar, 14Ludwig S. Hoffmeyer A. Goebeler M. Kilian K. Häfner H. Neufeld B. Han J. Rapp U.R. J. Biol. Chem. 1998; 273: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). It has been suggested that arsenic induces chromosome aberration and sister chromatid exchange which may be involved in arsenite-induced carcinogenesis (11Jha A.N. Noditi M. Nilsson R. Natarajan A.T. Mutat. Res. 1992; 284: 215-221Crossref PubMed Scopus (157) Google Scholar, 12Nakamuro K. Sayato Y. Mutat. Res. 1981; 88: 73-80Crossref PubMed Scopus (34) Google Scholar). Recently, Zhao et al. (13Zhao C.Q. Young M.R. Diwan B.A. Coogan T.P. Waalkes M.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10907-10912Crossref PubMed Scopus (479) Google Scholar) reported that arsenic may act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression. Additionally, it was found that arsenite is a potent stimulator of extracellular signal-regulated protein kinase (Erk) 1The abbreviations used are: Erk, extracellular signal-regulated protein kinases; AP-1, activated protein-1; BME, basal medium Eagle; CMV, cytomegalovirus; EGF, epidermal growth factor; FBS, fetal bovine serum; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinases; MEM, minimal essential medium; TPA, 12-O-tetradecanoylphorbol-13-acetate. and AP-1 transactivational activity and an efficient inducer of c-fosand c-jun gene expression (10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar, 14Ludwig S. Hoffmeyer A. Goebeler M. Kilian K. Häfner H. Neufeld B. Han J. Rapp U.R. J. Biol. Chem. 1998; 273: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). Induction of c-jun and c-fos by arsenite is associated with activation of JNK (10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar). However, the role of JNK activation by arsenite in cell transformation or tumor promotion is unclear. We have established cell culture conditions for studying arsenite-induced cell transformation in this report. Furthermore, our data have shown that activation of Erk, but not JNK, is required for cell transformation induced by arsenite. CMV-neo vector plasmid was constructed as previously reported (15Huang C. Ma W.-Y. Dong Z. Mol. Cell. Biol. 1996; 16: 6427-6435Crossref PubMed Scopus (153) Google Scholar, 16Dong Z. Huang C. Ma W.-Y. Malewicz B. Baumann W.J. Kiss Z. Oncogene. 1998; 17: 1845-1853Crossref PubMed Scopus (20) Google Scholar); dominant negative JNK1 (pcDNA-flag-JNK1 (APF)) was from Dr. Roger J. Davis, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School (17Chen Y.R. Wang X. Templeton D. Davis R.J. Tan T.H. J. Biol. Chem. 1996; 271: 31929-31936Abstract Full Text Full Text PDF PubMed Scopus (856) Google Scholar, 18Dérijard B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1025-1037Abstract Full Text PDF PubMed Scopus (2957) Google Scholar); fetal bovine serum (FBS) and Eagle's minimal essential medium (MEM) were from Biowhittaker; LipofectAMINE was from Life Technologies, Inc.; TPA was from Sigma; rabbit polyclonal IgG against PKCα was from Santa Cruz Biotechnology; EGF was from Collaborative Research; luciferase assay substrate was from Promega; and PhosphoPlus MAPK antibody kit, phospho-MEK1/2 antibody, and p44/42 MAP kinase assay kit were from New England Biolabs. JB6 P+ mouse epidermal cell line, Cl 41, and its dominant negative Erk2-K52R transfectants, C1 41 DN MAPK-DN B3 mass1 (19Watts R.G. Huang C. Young M.R. Li J.-J. Dong Z. Pennie W.D. Colburn N.H. Oncogene. 1998; 17: 3493-3498Crossref PubMed Scopus (107) Google Scholar), as well as dominant negative JNK1 (pcDNA-flag-JNK1 APF) transfectant, C141 DN JNK1 mass2, were cultured in monolayers at Eagle's minimal essential medium fetal and of Colburn N.H. 1995; 16: PubMed Scopus Google Scholar, C. Ma Dong Z. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). JB6 Cl 41 cells were cultured in a We used of CMV-neo vector with or of dominant negative JNK1 (pcDNA-flag-JNK1 APF) plasmid DNA and of LipofectAMINE to well in the of the medium was by the of the the cells were with and cell were into culture and cultured for with were by against JNK. Cl 41 mass1 and Cl 41 DN JNK1 established and cultured in for at for of Erk and JNK was MAPK against of Erk and JNK as previously C. Ma W.-Y. Dong Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, C. Ma W.-Y. Young M.R. Colburn Dong Z. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). were from New England and used to the PKCα was used as an for protein were by New England JNK assay was as previously C. Ma W.-Y. Dong Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, C. Ma M. Dong Z. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). JB6 C141 cells were for in in cells were with and exposed to or arsenite at the concentration and indicated in the the cells were with and in of were and and the was with of N-terminal c-Jun protein to at were with of with and with of kinase kinase were in the of at for c-Jun phosphorylation was by a and c-Jun against phosphorylation of c-Jun at Erk activity was as the of New England Biolabs. In JB6 Cl 41 were for in at cells were exposed to arsenite for the doses and cells were with and in of were and and the was with p44/42 MAP kinase antibody for at with protein at were with of with and with of kinase of phosphorylation of by with antibody, the kinase were in the of of protein and at for phosphorylation is by a and against phosphorylation of at of phosphorylation of by of from the kinase were in the of of protein and of at for results were as and the were and JB6 Cl 41 cells or were exposed to arsenite and TPA in of of in well of were in for of was to well and the in the for and arsenite-induced cell were at the of the and cells were exposed to TPA or was by the of the of expression of dominant negative of JNK1 or Erk2 on cell of Cl 41 AP-1 Cl 41 MAPK-DN B3 or Cl 41 cells were into well of a of the cells were or were not with TPA or EGF for of was to cells were and the of was with a results were as Arsenite is a carcinogen (1Bettley L.R. O'Shea J. Br. J. Dermatol. 1975; 92: 563-568Crossref PubMed Scopus (70) Google Scholar, 2Evans S. Br. J. Dermatol. 1977; 97: 13-16Crossref Scopus (18) Google Scholar, 3Landolph J.R. Environ. Health Perspect. 1994; 102: 119-125Crossref PubMed Scopus (71) Google Scholar, 4Waalkes M.P. Goyer R.A. Klaassen C.D. Waalkes M.P. Metal Toxicology. Academic Press, New York1995: 54-56Google Scholar). have suggested that arsenite as a tumor than an Cancer 1996; PubMed Scopus Google Scholar). However, is cell transformation model for studying the mechanism of the tumor promotion of arsenite. mouse epidermal JB6 cell is a model to tumor arsenite induces JB6 cell we exposed JB6 Cl 41 cells to arsenite in were in the arsenite However, the transformation was and the were than induced by TPA, which were of exposure cell transformation only be in cells exposed to low concentration μm) of while cell transformation were at high of arsenite μm) Previously, we and have reported that to AP-1 activation are required for cell transformation induced by tumor as TPA and EGF to C. Ma W.-Y. Young M.R. Colburn Dong Z. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, R.G. Colburn N.H. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, Z. Huang C. Ma J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). It was also reported that arsenite is a potent stimulator of AP-1 activity and JNK activity (10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar). the for transformation activity of we its effects on MAP kinase in our We found that arsenite activation of JNK and However, the activation of JNK and Erk by arsenite is the time and Erk activation be at exposure and at and was of Erk by arsenite a exposure In contrast, activation of JNK was only at high μm) and of exposure and results indicated that of arsenite for activation of Erk, but not JNK, are with for cell transformation. Erk activation may be involved in arsenite-induced cell transformation. Interestingly, we also in cells with arsenite for we used antibody were with the Erk activation we used the Erk antibody for this may be to of antibody with phosphorylation of Erk the Erk activity induced by we the Erk activity by from results that exposure of cells to arsenite markedly an increase of from to the Erk substrate to be in a of Erk activity by arsenite is to induced by of TPA or EGF We have Erk phosphorylation and phosphorylation of by of from from are However, the by is than that by Erk phosphorylation of activation of Erk and JNK by arsenite. JB6 Cl 41 cells were into well of at for the cells were for by medium with cells were exposed to TPA or the medium was to the cells were or were not exposed to TPA or or of arsenite as cells were at the time as of and JNK as well as protein kinase were as in the antibody kit England assay of JNK JB6 C1 41 cells were cultured in monolayers in to cells were by the medium with medium for the cells were or were not exposed to TPA for or of arsenite for cells were and JNK activity was as previously C. Ma M. Dong Z. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google of Erk activation by JB6 Cl 41 cells were into or and cultured in cells were for medium with cells were exposed to the medium was to the cells were with of arsenite for the cells were with antibody against Erk is used to Erk from cell were with of protein in the of kinase and of results were as and the were and the cells were with and Erk as well as were as in the PhosphoPlus MAPK antibody kit England a role of JNK activation in arsenite-induced cell we established a dominant negative JNK1 transfectant, Cl 41 DN JNK1 dominant negative JNK1 is the that the phosphorylation and to and B. Hibi M. Wu I.-H. Barrett T. Su B. Deng T. Karin M. Davis R.J. Cell. 1994; 76: 1025-1037Abstract Full Text PDF PubMed Scopus (2957) Google Scholar, R.G. Huang C. Young M.R. Li J.-J. Dong Z. Pennie W.D. Colburn N.H. Oncogene. 1998; 17: 3493-3498Crossref PubMed Scopus (107) Google Scholar). JNK activation. was by culture of as previously C. Ma W.-Y. Young M.R. Colburn Dong Z. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). dominant negative JNK1 have effects on JNK activation, we the JNK phosphorylation induced by arsenite dominant negative Cl 41 the Cl 41 CMV-neo results show that arsenite-induced JNK phosphorylation was by introduction of dominant negative while were effects on arsenite-induced Erk phosphorylation of dominant negative JNK1 was shown to increase the cell transformation by arsenite with the results the the for JNK activation and and the transformation at arsenite we the role of arsenite-induced JNK activation in cell transformation induced by arsenite is blocked by introduction of dominant negative but not dominant negative C1 41 C1 41 mass2, or C1 41 MAPK DN were or were not exposed to of arsenite in of of in well of were in for of was to well and the were in for arsenite-induced cell were at the cells were exposed to results that Erk activation by arsenite may be involved in its cell transformation. this we used dominant negative Erk2-K52R transfectant, Cl 41 MAPK-DN B3 mass1 (19Watts R.G. Huang C. Young M.R. Li J.-J. Dong Z. Pennie W.D. Colburn N.H. Oncogene. 1998; 17: 3493-3498Crossref PubMed Scopus (107) Google Scholar). We found that overexpression of dominant negative Erk2 arsenite-induced Erk activation and cell transformation while is on arsenite-induced of JNK or and However, the cell of the C1 41 MAPK DN cells are not from of C1 41 AP-1 mass1 cells and Cl 41 data is with that the cell transformation is from in JB6 cells (15Huang C. Ma W.-Y. Dong Z. Mol. Cell. Biol. 1996; 16: 6427-6435Crossref PubMed Scopus (153) Google Scholar, N.H. Proc. Natl. Acad. Sci. U. S. A. 1981; PubMed Scopus Google Scholar). data also that of cell transformation of C1 41 MAPK DN B3 mass1 cells in to arsenite is not to inhibition of cell growth by of dominant negative Erk2. Our results that Erk activation, but not JNK activation, is required for arsenite-induced cell of expression of dominant negative of Erk2 or JNK1 on cell was as and results were as the and of for of 41 AP-1 41 MAPK-DN B3 41 was as and results were as the and of for of in a the arsenite-induced and its role in arsenite-induced cell transformation. of JB6 Cl 41 cells to low (<25 μm) of arsenite to cell while are cell transformation at a high concentration μm) of arsenite. In contrast, Erk activation be at JNK activation only be at high doses of arsenite. Furthermore, introduction of dominant negative Erk2-K52R into cells Erk activation as well as cell transformation induced by while it not JNK activation and activation. In overexpression of dominant negative JNK1 arsenite-induced cell transformation even though it arsenite-induced JNK activation. results that arsenite induces Erk activation and for the first time that Erk activation, but not JNK activation, is required for arsenite-induced cell transformation. is the first to be as a human carcinogen Huang H. J. Cell. 1997; PubMed Scopus Google Scholar). in and and in or A.B.G. Crit. Rev. Toxicol. 1995; 25: 397-462Crossref PubMed Scopus (121) Google Scholar, Huang H. J. Cell. 1997; PubMed Scopus Google Scholar). and are by human and skin A.B.G. Crit. Rev. Toxicol. 1995; 25: 397-462Crossref PubMed Scopus (121) Google Scholar). show that arsenic in the skin and A.B.G. Crit. Rev. Toxicol. 1995; 25: 397-462Crossref PubMed Scopus (121) Google Scholar). It is that long-term arsenic exposure in carcinogenesis (5International Agency for Research on Cancer IARC Monogr. Eval. Carcinog. Risk Hum. 1980; 23: 37-141Google Scholar). 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EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar), but also induces Erk activation. results from time show that Erk activation only at while JNK activation It be that Erk activation be at doses JNK activation was only at high doses for of cell transformation are with that for activation of Erk, but not for JNK, that Erk activation may be involved in arsenite-induced cell transformation. was by our that dominant negative Erk2 inhibits arsenite-induced cell transformation while dominant negative JNK increased the cell transformation even though it JNK activation by arsenite for of Erk, but not cell transformation by high doses of may be to of at Our results that arsenite at than induces of JB6 Cl 41 cells not Our results for Erk activation by arsenite are from data reported by et al. (10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar) in which arsenite did not show of for this may be that cell were used in or the time for Erk activation was by et al. (10Cavigelli M. Li W.W. Lin A. Su B. Yoshioka K. Karin M. EMBO J. 1996; 15: 6269-6279Crossref PubMed Scopus (393) Google Scholar). the of this et al. S. Hoffmeyer A. Goebeler M. Kilian K. Häfner H. Neufeld B. Han J. Rapp U.R. J. Biol. Chem. 1998; 273: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar) reported that arsenite induces Erk activation in the human cell and this Erk activation to be and on activation of However, in JB6 cells, we found that Erk activation while kinase activation was than cell exposure to arsenite. Our indicated that expression of dominant negative kinase in Cl 41 cells not arsenite-induced Erk activation, while it kinase activation not Erk activation is not on kinase activation in JB6 for this may be to the of cell our results that arsenite induces Erk activation and Erk activation induced by arsenite is required for its cell transformation to role of JNK activation induced by arsenite is We Dr. for Dr. Roger S. Davis for the of dominant negative JNK1 and A. for