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  • Original Paper
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Signal transduction pathways regulated by arsenate and arsenite

Abstract

Arsenate and arsenite activate c-Jun N-terminal kinase (JNK), however, the mechanism by which this occurs is not known. By expressing inhibitory mutant small GTP-binding proteins, p21-activated kinase (PAK) and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinases (MEKKs), we have identified specific proteins that are involved in arsenate- and arsenite-mediated activation of JNK. We observe a distinct difference between arsenate and arsenite signaling, which demonstrates that arsenate and arsenite are capable of activating unique proteins. Both arsenate and arsenite activation of JNK requires Rac and Rho. Neither arsenate nor arsenite signaling was inhibited by a dominant-negative mutant of Cdc42 or Ras. Arsenite stimulation of JNK requires PAK, whereas arsenate-mediated activation of JNK was unaffected by inhibitory mutant PAK. Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsenate-mediated activation of JNK. In contrast, arsenite-mediated JNK activation requires MEKK2, MEKK3 and MEKK4. These results better define the mechanisms by which arsenate and arsenite activate JNK and demonstrate differences in the regulation of signal transduction pathways by these inorganic arsenic species.

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References

  • Adler V, Schaffer A, Kim J, Dolan L and Ronai Z. . 1995 J. Biol. Chem. 270: 26071–26077.

  • Bagrodia S, Derijard B, Davis RJ and Cerione RA. . 1995 J. Biol. Chem. 270: 27995–27998.

  • Blank JL, Gerwins P, Elliott EM, Sather S and Johnson GL. . 1996 J. Biol. Chem. 271: 5361–5368.

  • Bos JL. . 1989 Cancer Res. 49: 4682–4689.

  • Bradford MM. . 1976 Anal. Biochem. 72: 248–254.

  • Braman RS and Foreback CC. . 1973 Science 182: 1247–1249.

  • Cavigelli M, Li WW, Lin A, Su B, Yoshioka K and Karin M. . 1996 EMBO J. 15: 6269–6279.

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T and Gutkind JS. . 1995 Cell 81: 1137–1146.

  • Cullen BR. . 1987 Meth. Enzymol. 152: 684–704.

  • Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M and Davis RJ. . 1994 Cell 76: 1025–1037.

  • Elbirt KK, Whitmarsh AJ, Davis RJ and Bonkovsky HL. . 1998 J. Biol. Chem. 273: 8922–8931.

  • Fanger GR, Gerwins P, Widmann C, Jarpe MB and Johnson GL. . 1997a Curr. Opin. Genet. Dev. 7: 67–74.

  • Fanger GR, Johnson NL and Johnson GL. . 1997b EMBO J. 16: 4961–4972.

  • Fling SP and Gregerson DS. . 1986 Anal. Biochem. 155: 83–88.

  • Freeman JL, Abo A and Lambeth JD. . 1996 J. Biol. Chem. 271: 19794–19801.

  • Gerwins P, Blank JL and Johnson GL. . 1997 J. Biol. Chem. 272: 8288–8295.

  • Guo Y-L, Baysal K, Yang L-J and Williamson JR. . 1998 J. Biol. Chem. 273: 4027–4034.

  • Habets GG, Scholtes EH, Zuydgeest D, van der Kammen RA, Stam JC, Berns A and Collard JG. . 1994 Cell 77: 537–549.

  • Hanks SK, Quinn AM and Hunter T. . 1988 Science 241: 42–52.

  • Hibi M, Lin A, Smeal T, Minden A and Karin M. . 1993 Genes Dev. 7: 2135–2148.

  • Huang C, Ma W-Y, Li J, Goranson A and Dong Z. . 1999 J. Biol. Chem. 274: 14595–14601.

  • Jacobson-Kram D and Montalbano D. . 1985 Environ. Mutagen. 7: 787–804.

  • Joneson T and Bar-Sagi D. . 1998 J. Biol. Chem. 273: 17991–17994.

  • Kenney LJ and Kaplan JH. . 1988 J. Biol. Chem. 263: 7954–7960.

  • King AJ, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S and Marshall MS. . 1998 Nature 396: 180–183.

  • Kyriakis JM and Avruch J. . 1996 J. Biol. Chem. 271: 24313–24316.

  • Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ and Johnson GL. . 1993 Science 260: 315–319.

  • Lee TC, Oshimura M and Barrett JC. . 1985 Carcinogenesis 6: 1421–1426.

  • Liu Y, Guyton KZ, Gorospe M, Xu Q, Lee JC and Holbrook NJ. . 1996 Free Rad. Biol. Med. 21: 771–781.

  • Meier R, Rouse J, Cuenda A, Nebreda AR and Cohen P. . 1996 Eur. J. Biochem. 236: 796–805.

  • Michiels F, Habets GG, Stam JC, van der Kammen RA and Collard JG. . 1995 Nature 375: 338–340.

  • Michiels F, Stam JC, Hordijk PL, van der Kammen RA, Ruuls-Van Stalle L, Feltkamp CA and Collard JG. . 1997 J. Cell. Biol. 137: 387–398.

  • Mikami K, Katagiri T, Iuchi S, Yamaguchi-Shinozaki K and Shinozaki K. . 1998 Plant J. 15: 563–568.

  • Minden A, Lin A, Claret FX, Abo A and Karin M. . 1995 Cell 81: 1147–1157.

  • Minden A, Lin A, McMahon M, Lange-Carter C, Derijard B, Davis RJ, Johnson GL and Karin M. . 1994 Science 266: 1719–1723.

  • Qiu RG, Chen J, Kirn D, McCormick F and Symons M. . 1995 Nature 374: 457–459.

  • Ren XD, Bokoch GM, Traynor-Kaplan A, Jenkins GH, Anderson RA and Schwartz MA. . 1996 Mol. Biol. Cell. 7: 435–442.

  • Ren XD and Schwartz MA. . 1998 Curr. Opin. Genet. Dev. 8: 63–67.

  • Rossman TG, Stone D, Molina M and Troll W. . 1980 Environ. Mutagen. 2: 371–379.

  • Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T and Nebreda AR. . 1994 Cell 78: 1027–1037.

  • Sakurai T, Kaise T and Matsubara C. . 1998 Chem. Res. Toxicol. 11: 273–283.

  • Smith AH, Goycolea M, Haque R and Biggs ML. . 1998 Am. J. Epidemiol. 147: 660–669.

  • Stoner JC, Whanger PD and Weswig PH. . 1977 Environ. Health Pers. 19: 139–143.

  • Takekawa M, Posas F and Saito H. . 1997 EMBO J. 16: 4973–4982.

  • Takekawa M and Saito H. . 1998 Cell 95: 521–530.

  • Teramoto H, Crespo P, Coso OA, Igishi T, Xu N and Gutkind JS. . 1996 J. Biol. Chem. 271: 25731–25734.

  • Treisman R. . 1996 Curr. Opin. Cell. Biol. 8: 205–215.

  • Trigon S and Morange M. . 1995 J. Biol. Chem. 270: 13091–13098.

  • van Leeuwen FN, van der Kammen RA, Habets GG and Collard JG. . 1995 Oncogene 11: 2215–2221.

  • Xu S, Robbins DJ, Christerson LB, English JM, Vanderbilt CA and Cobb MH. . 1996 Proc. Natl. Acad. Sci. USA 93: 5291–5295.

  • Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR and Templeton DJ. . 1994 Nature 372: 798–800.

  • Yeh S, How SW and Lin CS. . 1968 Cancer 21: 312–339.

  • Zhang S, Han J, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ and Bokoch GM. . 1995 J. Biol. Chem. 270: 23934–23936.

  • Zhao CQ, Young MR, Diwan BA, Coogan TP and Waalkes MP. . 1997 Proc. Natl. Acad. Sci. USA 94: 10907–10912.

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Acknowledgements

This work was supported, in part, by grants from the American Cancer Society (IRG 110T), the Southwest Environmental Health Sciences Center (ES 06694), and the Arizona Disease Control Research Commission.

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Porter, A., Fanger, G. & Vaillancourt, R. Signal transduction pathways regulated by arsenate and arsenite. Oncogene 18, 7794–7802 (1999). https://doi.org/10.1038/sj.onc.1203214

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