The role of AP-1, NF-кB and ROS/ NOS in skin carcinogenesis: The JB6 model is predictive

  • Arindam Dhar
  • Mathew R. Young
  • Nancy H. Colburn
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 37)


Generation of reactive oxygen species (ROS) stimulates transcription by activating transcription factors activator protein 1 (AP-1) and nuclear factor KB (NF-KB). The mouse epidermal JB6 cells constitute a model system that has significantly contributed to the understanding of these events. Clonal variants of JB6 cells are differentially responsive to transformation induced by tumor promoters such as phorbol esters (TPA), epidermal growth factor (EGF) and tumor necrosis factor alpha (TNF-a), as well as oxidative stress. TPA and EGF, acting through the MAP kinase pathway, activate AP-1 and subsequently NF-KB proteins and downstream transcription processes that are involved in the transformation response in transformation-sensitive (P+) JB6 cells. The effect of TNF-a is primarily on the NF-KB pathway. ROS and other free radicals can activate AP-1 and NF-KB transcription coordinately. In JB6 cells, both ERK/Fra-1 and NF-KB activity is essential for the transformation response. Inhibition of NF-KB and AP-1 activity abrogates transformation in JB6 cells as well as in transgenic mice and human keratinocytes. A similar effect is seen with antioxidants, which inhibit NF-KB and AP-1 activity as well as transformation in JB6 cells. The JB6 model is therefore valuable for monitoring early events in oxidative stress related signaling leading to carcinogenesis, and for identifying molecular targets for cancer chemoprevention. (Mol Cell Biochem 234/235: 185–193, 2002)

Key words

AP-1 NF-KB ROS JB6 cells transformation 


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  1. 1.
    Allen RG: Oxygen-reactive species and antioxidant responses during development: The metabolic paradox of cellular differentiation. Proc Soc Exp Biol Med 196: 117–129, 1991Google Scholar
  2. 2.
    Remade J, Raes M, Toussaint O, Renard P, Rao G: Low levels of reactive oxygen species as modulators of cell function. Mutat Res 316: 103–122, 1995CrossRefGoogle Scholar
  3. 3.
    Allen RG, Tresini M: Oxidative stress and gene regulation. Free Radic Biol Med 28: 463–499, 2000PubMedCrossRefGoogle Scholar
  4. 4.
    Cerutti P, Larsson R, Krupitza G, Muehlematter D, Crawford D, Amstad P: Pathophysiological mechanisms of active oxygen. Mutat Res 214: 81–88, 1989PubMedCrossRefGoogle Scholar
  5. 5.
    Dalton TP, Li Q, Bittel D, Liang L, Andrews GK: Oxidative stress activates metal-responsive transcription factor-1 binding activity. Occupancyin vivoof metal response elements in the metallothionein-I gene promoter. J Biol Chem 2`11: 26233–26241, 1996Google Scholar
  6. 6.
    Dalton TP, Shertzer HG, Puga A: Regulation of gene-expression by reactive oxygen. Annu Rev Pharmacol Toxicol 39: 67–101, 1999PubMedCrossRefGoogle Scholar
  7. 7.
    Fu YC, Jin XP, Wei SM, Lin HF, Kacew S: Ultraviolet radiation and reactive oxygen generation as inducers ofkeratinocyte apoptosis: Protective role of tea polyphenols. J Toxicol Environ Health A 61: 177–188, 2000PubMedCrossRefGoogle Scholar
  8. 8.
    Cimino F, Esposito F, Ammendola R, Russo T: Gene regulation by reactive oxygen species. Curr Top Cell Reg 35: 123–148, 1997CrossRefGoogle Scholar
  9. 9.
    Oho E, Ohtsuka E, Saburi Y, Ono K, Kikuchi H, Nasu M: Reactive oxygen species production of neutrophils in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Am J Hematol 62: 120–121, 1999PubMedCrossRefGoogle Scholar
  10. 10.
    Mantymaa P, Guttorm T, Siitonen T, Saily M, Savolainen ER, Levonen AL, Kinnula V, Koistinen P: Cellular redox state and its relationship to the inhibition of clonal cell growth and the induction of apoptosis during all-trans retinoic acid exposure in acute myeloblastic leukemia cells. Haematologica 85: 238–245, 2000PubMedGoogle Scholar
  11. 11.
    Dong Z: Effects of food factors on signal transduction pathways. Biofactors 12: 17–28, 2000PubMedCrossRefGoogle Scholar
  12. 12.
    Dion LD, De Luca LM, Colburn NH: Phorbol ester-induced anchorage independence and its antagonism by retinoic acid correlates with altered expression of specific glycoproteins. Carcinogenesis 2: 951–958, 1981PubMedCrossRefGoogle Scholar
  13. 13.
    Amstad P, Moret R, Cerutti P: Glutathione peroxidase compensates for the hypersensitivity of Cu,Zn-superoxide dismutase overproducers to oxidant stress. J Biol Chem 269: 1606–1609, 1994PubMedGoogle Scholar
  14. 14.
    Amstad P, Peskin A, Shah G, Mirault ME, Moret R, Zbinden I, Cerutti P: The balance between Cu,Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress. Biochemistry 30: 9305–9313, 1991PubMedCrossRefGoogle Scholar
  15. 15.
    Cai L, Koropatnick J, Cherian MG: Roles of vitamin C in radiation-induced DNA damage in presence and absence of copper. Chem Biol Interact 137: 75–88, 2001PubMedCrossRefGoogle Scholar
  16. 16.
    Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, Miller SW, Parks JP, Parker WD Jr, Bennett JP Jr: Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim Biophys Acta 1362: 77–86, 1997PubMedCrossRefGoogle Scholar
  17. 17.
    Cavallo MG, Monetini L, Valente L, Barone F, Beales P, Russo M, Pozzilli P: Glutathione protects a human insulinoma cell line from tumor necrosis factor-alpha-mediated cytotoxicity. Int J Clin Lab Res 27: 447, 1997CrossRefGoogle Scholar
  18. 18.
    Davis W Jr, Ronai Z, Tew KD: Cellular thiols and reactive oxygen species in drug-induced apoptosis. J Pharmacol Exp Ther 296: 1–6, 2001PubMedGoogle Scholar
  19. 19.
    Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G, Fiers W: Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. Embo J 12: 3095–3104, 1993PubMedGoogle Scholar
  20. 20.
    Pinkus R, Bergelson S, Daniel V: Phenobarbital induction ofAP-1 binding activity mediates activation of glutathione S-transferase and quinone reductase gene expression. Biochem J 290: 637–640, 1993PubMedGoogle Scholar
  21. 21.
    Janssen-Heininger YM, Poynter ME, Baeuerle PA: Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radic Biol Med 28: 1317–1327, 2000PubMedCrossRefGoogle Scholar
  22. 22.
    Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS: Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481: 243–268, 2001PubMedCrossRefGoogle Scholar
  23. 23.
    Primiano T, Sutter TR, Kensler TW: Redox regulation of genes that protect against carcinogens. Comp Biochem Physiol B Biochem Mol Biol 118: 487–497, 1997PubMedCrossRefGoogle Scholar
  24. 24.
    Kovacic P, Jacintho JD: Mechanisms of carcinogenesis: Focus on oxidative stress and electron transfer. Curr Med Chem 8: 773–796, 2001PubMedCrossRefGoogle Scholar
  25. 25.
    Cerutti PA: Oxy-radicals and cancer. Lancet 344: 862–863, 1994PubMedCrossRefGoogle Scholar
  26. 26.
    Colburn NH, Former BF, Nelson KA, Yuspa SH: Tumour promoter induces anchorage independence irreversibly. Nature 281: 589–591, 1979PubMedCrossRefGoogle Scholar
  27. 27.
    Colburn NH, Gindhart TD, Hegamyer GA, Blumberg PM, Delclos KB, Magun BE, Lockyer J: Phorbol diester and epidermal growth factor receptors in 12-O- tetradecanoylphorbol-l3-acetate-resistant and-sensitive mouse epidermal cells. Cancer Res 42: 3093–3097, 1982PubMedGoogle Scholar
  28. 28.
    Bernstein LR, Colburn NH: AP1/jun function is differentially induced in promotion-sensitive and resistant JB6 cells. Science 244: 566–569, 1989PubMedCrossRefGoogle Scholar
  29. 29.
    Bernstein LR, Bravo R, Colburn NH: 12-O-tetradecanoylphorbol-13acetate-induced levels of AP-1 proteins: A 46-kDa protein immunoprecipitated by anti-fra-1 and induced in promotion-resistant but not promotion-sensitive JB6 cells. Mol Carcinogen 6: 221–229, 1992Google Scholar
  30. 30.
    Bernstein LR, Ferris DK, Colburn NH, Sobel ME: A family of mitogenactivated protein kinase-related proteins interactsin vivowith activator protein-1 transcription factor. J Biol Chem 269: 9401–9404, 1994PubMedGoogle Scholar
  31. 31.
    Frost JA, Geppert TD, Cobb MH, Feramisco JR: A requirement for extracellular signal-regulated kinase (ERK) function in the activation of AP-1 by Ha-Ras, phorbol 12-myristate 13-acetate, and serum. Proc Natl Acad Sci USA 91: 3844–3848, 1994PubMedCrossRefGoogle Scholar
  32. 32.
    Huang C, Ma WY, Young MR, Colburn N, Dong Z: Shortage of mitogen-activated protein kinase is responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Proc Natl Acad Sci USA 95: 156–161, 1998PubMedCrossRefGoogle Scholar
  33. 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, 1998PubMedCrossRefGoogle Scholar
  34. 34.
    Huang C, Ma WY, Dong Z: The extracellular-signal-regulated protein kinases (Erks) are required for UV-induced AP-1 activation in JB6 cells. Oncogene 18: 2828–2835, 1999PubMedCrossRefGoogle Scholar
  35. 35.
    Hsu T-C, Nair R, Tulsian P, Hegamyer G, Young MR, Colburn NH: Transformation non-responsive cells owe their resistance to lack of NF-KB activation. Cancer Res 61: 4160–4168, 2001PubMedGoogle Scholar
  36. 36.
    Young MR, Nair R, Bucheimer N, Tulsian P, Brown NS, Chapp C, Hsu T-C, Colburn NH: Transactivation of Fra-1 and consequent activation of AP-1 occur ERK dependently. Mol Cell Biol 22: 587–598, 2002PubMedCrossRefGoogle Scholar
  37. 37.
    Murakami A, Kawabata K, Koshiba T, Gao G, Nakamura Y, Koshimizu K, Ohigashi H: Nitric oxide synthase is induced in tumor promoter-sensitive, but not tumor promoter-resistant, JB6 mouse epidermal cells cocultured with interferon-gamma-stimulated RAW 264.7 cells: The role of tumor necrosis factor-alpha. Cancer Res 60: 6326–6331, 2000PubMedGoogle Scholar
  38. 38.
    Amstad PA, Liu H, Ichimiya M, Berezesky IK, Trump BF: Manganese superoxide dismutase expression inhibits soft agar growth in JB6 clone 41 mouse epidermal cells. Carcinogenesis 18: 479–484, 1997PubMedCrossRefGoogle Scholar
  39. 39.
    Li JJ, Oberley LW, Fan M, Colburn NH: Inhibition ofAP-1 and NFkappaB by manganese-containing superoxide dismutase in human breast cancer cells. Faseb J 12: 1713–1723, 1998PubMedGoogle Scholar
  40. 40.
    Li JJ, Colburn NH, Oberley LW: Maspin gene expression in tumor suppression induced by overexpressing manganese-containing superoxide dismutase cDNA in human breast cancer cells. Carcinogenesis 19: 833–839, 1998PubMedCrossRefGoogle Scholar
  41. 41.
    Nakamura Y, Colburn NH, Gindhart TD: Role of reactive oxygen in tumor promotion: Implication of superoxide anion in promotion of neoplastic transformation in JB-6 cells by TPA. Carcinogenesis 6: 229–235, 1985PubMedCrossRefGoogle Scholar
  42. 42.
    Nakamura Y, Gindhart TD, Winterstein D, Tomita I, Seed JL, Colburn NH: Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cells. Carcinogenesis 9: 203–207, 1988PubMedCrossRefGoogle Scholar
  43. 43.
    Dong Z, Biner MJ, Watts RG, Matrisian LM, Colburn NH: Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci USA 91: 609–613, 1994PubMedCrossRefGoogle Scholar
  44. 44.
    Li JJ, Westergaard C, Ghosh P, Colburn NH: Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response. Cancer Res 57: 3569–3576, 1997PubMedGoogle Scholar
  45. 45.
    Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, Colburn N: Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 96: 9827–9832, 1999PubMedCrossRefGoogle Scholar
  46. 46.
    Liu Y, Duysen E, Yaktine AL, Au A, Wang W, Birt DF: Dietary energy restriction inhibits ERK but not JNK or p38 activity in the epidermis of SENCAR mice. Carcinogenesis 22: 607–612, 2001PubMedCrossRefGoogle Scholar
  47. 47.
    Huang C, Ma WY, 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, 1997PubMedCrossRefGoogle Scholar
  48. 48.
    Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F: Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5: 828–831, 1999PubMedCrossRefGoogle Scholar
  49. 49.
    Li JJ, Rhim JS, Schlegel R, Vousden KH, Colburn NH: Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappaB trans-activation and suppresses anchorage independent growth of HPV immortalized human keratinocytes. Oncogene 16: 2711–2721, 1998PubMedCrossRefGoogle Scholar
  50. 50.
    Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin SM, Yen HC, Majima H, Hines J, St Clair D: Overexpression of manganese superoxide dis-mutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res 61: 6082–6088, 2001PubMedGoogle Scholar
  51. 51.
    Colburn NH, Smith BM: Genes that cooperate with tumor promoters in transformation. J Cell Biochem 34: 129–142, 1987PubMedCrossRefGoogle Scholar
  52. 52.
    Bernstein LR, Ben-Ari ET, Simek SL, Colburn NH: Gene regulation and genetic susceptibility to neoplastic transformation: AP-1 and p80 expression in JB6 cells. Environ Health Perspect 93: 111–119, 1991PubMedCrossRefGoogle Scholar
  53. 53.
    Bernstein L, Ben-Ari E, Simek S, Colburn N: Gene regulation during promotion of neoplastic transformation in mouse JB6 cells. Environ Health Perspect 93: 111–119, 1991PubMedCrossRefGoogle Scholar
  54. 54.
    Colburn N: Gene regulation by active oxygen and other stress inducers: Role in tumor promotion and progression. In L. Spatz, A. Bloom (eds). Biological Consequences of Oxidative Stress: Implications for Cardiovascular Disease and Carcinogenesis. Oxford University Press, Oxford, UK, 1992, pp 121–137Google Scholar
  55. 55.
    Colburn NH, Wendel E, Srinivas L: Responses of preneoplastic epidermal cells to tumor promoters and growth factors: Use of promoter-resistant variants for mechanism studies. J Cell Biochem 18: 261–270, 1982PubMedCrossRefGoogle Scholar
  56. 56.
    Cmarik JL, Colburn NH: Use of mouse JB6 cells to identify molecular targets and novel agents for prevention of carcinogenesis. In: H. Ohigashi (ed). Proc. International Conf. on Food Factors: Chemistry and Cancer Prevention. Springer-Verlag, Tokyo 1997, pp 67–76Google Scholar
  57. 57.
    Singh N, Sun Y, Nakamura K, Smith MR, Colburn NH: C-JUN/AP-1 as possible mediators of tumor necrosis factor-alpha-induced apoptotic response in mouse JB6 tumor cells. Oncol Res 7: 353–362, 1995PubMedGoogle Scholar
  58. 58.
    Ben-Ari ET, Bernstein LR, Colburn NH: Differential c-jun expression in response to tumor promoters in JB6 cells sensitive or resistant to neoplastic transformation. Mol Carcinogen 5: 62–74, 1992CrossRefGoogle Scholar
  59. 59.
    Li JJ, Dong Z, Dawson MI, Colburn NH: Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-1 without transactivating retinoic acid response element. Cancer Res 56: 483–489, 1996PubMedGoogle Scholar
  60. 60.
    Watts RG, Ben-Ari ET, Bernstein LR, Birrer MJ, Winterstein D, Wendel E, Colburn NH: c-jun and multistage carcinogenesis: Association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation. Mol Carcinogen 13: 27–36, 1995CrossRefGoogle Scholar
  61. 61.
    Bernstein LR, Walker SE: Tumor promotion resistant cells are deficient in AP-1 DNA binding, JunD DNA binding and JunD expression and form different AP-1-DNA complexes than promotion sensitive cells. Biochim Biophys Acta 1489: 263–280, 1999PubMedCrossRefGoogle Scholar
  62. 62.
    Lu YP, Chang RL, Lou YR, Huang MT, Newmark HL, Reuhl KR, Conney AH: Effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate-and ultraviolet B light-induced expression of c-Jun and c-Fos in JB6 cells and in mouse epidermis. Carcinogenesis 15: 2363–2370, 1994PubMedCrossRefGoogle Scholar
  63. 63.
    Dong Z, Ma W, Huang C, Yang CS: Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (—)-epigallocatechin gallate, and theaflavins. Cancer Res 57: 4414–4419, 1997PubMedGoogle Scholar
  64. 64.
    Nomura M, Ma W, Chen N, Bode AM, Dong Z: Inhibition of 12–0tetradecanoylphorbol- 13-acetate-induced NF-kappaB activation by tea polyphenols, (—)-epigallocatechin gallate and theaflavins. Carcinogenesis 21: 1885–1890, 2000PubMedCrossRefGoogle Scholar
  65. 65.
    Nomura M, Ma WY, Huang C, Yang CS, Bowden GT, Miyamoto K, Dong Z: Inhibition of ultraviolet B-induced AP-1 activation by theaflavins from black tea. Mol Carcinog 28: 148–155, 2000PubMedCrossRefGoogle Scholar
  66. 66.
    Huang C, Ma WY, Ryan CA, Dong Z: Proteinase inhibitors I and II from potatoes specifically block UV- induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase. Proc Natl Acad Sci USA 94: 11957–11962, 1997PubMedCrossRefGoogle Scholar
  67. 67.
    Liu G, Chen N, Kaji A, Bode AM, Ryan CA, Dong Z: Proteinase inhibitors I and II from potatoes block UVB-induced AP-1 activity by regulating the AP-1 protein compositional patterns in JB6 cells. Proc Natl Acad Sci USA 98: 5786–5791, 2001PubMedCrossRefGoogle Scholar
  68. 68.
    Bode AM, Ma WY, Surh YJ, Dong Z: Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by. Cancer Res 61: 850–853, 2001PubMedGoogle Scholar
  69. 69.
    Sang S, He K, Liu G, Zhu N, Cheng X, Wang M, Zheng Q, Dong Z, Ghai G, Rosen RT, Ho CT: A new unusual iridoid with inhibition of activator protein-1 (AP-1) from the leaves ofMorinda citrifolia L. Org Lett 3: 1307–1309, 2001Google Scholar
  70. 70.
    Liu G, Bibus DM, Bode AM, Ma WY, Holman RT, Dong Z: Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci USA 98: 7510–7515, 2001PubMedCrossRefGoogle Scholar
  71. 71.
    Liu G, Bode A, Ma WY, Sang S, Ho CT, Dong Z: Two novel glycosides from the fruits of Morinda citrifolia (noni) inhibit AP-1 transactivation and cell transformation in the mouse epidermal JB6 cell line. Cancer Res 61: 5749–5756, 2001PubMedGoogle Scholar
  72. 72.
    Dong Z, Huang C, Brown RE, Ma WY: Inhibition of activator protein 1 activity and neoplastic transformation by aspirin. J Biol Chem 272: 9962–9970, 1997PubMedCrossRefGoogle Scholar
  73. 73.
    Dong Z, Crawford HC, Lavrovsky V, Taub D, Watts R, Matrisian LM, Colburn NH: A dominant negative mutant of jun blocking 12–0tetradecanoylphorbol-13- acetate-induced invasion in mouse keratinocytes. Mol Carcinogen 19: 204–212, 1997CrossRefGoogle Scholar
  74. 74.
    Stein B, Baldwin AS, Jr, Ballard DW, Greene WC, Angel P, Herrlich P: Cross-coupling of the NF-kappa B p65 and Fos/Jun transcription factors produces potentiated biological function. Embo J 12: 3879–3891, 1993Google Scholar
  75. 75.
    Boulton TG, Yancopoulos GD, Gregory JS, Slaughter C, Moomaw C, Hsu J, Cobb MH: An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249: 64–67, 1990PubMedCrossRefGoogle Scholar
  76. 76.
    Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD: ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65: 663–675, 1991PubMedCrossRefGoogle Scholar
  77. 77.
    Davis RI: MAPKs: New JNK expands the group. Trends Biochem Sci 19: 470–473, 1994PubMedCrossRefGoogle Scholar
  78. 78.
    Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR: The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156–160, 1994PubMedCrossRefGoogle Scholar
  79. 79.
    Robbins DJ, Zhen E, Cheng M, Xu S, Vanderbilt CA, Ebert D, Garcia C, Dang A, Cobb MH: Regulation and properties of extracellular signal-regulated protein kinases 1, 2, and 3 (editorial). J Am Soc Nephrol 4: 1104–1110, 1993PubMedGoogle Scholar
  80. 80.
    Higgins KA, Perez JR, Coleman TA, Dorshkind K, McComas WA, Sarmiento UM, Rosen CA, Narayanan R: Antisense inhibition of the p65 subunit of NF-kappa B blocks tumorigenicity and causes tumor regression. Proc Natl Acad Sci USA 90: 9901–9905, 1993PubMedCrossRefGoogle Scholar
  81. 81.
    Gilmore TD, Koedood M, Piffat KA, White DW: Rel/NF-kappaB/ IkappaB proteins and cancer. Oncogene 13: 1367–1378, 1996PubMedGoogle Scholar
  82. 82.
    Baldwin AS Jr: The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu Rev Immunol 14: 649–683, 1996PubMedCrossRefGoogle Scholar
  83. 83.
    Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin AS Jr: Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem 272: 24113–24116, 1997PubMedCrossRefGoogle Scholar
  84. 84.
    Luque I, Gelinas C: Rel/NF-kappa B and I kappa B factors in oncogenesis. Semin Cancer Biol 8: 103–111, 1997PubMedCrossRefGoogle Scholar
  85. 85.
    Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K, Miano MP, de Nigris F, Casalino L, Curcio F, Santoro M, Fusco A: Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression. Oncogene 15: 1987–1994, 1997PubMedCrossRefGoogle Scholar
  86. 86.
    Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM: Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789, 1996PubMedCrossRefGoogle Scholar
  87. 87.
    Latimer M, Ernst MK, Dunn LL, Drutskaya M, Rice NR: The N-terminal domain of IkappaB alpha masks the nuclear localization signal(s) of p50 and c-Rel homodimers. Mol Cell Biol 18: 2640–2649, 1998PubMedGoogle Scholar
  88. 88.
    Li J-J, Cao Y, Young MR, Colburn NH: Induced expression of dominant negative cJun down regulates NF-KB and AP-1 target genes and suppresses tumor phenotype in human keratinocytes. Mol Carcinogen 29: 159–169, 2000Google Scholar
  89. 89.
    Cerutti P, Ghosh R, Oya Y, Amstad P: The role of the cellular antioxidant defense in oxidant carcinogenesis. Environ Health Perspect 102(suppl 10): 123–129, 1994PubMedCrossRefGoogle Scholar
  90. 90.
    Jain PT, Chang SH, Berezesky IK, Amstad P, Cerutti PA, Trump BF: Differential cytotoxicity in mouse epidermal JB6 cells: Apotential mechanism for oxidant tumor promotion. Mol Carcinogen 11: 164–169, 1994CrossRefGoogle Scholar
  91. 91.
    Huang C, Zhang Z, Ding M, Li J, Ye J, Leonard SS, Shen HM, Butterworth L, Lu Y, Costa M, Rojanasakul Y, Castranova V, Vallyathan V, Shi X: Vanadate induces p53 transactivation through hydrogen peroxide and causes apoptosis. J Biol Chem 275: 32516–32522, 2000PubMedCrossRefGoogle Scholar
  92. 92.
    Crawford DR, Amstad PA, Foo DD, Cerutti PA: Constitutive and phorbol-myristate-acetate regulated antioxidant defense of mouse epidermal JB6 cells. Mol Carcinogen 2: 136–143, 1989CrossRefGoogle Scholar
  93. 93.
    Huang C, Li J, Ding M, Leonard SS, Wang L, Castranova V, Vallyathan V, Shi X: UV Induces phosphorylation of protein kinase B (Akt) at Ser-473 and Thr- 308 in mouse epidermal Cl 41 cells through hydrogen peroxide. J Biol Chem 276: 40234–40240, 2001PubMedGoogle Scholar
  94. 94.
    Ding M, Li JJ, Leonard SS, Ye JP, Shi X, Colburn NH, Castranova V, Vallyathan V: Vanadate-induced activation of activator protein-1: Role of reactive oxygen species. Carcinogenesis 20: 663–668, 1999PubMedCrossRefGoogle Scholar
  95. 95.
    Ding M, Shi X, Lu Y, Huang C, Leonard S, Roberts J, Antonini J, Castranova V, Vallyathan V: Induction of activator protein-1 through reactive oxygen species by crystalline silica in JB6 cells. J Biol Chem 276: 9108–9114, 2001PubMedCrossRefGoogle Scholar
  96. 96.
    Perrella MA, Pellacani A, Wiesel P, Chin MT, Foster LC, Ibanez M, Hsieh CM, Reeves R, Yet SF, Lee ME: High mobility group-I (Y) protein facilitates nuclear factor-kappaB binding and transactivation of the inducible nitric-oxide synthase promoter/enhancer. J Biol Chem 274: 9045–9052, 1999PubMedCrossRefGoogle Scholar
  97. 97.
    Pellacani A, Chin MT, Wiesel P, Ibanez M, Patel A, Yet SF, Hsieh CM, Paulauskis JD, Reeves R, Lee ME, Perrella MA: Induction of high mobility group-I (Y) protein by endotoxin and interleukin-1 beta in vascular smooth muscle cells. Role in activation of inducible nitric oxide synthase. J Biol Chem 274: 1525–1532, 1999PubMedCrossRefGoogle Scholar
  98. 98.
    Bussemakers MJ, van de Ven WJ, Debruyne FM, Schalken JA: Identification of high mobility group protein I (Y) as potential progression marker for prostate cancer by differential hybridization analysis. Cancer Res 51: 606–6611, 1991PubMedGoogle Scholar
  99. 99.
    Giancotti V, Buratti E, Perissin L, Zorzet S, Balmain A, Portella G, Fusco A, Goodwin GH: Analysis of the HMGI nuclear proteins in mouse neoplastic cells induced by different procedures. Exp Cell Res 184: 538–545, 1989PubMedCrossRefGoogle Scholar
  100. 100.
    Tamimi Y, van der Poel HG, Denyn MM, Umbas R, Karthaus HF, Debruyne FM, Schalken JA: Increased expression of high mobility group protein I (Y) in high grade prostatic cancer determined by in situ hybridization. Cancer Res 53: 5512–5516, 1993PubMedGoogle Scholar
  101. 101.
    Tallini G, Dal CM P: HMGI (Y) and HMGI-C dysregulation: A common occurrence in human tumors. AdvAnat Pathol 6: 237–246, 1999Google Scholar
  102. 102.
    Reeves R, Edberg DD, Li Y: Architectural transcription factor HMGI (Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol 21: 575–594, 2001PubMedCrossRefGoogle Scholar
  103. 103.
    Cmarik JL, Li Y, Ogram SA, Min H, Reeves R, Colburn NH: Tumor promoter induces high mobility group HMG-Y protein expression in transformation-sensitive but not -resistant cells. Oncogene 16: 3387–3396, 1998PubMedCrossRefGoogle Scholar
  104. 104.
    Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S, Colburn NH: Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci USA 96: 14037–14042, 1999PubMedCrossRefGoogle Scholar
  105. 105.
    Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, Colburn NH: A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Oncogene 20: 669–676, 2001PubMedCrossRefGoogle Scholar
  106. 106.
    Jansen AP, Colburn NH, Verma AK: Tumor promoter-induced ornithine decarboxylase gene expression occurs independently of AP-1 activation. Oncogene 18: 5806–5813, 1999PubMedCrossRefGoogle Scholar
  107. 107.
    Smith JH, Denhardt DT: Molecular cloning of a tumor promoter-inducible mRNA found in JB6 mouse epidermal cells: Induction is stable at high, but not at low, cell densities. J Cell Biochem 34: 13–22, 1987PubMedCrossRefGoogle Scholar
  108. 108.
    Craig AM, Smith JH, Denhardt DT: Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12–0-tetradecanoylphorbol 13-acetate in mouse epidermis. J Biol Chem 264: 9682–9689, 1989PubMedGoogle Scholar
  109. 109.
    Chang PL, Prince CW: 1 alpha,25-Dihydroxyvitamin D3 enhances 12–0-tetradecanoylphorbol-13-acetate-induced tumorigenic transformation and osteopontin expression in mouse JB6 epidermal cells. Cancer Res 53: 2217–2220, 1993PubMedGoogle Scholar
  110. 110.
    Chang PL, Chambers AF: Transforming JB6 cells exhibit enhanced integrin-mediated adhesion to osteopontin. J Cell Biochem 78: 8–23, 2000PubMedCrossRefGoogle Scholar
  111. 111.
    Cmarik JL, Hegamyer G, Gerrard B, Dean M, Colburn NH: cDNA cloning and mapping of mouse pleckstrin (Plek), a gene upregulated in transformation-resistant cells. Genomics 66: 204–212, 2000PubMedCrossRefGoogle Scholar
  112. 112.
    Lemmon MA, Ferguson KM: Pleckstrin homology domains. Curr Top Microbiol Immunol 228: 39–74, 1998PubMedCrossRefGoogle Scholar
  113. 113.
    Tyers M, Haslam RJ, Rachubinski RA, Harley CB: Molecular analysis of pleckstrin: The major protein kinase C substrate of platelets. J Cell Biochem 40: 133–145, 1989CrossRefGoogle Scholar
  114. 114.
    Sun Y, Hegamyer G, Colburn NH: Molecular cloning of five messenger RNAs differentially expressed in preneoplastic or neoplastic JB6 mouse epidermal cells: One is homologous to human tissue inhibitor of metalloproteinases-3. Cancer Res 54: 1139–1144, 1994PubMedGoogle Scholar
  115. 115.
    Sun Y, Hegamyer G, Kim H, Sithanandam K, Li H, Watts R, Colburn NH: Molecular cloning of mouse tissue inhibitor of metalloproteinases-3 and its promoter. Specific lack of expression in neoplastic JB6 cells may reflect altered gene methylation. J Biol Chem 270: 19312–19319, 1995PubMedCrossRefGoogle Scholar
  116. 116.
    Pennie WD, Hegamyer GA, Young MR, Colburn NH: Specific methylation events contribute to the transcriptional repression of the mouse tissue inhibitor of metalloproteinases-3 gene in neoplastic cells. Cell Growth Diff 10: 279–286, 1999PubMedGoogle Scholar
  117. 117.
    Sun Y, Kim H, Parker M, Stetler-Stevenson WG, Colburn NH: Lack of suppression of tumor cell phenotype by overexpression of TIMP3 in mouse JB6 tumor cells identification of a transfectant with increased tumorigenicity and invasiveness. Anticancer Res 16: 1–7, 1996PubMedGoogle Scholar
  118. 118.
    Bian J, Wang Y, Smith MR, Kim H, Jacobs C, Jackman J, Kung HF, Colburn NH, Sun Y: Suppression ofin vivotumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis 17: 1805–1811, 1996PubMedCrossRefGoogle Scholar
  119. 119.
    Cmarik JL, Herschman H, Colburn NH: Preferential primary-response gene expression in promotion-resistant vs. promotion-sensitive JB6 cells. Mol Carcinogen 11: 115–124, 1994CrossRefGoogle Scholar
  120. 120.
    Eto I: Promotion-sensitive epidermal and mammary epithelial cells maintained in suspension over agarose. Cell Prolif 31: 71–92, 1998PubMedCrossRefGoogle Scholar
  121. 121.
    Huang C, Ma WY, Dong Z: Requirement for phosphatidylinositol 3-kinase in epidermal growth factor-induced AP-1 transactivation and transformation in JB6 P+ cells. Mol Cell Biol 16: 6427–6435, 1996PubMedGoogle Scholar
  122. 122.
    Huang C, Schmid PC, Ma WY, Schmid HH, Dong Z: Phosphatidylinositol-3 kinase is necessary for 12–0- tetradecanoylphorbol-13acetate-induced cell transformation and activated protein 1 activation. J Biol Chem 272: 4187–4194, 1997PubMedCrossRefGoogle Scholar
  123. 123.
    Schmidt KN, Traenckner EB, Meier B, Baeuerle PA: Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. J Biol Chem 270: 27136–27142, 1995PubMedCrossRefGoogle Scholar
  124. 124.
    Schmidt KN, Amstad P, Cerutti P, Baeuerle PA: Identification of hydrogen peroxide as the relevant messenger in the activation pathway of transcription factor NF-kappaB. Adv Exp Med Biol 387: 63–68, 1996PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Arindam Dhar
    • 1
  • Mathew R. Young
    • 1
  • Nancy H. Colburn
    • 1
  1. 1.Gene Regulation SectionNational Cancer Institute at FrederickFrederickUSA

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