Molecular and Cellular Biochemistry

, Volume 279, Issue 1–2, pp 163–168 | Cite as

Deficiency in Ikkβ gene enhances arsenic-induced gadd45α expression

  • Yadong Zhang
  • Yongju Lu
  • Min Ding
  • Vince Castranova
  • Xianglin Shi
  • Fei Chen


Chronic arsenic exposure is implicated in the pathophysiology of various human diseases, including cancer and diabetes. Using Ikkβ gene knockout mouse embryonic fibroblast cells (Ikkβ−/−), in the present study we demonstrated that NF-κB inhibition due to Ikkβ deficiency up-regulated basal and arsenic-induced expression of gadd45α. In addition to gadd45α, the basal expression of other gadd family members including gadd45β, gadd45γ and gadd153 was substantially increased in Ikkβ−/− cells. Ikkβ deficiency prevented the induction of gadd45β and gadd45γ by arsenic, whereas the induction of gadd45α and gadd153 was appreciably enhanced in Ikkβ−/− cells. Furthermore, a substantial decrease in the expression of c-myc, an established endogenous transcriptional repressor of gadd45α and gadd153 genes, was noted. Thus, these results uncover the molecular mechanism by which NF-κB signalling contributes to the regulation of gadd family gene expression induced by arsenic.

Key Words

Ikk gadd45 arsenic c-myc 


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  1. 1.
    Lucas PC, McAllister-Lucas LM, Nunez G: NF-kappaB signaling in lymphocytes: A new cast of characters. J Cell Sci 117: 31–39, 2004CrossRefPubMedGoogle Scholar
  2. 2.
    Chen F, Castranova V, Shi X, Demers LM: New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45: 7–17, 1999PubMedGoogle Scholar
  3. 3.
    Karin M, Yamamoto Y, Wang QM: The IKK NF-kappaB system: A treasure trove for drug development. Nat Rev Drug Discov 3: 17–26, 2004PubMedGoogle Scholar
  4. 4.
    Hayden MS, Ghosh S: Signaling to NF-κB. Genes Dev 18: 2195–2224, 2004CrossRefPubMedGoogle Scholar
  5. 5.
    Aggarwal BB: Nuclear factor-κB: The enemy within. Cancer Cell 6: 203–208, 2004CrossRefPubMedGoogle Scholar
  6. 6.
    Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr.: NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19: 5785–5799, 1999PubMedGoogle Scholar
  7. 7.
    Chen F, Lu Y, Zhang Z, Vallyathan V, Ding M, Castranova V, Shi X: Opposite effect of NF-κB and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem 276: 11414–11419, 2001CrossRefPubMedGoogle Scholar
  8. 8.
    Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ Jr: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587–597, 1992CrossRefPubMedGoogle Scholar
  9. 9.
    Kovalsky O, Lung FD, Roller PP, Fornace AJ Jr: Oligomerization of human Gadd45a protein. J Biol Chem 276: 39330–39339, 2001CrossRefPubMedGoogle Scholar
  10. 10.
    Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ Jr: Genomic instability in Gadd45a-deficient mice. Nat Genet 23: 176–184, 1999CrossRefPubMedGoogle Scholar
  11. 11.
    Carrier F, Georgel PT, Pourquier P, Blake M, Kontny HU, Antinore MJ, Gariboldi M, Myers TG, Weinstein JN, Pommier Y, Fornace AJ Jr: Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol Cell Biol 19: 1673–1685, 1999PubMedGoogle Scholar
  12. 12.
    Sheikh MS, Hollander MC, Fornance AJ Jr: Role of Gadd45 in apoptosis. Biochem Pharmacol 59: 43–45, 2000CrossRefPubMedGoogle Scholar
  13. 13.
    Hollander MC, Alamo I, Jackman J, Wang MG, McBride OW, Fornace AJ Jr.: Analysis of the mammalian gadd45 gene and its response to DNA damage. J Biol Chem 268: 24385–24393, 1993PubMedGoogle Scholar
  14. 14.
    Takahashi S, Saito S, Ohtani N, Sakai T: Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation. Cancer Res 61: 1187–1195, 2001PubMedGoogle Scholar
  15. 15.
    Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW, Greenberg ME: DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296: 530–534, 2002CrossRefPubMedGoogle Scholar
  16. 16.
    Bush A, Mateyak M, Dugan K, Obaya A, Adachi S, Sedivy J, Cole M: c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets. Genes Dev 12: 3797–3802, 1998PubMedGoogle Scholar
  17. 17.
    Zheng L, Pan H, Li S, Flesken-Nikitin A, Chen PL, Boyer TG, Lee WH: Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell 6: 757–768, 2000PubMedGoogle Scholar
  18. 18.
    Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, Horwitz KB: Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 277: 5209–5218, 2002CrossRefPubMedGoogle Scholar
  19. 19.
    Burgering BM, Kops GJ: Cell cycle and death control: Long live Forkheads. Trends Biochem Sci 27: 352–360, 2002CrossRefPubMedGoogle Scholar
  20. 20.
    Chen F, Zhang Z, Leonard SS, Shi X: Contrasting roles of NF-kappaB and JNK in arsenite-induced p53-independent expression of GADD45alpha. Oncogene 20: 3585–3589, 2001CrossRefPubMedGoogle Scholar
  21. 21.
    Ayer DE, Eisenman RN: A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev 7: 2110–2119, 1993PubMedGoogle Scholar
  22. 22.
    Barsyte-Lovejoy D, Mao DY, Penn LZ: c-Myc represses the proximal promoters of GADD45a and GADD153 by a post-RNA polymerase II recruitment mechanism. Oncogene 23: 3481–3486, 2004CrossRefPubMedGoogle Scholar
  23. 23.
    Chen F, Castranova V, Li Z, Karin M, Shi X: Inhibitor of nuclear factor κB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. Cancer Res 63: 7689–7693, 2003PubMedGoogle Scholar
  24. 24.
    Zerbini LF, Wang Y, Czibere A, Correa RG, Cho JY, Ijiri K, Wei W, Joseph M, Gu X, Grall F, Goldring MB, Zhou JR, Libermann TA: NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45 alpha and gamma is essential for cancer cell survival. Proc Natl Acad Sci USA 101: 13618–13623, 2004CrossRefPubMedGoogle Scholar
  25. 25.
    Nozaki S, Sledge Jr GW, Nakshatri H: Repression of GADD153/CHOP by NF-κB: a possible cellular defense against endoplasmic reticulum stress-induced cell death. Oncogene 20: 2178–2185, 2001CrossRefPubMedGoogle Scholar
  26. 26.
    Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC: IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117: 225–237, 2004CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Yadong Zhang
    • 1
  • Yongju Lu
    • 2
  • Min Ding
    • 2
  • Vince Castranova
    • 2
  • Xianglin Shi
    • 1
    • 2
  • Fei Chen
    • 2
    • 3
  1. 1.Institute for Nutritional Sciences, Shanghai Institutes for Biological SciencesChinese Academy of ScienceShanghaiP.R. China
  2. 2.The Health Effects Laboratory Division, Pathology and Physiology Research BranchNational Institute for Occupational Safety and HealthMorgantownUSA
  3. 3.Pathology and Physiology Research BranchNational Institute for Occupational Safety and HealthMorgantownUSA

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