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NF-κB prevents cells from undergoing Cr(VI)-induced apoptosis

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Abstract

The transcription factor NF-κB has been reported to prevent cells from undergoing apoptosis as well as promote cell apoptosis. To investigate the role of NF-κB in Cr(VI)-induced apoptosis, two cell lines were developed from human bronchial epithelial BEAS-2B cells: IKK cells, which were stably transfected with Iκ-Bα expression vector, that have normal NF-κB activity, and KM cells, which were stably transfected with mutated Iκ-Bα kinase expression vector, that exhibit very little NF-κB activity. With Cr(VI) stimulation, KM cells, but not IKK cells, exhibited substantial cell death. Cell morphological and TUNEL analyses indicated that the KM cells showed apoptotic features. These results suggest that NF-κB activation is required to prevent the cells from undergoing Cr(VI)-induced apoptosis.

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References

  1. Baeuerle PA: The inducible transcription activator NF-κB: Regulation by distinct protein subunits. Biochim Biophys Acta 1072: 63–80, 1991

    Google Scholar 

  2. Baeuerle PA, Henkel T: Function and activation of NF-κB in the immune system. Annu Rev Immunol 12: 141–179, 1994

    Google Scholar 

  3. Blagosklonny MV: Loss of function and p53 protein stabilization. Oncogene 15: 1889–1893, 1997

    Google Scholar 

  4. Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD: Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci USA 96: 13777–13782, 1999

    Google Scholar 

  5. Chen F, Castranova V, Shi X, Demers LM: New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45: 7–17, 1999

    Google Scholar 

  6. Chen F, Demers LM, Vallyathan V, Lu Y, Castranova V, Shi X: Impairment of NF-κB activation and modulation of gene expression by calpastatin. Am J Physiol 279: C709–C716, 2000

    Google Scholar 

  7. Chen F, Sun SC, Kuhn DC, Gaydos LJ, Demers LM: Essential role of NF-κB activation in silica-induced inflammatory mediator production in macrophages. Biochem Biophys Res Commun 214: 985–992, 1995

    Google Scholar 

  8. De Flora S, Bagnasco M, Serra D, Zanacchi P: Genotoxicity of chromium compounds: A review. Mutat Res 238: 99–172, 1990

    Google Scholar 

  9. Dumaz N, Meek DW: Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J 18: 7002–7010, 1999

    Google Scholar 

  10. Foo SY, Nolan GP: NF-κB to the rescue: RELs, apoptosis and cellular transformation. Trends Genet 15: 229–235, 1999

    Google Scholar 

  11. Freedman DA, Levine AJ: Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 18: 7288–7293, 1998

    Google Scholar 

  12. Freedman DA, Levine AJ: Regulation of the p53 protein by the MDM2 oncoprotein—thirty-eighth G.H.A. Clowes Memorial Award Lecture. Cancer Res 59: 1–7, 1999

    Google Scholar 

  13. Freeman N, Lioy PJ: Exposure to chromium dust from homes in a chromium surveillance project. Arch Environ Health 52: 213–226, 1997

    Google Scholar 

  14. Fritsche M, Haessler C, Brandner G: Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene 8: 307–318, 1993

    Google Scholar 

  15. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z: Mdm2 association with p53 targets its ubiquitination. Oncogene 17: 2543–2547, 1998

    Google Scholar 

  16. Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Jr., Giaccia AJ: Hypoxia induces assumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14: 6264–6277, 1994

    Google Scholar 

  17. Hall SR, Campbell LE, Meek DW: Phosphorylation of p53 at the casein kinase II site selectively regulates p53-dependent transcriptional repression but not transactivation. Nucleic Acids Res 24: 1119–1126, 1996

    Google Scholar 

  18. Haupt Y, Maya R, Kazaz A, Oren M: Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299, 1997

    Google Scholar 

  19. Hayes RB: Review of occupational epidemiology of chromium chemicals and respiratory cancer. Sci Total Environ 71: 331–339, 1988

    Google Scholar 

  20. Hecker D, Page G, Lohrum M, Weiland S, Scheidtmann LH: Complex regulation of the DNA-binding activity of p53 by phosphorylation: Differential effects of individual phosphorylation sites on the interaction with different binding motifs. Oncogene 12: 953–961, 1996

    Google Scholar 

  21. Hellin AC, Calmant P, Gielen J, Bours V, Merville MP: Nuclear factor — κB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug. Oncogene 16: 1187–1195, 1998

    Google Scholar 

  22. Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC: Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res, 22: 3551–3555, 1994

    Google Scholar 

  23. Hupp TR, Meek DW, Midgley CA, Lane DP: Regulation of the specific DNA binding function of p53. Cell 71: 875–886, 1992

    Google Scholar 

  24. Karin M: The NF-κB activation pathway: Its regulation and role in inflammation and cell survival. Cancer J Sci Am 4(Suppl 1): S92–99, 1998

    Google Scholar 

  25. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51: 6304–6311, 1991

    Google Scholar 

  26. Klefstrom J, Arighi E, Littlewood T, Jaattela M, Saksela E, Evan GI, Alitalo K: Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-κB activation. EMBO J 16: 7382–7392, 1997

    Google Scholar 

  27. Ko JL, Prives C: P53: Puzzle and paradigm. Genes Dev 10: 1054–1072, 1996

    Google Scholar 

  28. Kubbutat MH, Jones SN, Vousden KH: Regulation of p53 stability by Mdm2. Nature 387: 299–303, 1997

    Google Scholar 

  29. Langard S: One hundred years of chromium and cancer: A review of epidemiological evidence and selected case reports. Am J Ind Med 17: 189–215, 1990

    Google Scholar 

  30. Levine AJ: P53, the cellular gatekeeper for growth and division. Cell 88: 323–331, 1997

    Google Scholar 

  31. Linke SP, Clarkin KC, DiLeonardo A, Tsou A, Wahl GM: A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev 10: 934–947, 1996

    Google Scholar 

  32. Meek DW: Post-translational modification of p53. Semi Cancer Biol 5: 203–210, 1994

    Google Scholar 

  33. Meek DW: Multisite phosphorylation and the integration of stress signals at p53. Cell Signal 10: 159–166, 1997

    Google Scholar 

  34. Meek DW: New developments in the multi-site phosphorylation and integration of stress signaling at p53. Int J Radiat Biol 74: 729–737, 1998

    Google Scholar 

  35. Mundt M, Hupp T, Fritsche M, Merkle C, Hansen S, Lane D, Groner B: Protein interactions at the carboxyl terminus of p53 result in the induction of its in vitro transactivation potential. Oncogene 15: 237–244, 1997

    Google Scholar 

  36. Pei XH, Nakanishi Y, Takayama K, Bai F, Hara N: Benzo[α]pyrene activates the human p53 gene through induction of nuclear factor κB activity. J Biol Chem 274: 35240–35246, 1999

    Google Scholar 

  37. Pise-Masison CA, Mahieux R, Jiang H, Ashcroft M, Radonovich M, Duvall J, Guillerm C, Brady JN: Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-κB pathway and is dependent on p53 phosphorylation. Mol Cell Biol 20: 3377–3386, 2000

    Google Scholar 

  38. Shen HM, Yang CF, Ong CN: Induction of oxidative stress and apoptosis in sodium Selenite-treated human hepatoma cells (HepG2). Int J Cancer 81: 820–828, 1999

    Google Scholar 

  39. Shi X, Castranova V, Halliwell B, Vallyathan V: Reactive oxygen species and silica-induced carcinogenesis. J Toxicol Environ Health B Crit Rev 1: 181–197, 1998

    Google Scholar 

  40. Shi X, Dalal NS: Chromium(V) and hydroxyl radical formation during the glutathione reductase-catalyzed reduction of chromium(VI). Biochem Biophys Res Commun 163: 627–634, 1989

    Google Scholar 

  41. Shi X, Dalal NS: Evidence for a Fenton-type mechanism for the generation of hydroxyl radical in the reduction of Cr(VI) in cellular media. Arch Biochem Biophys 281: 90–95, 1990

    Google Scholar 

  42. Shi X, Mao Y, Knapton A, Ding M, Rojanasakul Y, Gannett PM, Dalal NS, Liu K: Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: Role of a Cr(VI)-mediated Fenton-like reaction. Carcinogenesis 15: 2475–2478, 1994

    Google Scholar 

  43. Shieh SY, Ikeda M, Taya Y, Prives C: DNA damage-induced phosphorylation of p53 alleviates inhibition by mdm2. Cell 91: 325–334, 1997

    Google Scholar 

  44. Singh J, Carlisle DL, Pritchard DE, Patierno S: Chromium-induced genotoxicity and apoptosis: Relationship to chromium carcinogenesis. Oncol Rep 5: 1307–1318, 1998

    Google Scholar 

  45. Steegenga WT, van der Eb AJ, Jochemsen AG: How phosphorylation regulates the activity of p53. J Mol Biol 263: 103–113, 1996

    Google Scholar 

  46. Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, Lozano G, Oren M, Haupt Y: Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J 18: 1805–1814, 1999

    Google Scholar 

  47. Wang S, Leonard SS, Ye J, Ding M, Shi X: The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. Am J Physiol 279: C868–C875, 2000

    Google Scholar 

  48. Wang S, Shi X: Mechanisms of Cr(VI)-induced p53 activation: The role of phosphorylation, mdm2, and ERK. Carcinogenesis (submitted)

  49. Webster GA, Perkins ND: Transcriptional cross talk between NF-κB and p53. Mol Cell Biol 19: 3485–3495, 1999

    Google Scholar 

  50. Wu H, Lozano G: NF-κB activation of p53. A potential mechanism for suppressing cell growth in response to stress. J Biol Chem 269: 20067–20074, 1994

    Google Scholar 

  51. Yang CR, Wilson-Van Patten C, Planchon SM, Wuerzberger-Davis SM, Davis TW, Cuthill S, Miyamoto S, Boothman DA: Coordinate modulation of Sp1, NF-κB, and p53 in confluent human malignant melanoma cells after ionizing radiation. FASEB J 14: 379–390, 2000

    Google Scholar 

  52. Ye J, Wang S, Leonard SS, Sun Y, Butterworth L, Antonini J, Ding M, Rojanasakul Y, Vallyathan V, Castranova V, Shi X: Role of reactive oxygen species and p53 in chromium(VI)-induced apoptosis. J Biol Chem 274: 34974–34980, 1999

    Google Scholar 

  53. Ye J, Zhang X, Young HA, Mao Y, Shi X: Chromium(VI)-induced nuclear factor-κB activation in intact cells via free radical reactions. Carcinogenesis 16: 2401–2405, 1995

    Google Scholar 

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Wang, S., Chen, F., Zhang, Z. et al. NF-κB prevents cells from undergoing Cr(VI)-induced apoptosis. Mol Cell Biochem 255, 129–137 (2004). https://doi.org/10.1023/B:MCBI.0000007269.74532.98

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