Skip to main content
Journal cover image

Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Publication ,  Journal Article
Puga, A; Barnes, SJ; Chang, C; Zhu, H; Nephew, KP; Khan, SA; Shertzer, HG
Published in: Biochem Pharmacol
April 15, 2000

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin), the prototype agonist of the aromatic hydrocarbon (Ah) receptor, is a potent tumor promoter as well as a complete liver carcinogen that produces an oxidative stress response in rodents and in cultured cell lines. It has been proposed that TCDD promotes neoplastic transformation through oxidative signal transduction pathways, which results in activation of immediate-early response transcription factors. To set the stage for a test of this hypothesis, we evaluated the effect of TCDD treatment on the activation of several transcription factors, including those in the nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) families, which are activated by changes in the redox state of cells. In an extension of prior results, we found that TCDD treatment produced a sustained overexpression of AP-1 for at least 72 hr in wild-type mouse hepatoma Hepa-1 cells, but not in the Ah receptor-deficient derivative c35 or in cytochrome P450-1A1 (CYP1A1)-negative c37 cells. In addition, TCDD treatment caused a significant increase in the DNA binding activity of NF-kappaB, but not in the activities of the other transcription factors tested. AP-1 and NF-kappaB activation were blocked by the thiol antioxidant N-acetylcysteine and by nordihydroguaiaretic acid, an antioxidant and lipooxygenase inhibitor and an inhibitor of the epoxygenase activity of CYP1A1, and did not take place in c35, c37, or in Ah nuclear translator-deficient c4 cells. Hence, sustained activation of these two transcription factors by TCDD is likely to result from a CYP1A1-dependent and Ah receptor complex-dependent oxidative signal. Electrophoretic mobility supershift analyses with specific antibodies showed that most of the increase in NF-kappaB binding activity could be accounted for by increases in p50/p50 complexes. Since these complexes are known to repress NF-kappaB-dependent gene transcription, our results delineate a second molecular mechanism, in addition to the recently found block of tumor necrosis factor-alpha-mediated p50/p65 activation, that may be responsible for the immunosuppresive effects of TCDD.

Duke Scholars

Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

April 15, 2000

Volume

59

Issue

8

Start / End Page

997 / 1005

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription Factor AP-1
  • Receptors, Aryl Hydrocarbon
  • Polychlorinated Dibenzodioxins
  • Pharmacology & Pharmacy
  • Oxidative Stress
  • NF-kappa B
  • Mice
  • DNA
  • Cytochrome P-450 CYP1A1
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Puga, A., Barnes, S. J., Chang, C., Zhu, H., Nephew, K. P., Khan, S. A., & Shertzer, H. G. (2000). Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol, 59(8), 997–1005. https://doi.org/10.1016/s0006-2952(99)00406-2
Puga, A., S. J. Barnes, C. Chang, H. Zhu, K. P. Nephew, S. A. Khan, and H. G. Shertzer. “Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin.Biochem Pharmacol 59, no. 8 (April 15, 2000): 997–1005. https://doi.org/10.1016/s0006-2952(99)00406-2.
Puga A, Barnes SJ, Chang C, Zhu H, Nephew KP, Khan SA, et al. Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol. 2000 Apr 15;59(8):997–1005.
Puga, A., et al. “Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin.Biochem Pharmacol, vol. 59, no. 8, Apr. 2000, pp. 997–1005. Pubmed, doi:10.1016/s0006-2952(99)00406-2.
Puga A, Barnes SJ, Chang C, Zhu H, Nephew KP, Khan SA, Shertzer HG. Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol. 2000 Apr 15;59(8):997–1005.
Journal cover image

Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

April 15, 2000

Volume

59

Issue

8

Start / End Page

997 / 1005

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription Factor AP-1
  • Receptors, Aryl Hydrocarbon
  • Polychlorinated Dibenzodioxins
  • Pharmacology & Pharmacy
  • Oxidative Stress
  • NF-kappa B
  • Mice
  • DNA
  • Cytochrome P-450 CYP1A1