2,3,7,8-tetrachlorodibenzo-p-dioxin-induced MUC5AC expression: Aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription

Yong C. Lee, Karen L. Oslund, Philip Thai, Sharlene Velichko, Tomoyuki Fujisawa, Trang Duong, Michael S. Denison, Reen Wu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant. Epidemiological studies have associated TCDD exposure with the development of chronic obstructive pulmonary disease, which is manifested by mucous/goblet cell hyperplasia. The purpose of this research was to elucidate the pathway/mechanisms that lead to TCDD-induced gene expression in both primary normal human bronchial epithelial cells and an immortalized cell line, HBE1, under air-liquid interface conditions. TCDD exposure induced a time-dependent elevation of MUC5AC mRNA and protein synthesis, and cytochrome p450 1A1 (CYP1A1) expression in these cells. Treatment with an aryl hydrocarbon receptor antagonist had no effect on TCDD-induced MUC5AC expression, but significantly suppressed CYP1A1 induction. However, treatments with inhibitors of signaling pathways and the expression of dominant negative mutants of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK)andp38, but not the inhibition of c-Jun N-terminal kinase pathway, abrogated MUC5AC induction, but not that of CYP1A1. These effects also occurred at the MUC5AC promoter-reporter level using the chimeric construct for a transient transfection study. Western blot analysis confirmed the phosphorylation of activated EGFR, ERK, and p38 signaling molecules, but not the c-Jun N-terminal kinase, in cells after TCDD exposure. Specificity protein 1 (Sp1) phosphorylation also occurred in cells after TCDD exposure. Both MUC5AC expression and the promoter activity were inhibited by mithramycin A, an inhibitor specific to Sp1-based transcription. These results lead to the conclusion that TCDD induced MUC5AC expression through a noncanonical aryl hydrocarbon receptor-independent, EGFR/ERK/p38-mediated signaling pathway-mediated/Sp1-based transcriptional mechanism.

Original languageEnglish (US)
Pages (from-to)270-276
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number2
StatePublished - Aug 1 2011


  • 2,3,7,8-tetrachlorodibenzo-p-dioxin
  • Airways
  • Aryl hydrocarbon receptor
  • Mucin
  • Signaling

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry


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