Dioxin-induced immortalization of normal human keratinocytes and silencing of p53 and p16INK4a

Soma S. Ray, Hollie I. Swanson

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Dioxin, a potent tumor promoter, activates the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor belonging to the basic helix-loop-helix-PAS family, to enhance tumorigenesis via unknown mechanisms. We undertook this study to determine the mechanisms underlying the impact of dioxin on cell fate, in particular senescence that occurs in normal human cells and is considered to play important tumor suppressive function. We have previously shown that in primary human keratinocytes, dioxin attenuates senescence while retaining the proliferative capacity and represses expression of the tumor suppressors, p16INK4a and p53. Here, we show that repression of p16INK4a and p53 transcriptional activity by dioxin absolutely requires the AHR and is accompanied by promoter methylation. Furthermore, dioxin alone is sufficient to immortalize normal human keratinocytes. Our data introduce a previously unrecognized regulatory pathway, that of the AHR, that impacts senescence. More importantly, this is the first report of a tumor promoter capable of inhibiting senescence in a receptor mediated manner and introduces a novel mechanism by which this carcinogen may contribute to human malignancies.

Original languageEnglish
Pages (from-to)27187-27193
Number of pages7
JournalJournal of Biological Chemistry
Issue number26
StatePublished - Jun 25 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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