Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin

Soma S. Ray, Hollie I. Swanson

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Exposure to the environmental contaminant dioxin, elicits a variety of responses, which includes tumor promotion, embryotoxicity/teratogenesis, and carcinogenesis in both animals and humans. Many of the effects of dioxin are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated bHLH (basic helix-loop-helix)/PAS transcription factor. We initiated this study to determine whether dioxin's tumor-promoting activities may lie in its ability to alter proliferation, differentiation, and/or senescence using normal human epidermal keratinocytes (HEKs). Here, we report that dioxin appears to accelerate differentiation as measured by flow cytometry and by increased expression of the differentiation markers involucrin and filaggrin. In addition, dioxin appears to increase proliferation as indicated by an increase in NADH/NADPH production and changes in cell cycle. Finally, dioxin decreases SA (senescence associated) β-galactosidase staining, an indicator of senescence, in the differentiating keratinocytes. These changes were accompanied by decreases in the expression levels of key cell cycle regulatory proteins p53, p16INK4a, and p14ARF. Our findings support the idea that dioxin may exert its tumor-promoting actions, in part, by downregulating the expression levels of key tumor suppressor proteins, which may impair the cell's ability to maintain its appropriate cellular status.

Original languageEnglish
Pages (from-to)131-145
Number of pages15
JournalToxicology and Applied Pharmacology
Issue number2
StatePublished - Oct 15 2003

Bibliographical note

Funding Information:
We thank Erica M. Harthun for providing technical assistance in our preliminary experiments. We thank Dr. Olivier Thibault and Veronique Thibault for assisting with fluorescent microscopy and Greg Bauman and Jennifer Strange for flow cytometric analysis. Also we thank Dr. Susan D. Kraner for helpful discussions. This work was supported by grant 1RO1ES11295-01 from NIEHS.


  • Aryl hydrocarbon receptor
  • Differentiation
  • Dioxin
  • Keratinocytes
  • P16
  • Proliferation and senescence
  • p14
  • p53

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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