Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential

Timothy J. Patterson, Robert H. Rice

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Previous work has suggested that arsenic exposure contributes to skin carcinogenesis by preserving the proliferative potential of human epidermal keratinocytes, thereby slowing the exit of putative target stem cells into the differentiation pathway. To find a molecular basis for this action, present work has explored the influence of arsenite on keratinocyte responses to epidermal growth factor (EGF). The ability of cultured keratinocytes to found colonies upon passaging several days after confluence was preserved by arsenite and EGF in an additive fashion, but neither was effective when the receptor tyrosine kinase activity was inhibited. Arsenite prevented the loss of EGF receptor protein and phosphorylation of tyrosine 1173, preserving its capability to signal. The level of nuclear β-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative β-catenin suppressed the increase in both colony forming ability and yield of putative stem cells induced by arsenite and EGF. As judged by expression of three genes regulated by β-catenin, this transcription factor had substantially higher activity in the arsenite/EGF-treated cells. Trivalent antimony exhibited the same effects as arsenite. A novel finding is that insulin in the medium induced the loss of EGF receptor protein, which was largely prevented by arsenite exposure.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalToxicology and Applied Pharmacology
Volume221
Issue number1
DOIs
StatePublished - May 15 2007

Keywords

  • β-catenin
  • Antimony
  • Arsenite
  • Epidermal growth factor
  • Insulin
  • Keratinocyte

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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