Opposing actions of insulin and arsenite converge on PKCδ to alter keratinocyte proliferative potential and differentiation

Tatiana V. Reznikova, Marjorie A. Phillips, Timothy J. Patterson, Robert H. Rice

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


When cultured human keratinocytes reach confluence, they undergo a program of changes replicating features of differentiation in vivo, including exit from the proliferative pool, increased cell size, and expression of specialized differentiation marker proteins. Previously, we showed that insulin is required for some of these steps and that arsenite, a human carcinogen in skin and other epithelia, opposes the differentiation process. In present work, we show that insulin signaling, probably through the IGF-I receptor, is required for the increase in cell size accompanying differentiation and that this is opposed by arsenite. We further examine the impact of insulin and arsenite on PKCδ, a known key regulator of keratinocyte differentiation, and show that insulin increases the amount, tyrosine phosphorylation, and membrane localization of PKCδ. All these effects are prevented by exposure of cells to arsenite or to inhibitors of downstream effectors of insulin (phosphotidylinositol 3-kinase and mammalian target of rapamycin). Retrovirally mediated expression of activated PKCδ resulted in increased loss of proliferative potential after confluence and greatly increased formation of cross-linked envelopes, a marker of keratinocyte terminal differentiation. These effects were prevented by removal of insulin, but not by arsenite addition. We further demonstrate a role for src family kinases in regulation of PKCδ. Finally, inhibiting epidermal growth factor receptor kinase activity diminished the ability of arsenite to prevent cell enlargement and to suppress insulin-dependent PKCδ amount and tyrosine 311 phosphorylation. Thus suppression of PKCδ signaling is a critical feature of arsenite action in preventing keratinocyte differentiation and maintaining proliferative capability.

Original languageEnglish (US)
Pages (from-to)398-409
Number of pages12
JournalMolecular Carcinogenesis
Issue number4
StatePublished - Apr 2010


  • Cell size
  • EGF receptor
  • IGF-I receptor
  • mTOR
  • PI3-kinase

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology


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