Induction of cyclin D1 by submicromolar concentrations of arsenite in human epidermal keratinocytes

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Bor-Jang Hwang1, Charles Utti, Mark Steinberg

  • 1Department of Chemistry, The City College of the City University of New York, Convent Avenue and 138th Street, New York, NY 10031, USA.

Toxicology and Applied Pharmacology
|September 29, 2006
PubMed

Insights

Arsenic exposure, though not directly mutagenic, promotes cancer by increasing cell growth and altering cell cycle control. This study shows arsenite upregulates cyclin D1, impacting cell cycle checkpoints.

Area of Science:

  • Environmental Health
  • Molecular Biology
  • Cell Biology

Background:

  • Arsenic is a known environmental carcinogen.
  • The precise mechanism of arsenite-induced oncogenesis is not fully understood.
  • Arsenite is not directly mutagenic.

Purpose of the Study:

  • To investigate the oncogenic properties of arsenic.
  • To examine the effect of sodium arsenite on cyclin D1 expression in human epidermal keratinocytes.
  • To elucidate the mechanism of arsenite-induced cell proliferation and transformation.

Main Methods:

  • Cell culture of human epidermal keratinocytes.
  • Treatment with submicromolar concentrations of sodium arsenite.
  • Analysis of cell viability, cell cycle progression (flow cytometry), cyclin D1 transcription (real-time PCR), cyclin D protein levels (Western blot), and transcription factor binding (EMSA).

Main Results:

  • Submicromolar arsenite concentrations (200-800 nM) increased cell growth rate and viability.
  • Arsenite treatment led to a shift in cell cycle from G1 to S/G2 phases.
  • Significant upregulation of cyclin D1 transcription (over 3-fold) and protein levels (approx. 2-fold) was observed.
  • Arsenite stimulated the binding of transcription factors AP1 and CREBP.

Conclusions:

  • Arsenite promotes oncogenesis through persistent upregulation of cyclin D1.
  • This upregulation leads to a loss of G1/S cell cycle checkpoint control.
  • The findings provide insight into the molecular mechanisms of arsenite-induced cancer.

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