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Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells

Priya Ranjan1, Vikas Anathy, Peter M Burch

  • 1Department of Pathology and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, 05405, USA.

Antioxidants & Redox Signaling
|September 22, 2006
PubMed

Insights

NADPH oxidases, like Nox1, regulate cell proliferation by controlling cyclin D1. Nox1 promotes proliferation in cycling cells but inhibits it during cell cycle re-entry, impacting Fos gene activation.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • NADPH oxidases (NOX) generate reactive oxygen species (ROS) involved in cell signaling.
  • ROS act as co-stimulatory signals for cell proliferation.
  • Specific NOX isoforms and their roles in cell cycle regulation are not fully elucidated.

Purpose of the Study:

  • To investigate the role of Nox1 in regulating cell proliferation and cell cycle progression in mouse lung epithelial cells.
  • To determine the impact of Nox1 expression levels and NADPH oxidase activity on cyclin D1 and downstream signaling pathways.
  • To elucidate the differential effects of Nox1 and Nox4 on cell cycle dynamics.

Main Methods:

  • Overexpression of Nox1 and Nox4 in mouse lung epithelial cells.
  • Measurement of reactive oxygen species (ROS) production.
  • Analysis of cell cycle progression and proliferation.
  • Western blotting for phosphorylated ERK1/2, Akt, c-Fos, and Fra-1.
  • Assessment of cyclin D1 expression.
  • Inhibition of NADPH oxidase activity using diphenylene iodonium (DPI).
  • Reversal of effects using catalase.

Main Results:

  • Overexpression of Nox1 delayed cell cycle withdrawal by maintaining AP-1-dependent cyclin D1 expression under low serum conditions.
  • Dose-dependent effects of Nox1: moderate ROS increases promoted ERK1/2 phosphorylation and cyclin D1 expression, while high ROS inhibited them.
  • Nox1, Noxo1, Noxa1, or Nox4 overexpression induced significant ROS, inhibiting cyclin D1 and proliferation.
  • Catalase reversed Nox1-mediated effects on cyclin D1 and proliferation.
  • DPI inhibited the induction of c-Fos and Fra-1 during cell cycle re-entry, without affecting serum-dependent ERK1/2 or Akt responses.
  • Nox1 stimulates proliferation in cycling cells by decreasing growth factor dependency for cyclin D1 maintenance.

Conclusions:

  • Nox1 plays a dual role in cell proliferation, promoting it in cycling cells and inhibiting it during re-entry.
  • NADPH oxidase activity is crucial for the transcriptional activation of Fos family genes during the immediate early gene response in cell cycle re-entry.
  • Nox1 modulates cell proliferation by influencing cyclin D1 expression and downstream signaling pathways in a context-dependent manner.

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