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Role of reactive oxygen species and MAPKs in vanadate-induced G(2)/M phase arrest

Zhuo Zhang1, Stephen S Leonard, Chuanshu Huang

  • 1Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.

Free Radical Biology & Medicine
|May 3, 2003
PubMed

Insights

Vanadate exposure causes cell growth arrest by generating reactive oxygen species (ROS) that activate protein kinases, leading to cell cycle regulation. This study clarifies the ROS-MAPK-p21 pathway in vanadate-induced cell cycle arrest.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Cell growth arrest is crucial for maintaining genomic stability against environmental stressors.
  • Reactive oxygen species (ROS) play a complex role in cellular signaling and stress responses.

Purpose of the Study:

  • To investigate the roles of ROS, extracellular signal-regulated protein kinase (ERK), and p38 protein kinase in vanadate-induced cell growth arrest in A549 cells.
  • To elucidate the molecular mechanisms linking vanadate exposure to cell cycle regulation.

Main Methods:

  • Utilized A549 human lung alveolar epithelial cancer cell line.
  • Assessed cell growth arrest, cell cycle phase distribution (G2/M), protein expression (p21, phospho-cdc2, cdc25C), and mitogen-activated protein kinase (MAPK) activation (ERK, p38 phosphorylation).
  • Employed specific inhibitors (PD98059, SB202190) and antioxidant enzymes (superoxide dismutase, catalase) to determine the involvement of ROS and MAPKs.

Main Results:

  • Vanadate induced G2/M phase cell growth arrest, upregulated p21 and phospho-cdc2, and decreased cdc25C in a dose- and time-dependent manner.
  • Vanadate stimulated ERK and p38 phosphorylation, indicating MAPK activation.
  • Inhibition of ERK and p38 pathways abrogated vanadate-induced cell cycle arrest and associated molecular changes.
  • Vanadate generated hydroxyl radical, superoxide radical, and hydrogen peroxide, which were mitigated by specific antioxidants.

Conclusions:

  • Vanadate-induced cell growth arrest at G2/M phase is mediated by ROS generation.
  • ROS activate the ERK and p38 MAPK pathways, which subsequently regulate p21, cdc2, and cdc25C, leading to cell cycle arrest.
  • Specific ROS species differentially impact MAPK signaling and cell cycle regulators.

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