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Ras-induced ROS upregulation affecting cell proliferation is connected with cell type-specific alterations of

Maria Zamkova1, Natalia Khromova, Boris P Kopnin

  • 1Institute of Carcinogenesis, Russian Blokhin Cancer Research Center, Moscow, Russia.

Cell Cycle (Georgetown, Tex.)
|February 8, 2013
PubMed

Insights

Ras mutations impact cell proliferation via reactive oxygen species (ROS) and SESN3 gene repression, mediated by HSF1. This pathway, involving p21(Cip1/WAF1), acts as a defense against excessive cell growth in cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • RAS oncogenes regulate crucial cell activities like proliferation and survival.
  • Activating RAS mutations are frequent in various cancers, but their proliferative effects can be contradictory.
  • Ras proteins influence cell growth by modulating intracellular reactive oxygen species (ROS) levels.

Purpose of the Study:

  • To investigate the mechanism linking Ras-induced ROS upregulation to SESN3 gene repression.
  • To elucidate the role of Heat Shock Factor 1 (HSF1) in mediating Ras's effects on SESN3 expression and ROS levels.
  • To understand how these molecular changes impact cell proliferation and potentially contribute to cancer defense.

Main Methods:

  • Analysis of Ras-induced changes in SESN3 gene expression.
  • Investigation of HSF1 transcriptional activity modifications in response to mutant Ras.
  • Measurement of intracellular ROS levels.
  • Assessment of cell proliferation rates and p21(Cip1/WAF1) expression.

Main Results:

  • Mutant Ras overexpression leads to repression of SESN3 expression and upregulation of ROS.
  • This repression is mediated by alterations in HSF1 transcriptional activity, which can occur in opposite directions depending on the cell context.
  • Both normal fibroblasts and HaCaT keratinocytes showed decreased proliferation due to elevated ROS and p21(Cip1/WAF1) upregulation.
  • The HSF1/SESN3/ROS/p21(Cip1/WAF1) pathway was identified as a key mediator of Ras-induced growth inhibition.

Conclusions:

  • Ras-induced repression of SESN3 and subsequent ROS elevation are controlled by HSF1 transcriptional modifications.
  • This molecular cascade results in cell proliferation inhibition, mediated by p21(Cip1/WAF1).
  • The HSF1/SESN3/ROS/p21(Cip1/WAF1) pathway represents a cellular defense mechanism against uncontrolled proliferation driven by activated Ras oncoproteins.
Keywords:
HSF1ROSRasSESN3cell growth

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