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TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis

Ziv Manasija Radisavljevic1, Beatriz González-Flecha

  • 1Harvard University, School of Public Health, Physiology Program, Boston, Massachusetts 02115, USA. zradisav@hsph.harvard.edu

Journal of Cellular Biochemistry
|March 30, 2004
PubMed

Insights

Hydrogen peroxide (H2O2) drives cell proliferation by activating a signaling pathway involving PI3K, Akt, mTOR, and Ran protein in lung cells. Inhibiting these key molecules blocks H2O2-induced mitosis, highlighting their essential roles.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • Hydrogen peroxide (H2O2) is recognized as a crucial signaling molecule in cellular processes.
  • Mitogenic signaling pathways, including those involving phosphatidylinositol-3-kinase (PI3K) and Akt, are vital for cell proliferation.
  • Primary type II pneumocytes are implicated in the pathogenesis of lung adenocarcinoma.

Purpose of the Study:

  • To elucidate the specific signaling cascade initiated by H2O2 in primary type II pneumocytes.
  • To determine the roles of PI3K, Akt, mammalian target of rapamycin (mTOR), and Ran protein in H2O2-mediated mitogenesis.
  • To investigate the upstream and downstream relationships between these signaling molecules.

Main Methods:

  • Utilized primary type II pneumocytes for experimental analysis.
  • Employed specific inhibitors wortmannin (PI3K inhibitor) and rapamycin (mTOR inhibitor) to block signaling pathways.
  • Assessed H2O2-induced mitosis and phosphorylation of Akt (ser-473).
  • Investigated the effects of myr-Akt and Ran-wt overexpression in a catalase-dependent manner.

Main Results:

  • H2O2 activates a sequential signaling cascade: PI3K → Akt → mTOR → Ran protein.
  • Inhibition of PI3K or mTOR with wortmannin or rapamycin, respectively, abrogated H2O2-induced mitosis.
  • Wortmannin prevented H2O2-induced Akt ser-473 phosphorylation and Ran upregulation, while rapamycin did not, confirming PI3K upstream of Akt and mTOR downstream of Akt.
  • Overexpression of myr-Akt or Ran-wt enhanced Akt phosphorylation and mitosis in a catalase-dependent manner, underscoring H2O2's essential role.

Conclusions:

  • H2O2-induced mitogenic signaling in primary type II pneumocytes is critically mediated by the PI3K/Akt/mTOR/Ran pathway.
  • This pathway plays a significant role in cell proliferation and may be a target for lung adenocarcinoma therapies.
  • H2O2 is an essential component for the activation of Akt and Ran signaling in these cells.

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