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Activation of the JAK-STAT pathway by reactive oxygen species

A R Simon1, U Rai, B L Fanburg

  • 1Pulmonary and Critical Care Division, Tupper Research Institute, New England Medical Center, Boston 02111, Massachusetts, USA.

The American Journal of Physiology
|December 9, 1998
PubMed

Insights

Reactive oxygen species (ROS) activate the JAK-STAT pathway in mammalian cells. Platelet-derived growth factor (PDGF) utilizes ROS as a second messenger to regulate STAT activation, impacting cellular responses.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Reactive oxygen species (ROS) are implicated in numerous human diseases.
  • ROS can induce genes like c-fos and c-myc in mammalian cells.
  • The role of ROS in specific signaling pathways remains an area of investigation.

Purpose of the Study:

  • To investigate the effect of ROS on the STAT (Signal Transducer and Activator of Transcription) family of transcription factors.
  • To determine if ROS act as second messengers in growth factor-induced signaling.
  • To elucidate the involvement of the JAK-STAT pathway in ROS-mediated cellular responses.

Main Methods:

  • Treatment of fibroblasts and A-431 carcinoma cells with hydrogen peroxide (H2O2).
  • Assessment of STAT1 and STAT3 activation using biochemical assays.
  • Inhibition studies using antioxidants (N-acetyl-L-cysteine) and glutathione-depleting agents (buthionine sulfoximine).
  • Analysis of JAK2 and TYK2 kinase activity.
  • Investigation of platelet-derived growth factor (PDGF)-induced STAT activation in the presence of ROS modulators.

Main Results:

  • Hydrogen peroxide (H2O2) rapidly activates STAT1 and STAT3 in mammalian cells within 5 minutes.
  • STAT activation by H2O2 is oxidant-specific and does not require new protein synthesis.
  • Glutathione depletion also leads to STAT pathway activation.
  • H2O2 stimulates the activity of JAK2 and TYK2, known STAT kinases.
  • ROS production contributes to PDGF-induced STAT activation, with antioxidants inhibiting this process.

Conclusions:

  • The JAK-STAT signaling pathway is responsive to intracellular reactive oxygen species (ROS).
  • Platelet-derived growth factor (PDGF) employs ROS as a second messenger to regulate STAT activation.
  • These findings reveal a novel mechanism linking ROS signaling to the JAK-STAT pathway.

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