Activation of the jak/stat pathway by reactive oxygen
intermediates.
Simon, Amy R., Usha Rai, Barry L. Fanburg and Brent H. Cochran.
1Pulmonary and Critical Care Division, Tupper Research Insititute,
New England Medical Center. Boston, MA 02111 and 2Department of
Physiology, Tufts University School of Medicine, Boston, MA 02111
APStracts 5:0240C, 1998.
Reactive oxygen species (ROS) play an important role in the
pathogenesis of many human diseases, including the adult respiratory
distress syndrome, Parkinson's disease, pulmonary fibrosis, and
Alzheimer's disease(4, 42). In mammalian cells, several genes known
to be induced during the immediate early response to growth factors
including the proto-oncogenes c-fos and c-myc have also been shown to
be induced by reactive oxygen species (ROS)(1, 74). Here we show that
members of the STAT family of transcription factors including STAT1
and STAT3 are activated in fibroblasts and A431 carcinoma cells in
response to hydrogen peroxide. This activation occurs within five
minutes, can be inhibited by antioxidants, and does not require
protein synthesis. STAT activation in these cell lines is oxidant
specific and does not occur in response to superoxide or nitric oxide
generating stimuli. Buthionine sulfoximine (BSO) which depletes
intracellular glutathione also activates the STAT pathway. Moreover,
H2O2 stimulates the activity of the known STAT kinases JAK2 and TYK2.
Activation of STATs by PDGF is significantly inhibited by N
-acetylcysteine(NAC) and diphenylene iodonium (DPI), indicating that
ROS production contributes to STAT activation in response to PDGF.
These findings indicate that the JAK/STAT pathway responds to
intracellular ROS and that PDGF uses ROS as a second messenger to
regulate STAT activation.
Received 28 April 1998; accepted in final form 29 August 1998.
APS Manuscript Number C129-8.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 21 September 1998