STAT1 AND STAT3 ACTIVATION BY OXIDATIVE STRESS IN A431 CELLS INVOLVES SRC-DEPENDENT
EGF RECEPTOR TRANSACTIVATION
E. B. Burova, I. V. Gonchar, N. N. Nikolsky
Institute of Cytology RAS, St. Petersburg;
e-mail: burova_e@mail.cyt.spb.rssi.ru
Different cellular signal transduction cascades are affected by environmental stressors (UV-radiation,
γ-irradiation, hyperosmotic conditions, oxidants). In this study, we examined oxidative stress-evoked signal
transduction pathways leading to activation of STATs in A431 carcinoma cells. Oxidative stress, initiated by
addition of H2O2 (1-2mM) to A431 cells, activates STATS and, to a lesser extent, STATl in
dose- and time-dependent manner. Maximum phosphorylation levels were observed after a 2 minutes stimulation at
1-2 mM H2O2. Phosphorylation was blocked by AG1478, a pharmacological inhibitor of the
epidermal growth factor receptor tyrosine kinase, implicating intrinsic EGF receptor tyrosine kinase in this
process. Consistent with this observation, H2O2-stimulated EGFR tyrosine phosphorylation was
abolished by specific Src kinase family inhibitor CGP77675, implicating Src in H2O2-induced EGFR activation. An
essential role for Src and JAK2 in STATs activation was suggested by three findings. l. Src kinase family inhibitor
CGP77675 blocked STATS and STAT1 activation by H2O2 in a concentration-dependent manner. 2.
In Src-fibroblasts, activation of both STATS and STAT1 by H2O2 was significantly attenuated.
3. Inhibiting JAK2 activity with the specific inhibitor AG490 reduced the level of H2O2-
induced STATS phosphorylation, but not STAT1 in A431 cells. These data show essential roles for Src and JAK2
inactivation of STATS. In contrast, H2O2-mediated activation of STATl requires only Src kinase activity. Herein,
we postulate also that H2O2-induced STAT activation in carcinoma cells involves Src-dependent
EGFR transactivation.
Key words: oxidative stress, STAT1, STAT3, hydrogen peroxide, Src kinase, JAK2 kinase, epidermal
growth factor receptor
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