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A more recent version of this article appeared on July 1, 2002
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Submitted on December 5, 2001
Revised on February 21, 2002
Accepted on March 28, 2002
1 Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298
* Corresponding author. E-mail address: RULLRICH{at}HSC.VCU.EDU.
Ionizing radiation (1 to 5 Gy) activates the epidermal growth factor receptor (EGFR), a major effector of the p42/44 mitogen-activated protein kinase (MAPK) pathway. MAPK and its downstream effector, p90 ribosomal S6 kinase (p90RSK), phosphorylate transcription factors involved in cell proliferation. To establish the role of the EGFR/MAPK pathway in radiation-induced transcription factor activation, MDA-MB-231 human breast carcinoma cells were examined using specific inhibitors of signaling pathways. Gel-shift analysis revealed three different profile groups: A) transcription factors that responded to both radiation (2 Gy) and epidermal growth factor (EGF) (CREB, Egr, Ets, and Stat3); B) factors that responded to radiation, but not EGF (C/EBP and Stat1); and C) those that did not respond significantly to either radiation or EGF (AP-1 and Myc). Within groups A and B, a 2- to 5-fold maximum stimulation of binding activity was observed at 30-60 min after irradiation. Interestingly, only transcription factors that responded to EGF had radiation responses significantly inhibited by the EGFR tyrosine kinase inhibitor, AG1478; these responses were also abrogated by farnesyltransferase inhibitor (FTI) or PD98059, inhibitors of Ras and MEK1/2, respectively. Moreover, radiation-induced increases in CREB and p90RSK phosphorylation, and activation of Stat3 and Egr-1 reporter constructs by radiation, were all abolished by AG1478. This data demonstrates a distinct radiation response profile at the transcriptional level that is dependent upon enhanced EGFR/Ras/MAPK signaling.
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