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A more recent version of this article appeared on July 1, 2004
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Submitted on November 13, 2003
Revised on March 8, 2004
Accepted on March 29, 2004
1 Gene Expression Analysis Laboratories, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, U.K.
2 Signal Transduction Laboratories, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, U.K.
3 Comparative Genome Analysis Laboratories, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, U.K.
* Corresponding author. E-mail address: almut.schulze{at}cancer.org.uk.
The Raf protein kinases are major effectors of Ras GTPases and key components of the transcriptional response to serum factors, acting at least in part through the ERK/MAP kinase pathway. It has recently been suggested that Raf may also trigger other as yet uncharacterised signaling pathways. Here we have used cDNA microarrays to dissect changes in gene expression induced by activation of inducible c-Raf-1 constructs in human mammary epithelial and ovarian epithelial cells. The majority of Raf-induced transcriptional responses are shown to be blocked by pharmacological inhibition of the Raf substrate MEK, indicating that potential MEK-independent Raf signaling pathways have no significant influence on gene expression. In addition, we used epidermal growth factor receptor inhibitory drugs to address the contribution of autocrine signaling by Raf-induced EGF family proteins to the Raf transcriptional response. At least half of the transcription induced by Raf activation requires EGF receptor function The EGF receptor-independent component of the Raf transcriptional response is entirely up-regulation of gene expression, while the EGF receptor-dependent component is an equal mixture of up- and down-regulation. The use of transcriptional profiling in this way allows detailed analysis of the architecture of signaling pathways to be undertaken.
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