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Vol. 15, No. 8, pp. 981-994, April 15, 2001
1 Signal Transduction Laboratory, Imperial Cancer Research
Fund, London WC2A 3PX, UK; 2 Cancer Research Institute,
University of California at San Francisco/Mt. Zion Cancer Center,
San Francisco, California 94115-0128, USA
Activation of the Raf/MAP kinase pathway is a critical event in
tumorigenesis induced by RAS and other oncogenes, a major role of this
signaling system being the regulation of cellular transcription
factors. To address the contribution of MAP kinase mediated
transcriptional changes to the transformed phenotype, we used an
inducible form of Raf to analyze early changes in the transcription of
some 6000 genes following activation of the kinase in a normal human
breast epithelial cell line. Of the more than 120 significant changes
in mRNA level detected, genes promoting cell proliferation,
invasiveness, and angiogenesis featured prominently. Some of the most
strongly induced genes encoded growth factors of the EGF family:
Autocrine activation of the EGF receptor was shown to be responsible
for the ability of Raf activation to protect these cells from apoptosis
induced by detachment of cells from extracellular matrix (anoikis),
which is a critical component of the transformed phenotype.
[Key Words: Ras; Raf; transcription; apoptosis; matrix; microarray]
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