Analysis of the transcriptional program induced by Raf in epithelial cells.
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.
Schulze
A
A
Signal Transduction Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK.
Lehmann
K
K
Jefferies
H B
HB
McMahon
M
M
Downward
J
J
D017209:Apoptosis; D015152:Blotting, Northern; D002455:Cell Division; D003574:Cytochrome c Group / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1