Analysis of the epidermal growth factor receptor specific transcriptome: effect of receptor expression level and an activating mutation.
Overexpression or expression of activating mutations of the epidermal growth factor receptor (EGFR) is common in cancer and correlates with neoplastic progression. The present study employed Affymetrix oligonucleotide arrays to profile genes induced by ligand-activated EGFR with the receptor either moderately expressed or overexpressed at an in-itself transforming level. These changes were compared to those induced by the naturally occurring constitutively active variant EGFRvIII. This study provides novel insight on the activities and mechanisms of EGFRvIII and EGFR mediated transformation, as genes encoding proteins with functions in promoting cell proliferation, invasion, antiapoptosis, and angiogenesis featured prominently in the EGFRvIII- and EGFR-expressing cells. Surprisingly, it was found that ligand-activated EGFR induced the expression of a large group of genes known to be inducible by interferons. Expression of this module was absent in the EGFRvIII-expressing cell line and the parental cell line. Treatment with the specific EGFR inhibitor AG1478 indicated that the regulations were primary, receptor-mediated events. Furthermore, activation of this module correlated with activation of STAT1 and STAT3. The results thus demonstrate that ligand-activated EGFR at different expression levels results in different kinetics of signaling and induction of gene expression. In addition, the constitutively active variant EGFRvIII seems to activate only a subset of signal pathways and induce a subset of genes as compared to the ligand-activated EGFR.
Pedersen
Mikkel W
MW
Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Pedersen
Nina
N
Damstrup
Lars
L
Villingshøj
Mette
M
Sønder
Søren U
SU
Rieneck
Klaus
K
Bovin
Lone F
LF
Spang-Thomsen
Mogens
M
Poulsen
Hans S
HS
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008024:Ligands; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D004268:DNA-Binding Proteins; D008024:Ligands; D012333:RNA, Messenger; D015534:Trans-Activators; D066246:ErbB Receptors