TY - JOUR

T1 - Analysis of the epidermal growth factor receptor specific transcriptome: effect of receptor expression level and an activating mutation.

AU - Pedersen, Mikkel W

AU - Pedersen, Nina

AU - Damstrup, Lars

AU - Villingshøj, Mette

AU - Sønder, Søren U

AU - Rieneck, Klaus

AU - Bovin, Lone F

AU - Spang-Thomsen, Mogens

AU - Poulsen, Hans S

N1 - Keywords: Animals; Cell Line; DNA-Binding Proteins; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Humans; Ligands; Mutation; RNA, Messenger; Receptor, Epidermal Growth Factor; Signal Transduction; Trans-Activators; Transcription, Genetic

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1002/jcb.20554

DO - 10.1002/jcb.20554

M3 - Journal article

C2 - 16075456

VL - 96

SP - 412

EP - 427

JO - Journal of cellular biochemistry. Supplement

JF - Journal of cellular biochemistry. Supplement

SN - 0733-1959

IS - 2

ER -