Downregulation of the early genomic growth factor response in neu oncogene-transformed cells.
Peptide growth factor-induced signal transduction leads to a long-term adjustment of the genetic programs of responding cells. A point mutation in the transmembrane domain of the neu receptor has been found to activate its tyrosine kinase and oncogenic potential. Our previous studies show that ligand stimulation of a chimeric epidermal growth factor receptor-neu proto-oncogene (EGF-R/neu) induces the neu tyrosine kinase and leads to the programmed activation of cell growth-regulated genes. We have now studied the effect of the neu oncoprotein on the genomic growth factor response in cells expressing the EGF-regulated neu tyrosine kinase. Expression of the neu oncogene in these cells inhibited 75-90% of the EGF-stimulated mRNA induction of the immediate early serum response genes, such as junB encoding a transcription factor, N10 encoding a putative nuclear hormone binding receptor for an as yet undefined ligand, and B10, the protein product of which is still unknown. The relative lack of mRNA induction was not due to a loss of the chimeric EGF-R/neu receptors from the cell surface. Also, the neu oncogene decreased serum- and tumor promoter induction of these genes. Our results suggest that the neu oncogene is capable of deregulating mRNA responses to extracellular signalling, similar to the effects of the c-Ha-ras oncogene. Knowledge of the mechanisms responsible for these changes in gene regulation will help to define oncogenic transformation of cells in molecular terms.
Sistonen
L
L
Department of Virology, University of Helsinki, Finland.
Koskinen
P J
PJ
Lehväslaiho
H
H
Lehtola
L
L
Bravo
R
R
Alitalo
K
K
D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002678:Chimera / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology*; D066246:ErbB Receptors / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D007150:Immunohistochemistry; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D066246:ErbB Receptors; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate; C064740:epidermal growth factor receptor-neu receptor