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Downregulation of the early genomic growth factor response in neu oncogene-transformed cells
L Sistonen1, P J Koskinen, H Lehväslaiho
1Department of Virology, University of Helsinki, Finland.
Abstract:
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.
Insights
The neu oncogene significantly inhibits epidermal growth factor (EGF)-stimulated gene expression, disrupting cellular responses to growth factors. This deregulation of mRNA induction by the neu oncogene impacts key early response genes.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Oncogenesis
Background:
- Growth factor signaling pathways regulate cellular genetic programs.
- The neu receptor, when mutated, exhibits tyrosine kinase activity and oncogenic potential.
- Previous work demonstrated that EGF-R/neu chimeras activate neu tyrosine kinase and cell growth genes.
Purpose of the Study:
- To investigate the impact of the neu oncogene on genomic growth factor responses.
- To analyze the effect of EGF-regulated neu tyrosine kinase on gene expression.
- To understand how the neu oncogene deregulates mRNA induction of immediate early serum response genes.
Main Methods:
- Studied cells expressing a chimeric epidermal growth factor receptor-neu proto-oncogene (EGF-R/neu).
- Assessed the effect of neu oncogene expression on EGF-stimulated mRNA induction of immediate early serum response genes (junB, N10, B10).
- Evaluated changes in gene induction by serum and tumor promoters in the presence of the neu oncogene.
Main Results:
- Expression of the neu oncogene inhibited 75-90% of EGF-stimulated mRNA induction for immediate early serum response genes.
- The neu oncogene decreased serum- and tumor promoter induction of these genes.
- Inhibition was not due to reduced cell surface expression of chimeric EGF-R/neu receptors.
Conclusions:
- The neu oncogene deregulates cellular mRNA responses to extracellular signaling.
- This deregulation is similar to the effects observed with the c-Ha-ras oncogene.
- Understanding these mechanisms is crucial for defining oncogenic transformation at a molecular level.