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Genetic determinants of neoplastic transformation by the retroviral oncogene v-erbB
1Department of Microbiology and Immunology, University of California, San Francisco 94143.
Abstract:
The retroviral oncogene v-erbB is a mutant version of the gene (c-erbB or ERBB1) that encodes the cell-surface epidermal growth factor receptor (EGFR). The mutations take three forms: (i) a large deletion that removes the entire ligand-binding domain of EGFR, (ii) smaller deletions that affect the carboxyl-terminal domain of EGFR, and (iii) point mutations that cause conservative substitutions of amino acids. Previous work has shown that, in the absence of the large deletion, ERBB1 cannot transform cells autonomously. Here we report that when the large deletion is present, no other mutation is required for ERBB1 to transform established rodent fibroblasts to a tumorigenic phenotype. In particular, there is no need for deletions affecting the carboxyl terminus of the gene product. It appears, therefore, that removal of the ligand-binding domain from the EGFR suffices to create a transforming protein. Deletions at the carboxyl terminus of the EGFR apparently play only a secondary role in transformation by affecting the host range and perhaps the potency of transformation; and there is as yet no evidence to implicate point mutations in the activation of ERBB1 to an oncogene. Our findings support the view that augmented activity of the EGFR can contribute to tumorigenesis.
Insights
The retroviral oncogene v-erbB transforms cells when its ligand-binding domain is deleted from the epidermal growth factor receptor (EGFR). This deletion alone is sufficient for oncogenic transformation, indicating EGFR
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The retroviral oncogene v-erbB is a mutated form of the epidermal growth factor receptor (EGFR) gene (c-erbB or ERBB1).
- EGFR mutations include deletions in the ligand-binding domain, carboxyl-terminal domain, and point mutations.
- Previous studies indicated ERBB1 requires additional mutations to transform cells autonomously.
Purpose of the Study:
- To investigate the specific mutations in ERBB1 required for cellular transformation.
- To determine if the deletion of the ligand-binding domain alone is sufficient for oncogenic activity.
Main Methods:
- Analysis of v-erbB oncogene structure and function.
- Cell transformation assays using rodent fibroblasts.
- Comparison of transformation phenotypes with different ERBB1 mutation types.
Main Results:
- A large deletion removing the EGFR ligand-binding domain in v-erbB is sufficient for transforming fibroblasts into a tumorigenic phenotype.
- Other mutations, such as those in the carboxyl terminus, are not required for this transformation.
- Carboxyl-terminal deletions appear to influence host range and transformation potency, not initial activation.
Conclusions:
- Removal of the EGFR ligand-binding domain is sufficient to create a potent transforming protein.
- Augmented activity of EGFR, driven by specific mutations, can contribute to cancer development (tumorigenesis).
- Point mutations have not been implicated in the activation of ERBB1 to an oncogene.