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Normal ras genes: their onco-suppressor and pro-apoptotic functions (review)
D A Spandidos1, G Sourvinos, C Tsatsanis
1Medical School, University of Crete, Heraklion 71409, Crete, Greece. spandidos@spandidos.gr
Abstract:
The ras family of oncogenes has been extensively studied for its implication in several types of human malignancies. Activation of ras genes involves mutations that alter the catalytic activity of the protein enhancing the downstream signals mostly towards cell proliferation and malignant transformation. Ras genes are also involved in induction of senescence or apoptosis, suggesting activation of alternative pathways that may be anti-oncogenic. Early experiments showed that transfection of wild-type ras in transformed cells reversed the oncogenic phenotype suggesting that wild-type ras has onco-suppressive properties. Indeed, expression of wild-type ras genes in several human malignancies is associated with good prognosis. In tumors carrying mutant ras genes the levels of expression of the wild-type allele never exceeded the mutant counterpart, indicating that the wild-type protein suppresses the effect of the mutant one. Recent development of the Kras2 deficient mice provided the tool to study the role of wild-type ras genes in tumorigenesis.
Insights
Wild-type ras genes can suppress cancer development, acting as tumor suppressors. This contrasts with mutant ras genes that promote cancer, highlighting a complex role for ras in oncogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ras genes are key oncogenes implicated in human cancers.
- Mutant ras proteins enhance signals for cell proliferation and malignant transformation.
- Ras genes also participate in senescence and apoptosis, suggesting anti-oncogenic pathways.
Purpose of the Study:
- To investigate the tumor-suppressive role of wild-type ras genes.
- To understand the interaction between wild-type and mutant ras in tumorigenesis.
- To leverage Kras2 deficient mice for studying wild-type ras function.
Main Methods:
- Transfection of wild-type ras into transformed cells.
- Analysis of wild-type ras gene expression in human malignancies.
- Utilizing Kras2 deficient mouse models.
Main Results:
- Wild-type ras expression in transformed cells reversed oncogenic phenotypes.
- High wild-type ras expression correlated with good prognosis in human cancers.
- Wild-type ras alleles were found to suppress the effects of mutant ras alleles in tumors.
Conclusions:
- Wild-type ras possesses significant tumor-suppressive properties.
- The balance between wild-type and mutant ras is critical in cancer development.
- Further research using models like Kras2 deficient mice is essential.