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The molecular basis of cancer suppression by the retinoblastoma gene
1Department of Pathology, University of California, San Diego, La Jolla 92093.
Abstract:
A class of cellular genes in which loss-of-function mutations are tumorigenic has been proposed. Such genes would normally act to suppress the cancer phenotype at the cellular or organism level. The gene determining susceptibility to hereditary retinoblastoma (RB) appears to operate in exactly this fashion, and is the first cancer suppressor gene to be molecularly cloned. The RB gene contains 27 exons dispersed over more than 200 kb and ubiquitously expresses a 4.7 kb mRNA. From sequence analysis of RB cDNA clones, the predicted RB protein has 928 amino acids. The RB protein is a nuclear phosphoprotein capable of binding to DNA and forming a complex with oncoproteins of several DNA tumor viruses. Consistent with its ubiquitous expression pattern, RB gene inactivation was found in many other cancers such as osteosarcoma, breast carcinoma, small cell lung carcinoma and prostate carcinoma. A cloned RB gene was introduced, via retrovirus-mediated gene transfer, into such tumor cells that have inactivated endogenous RB genes. Expression of the exogenous RB gene consistently suppressed their tumorigenicity in nude mice, suggesting that RB may act as a general cancer suppressor. In an attempt to address the potential cellular function of this gene, we have observed that RB protein phosphorylation oscillates with cell-cycle and the unphosphorylated form is present predominantly in the G0/G1 phase. Furthermore, when cells were induced to differentiate only the unphosphorylated form of RB could be detected, suggesting that RB protein was modulated through phosphorylation, may play an important role in these cellular functions. A hypothesis is proposed to explain how RB participates in cell proliferation and differentiation and its role in tumorigenesis.
Insights
The retinoblastoma (RB) gene, the first cloned cancer suppressor, inhibits tumor formation. Introducing the RB gene into cancer cells suppressed their growth, highlighting its potential as a general cancer suppressor.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- A class of cellular genes, known as cancer suppressor genes, normally inhibit tumor formation.
- The gene responsible for hereditary retinoblastoma (RB) is the first identified and cloned cancer suppressor gene.
- RB gene inactivation is observed in various cancers, including osteosarcoma, breast, lung, and prostate carcinomas.
Purpose of the Study:
- To investigate the function of the RB gene as a cancer suppressor.
- To explore the role of RB protein in cell proliferation and differentiation.
- To understand the mechanism by which RB influences tumorigenesis.
Main Methods:
- Molecular cloning of the RB gene.
- Retrovirus-mediated gene transfer to introduce the RB gene into tumor cells.
- Analysis of RB protein phosphorylation and its correlation with the cell cycle and differentiation.
Main Results:
- The RB gene, encoding a 928-amino acid nuclear phosphoprotein, was cloned and characterized.
- Expression of the introduced RB gene suppressed tumorigenicity in experimental models.
- RB protein phosphorylation is cell-cycle dependent, with the unphosphorylated form prevalent in G0/G1 and during differentiation.
Conclusions:
- The RB gene functions as a potent cancer suppressor, with potential therapeutic applications.
- RB protein phosphorylation plays a critical role in regulating cell proliferation and differentiation.
- Dysregulation of RB's function contributes to tumorigenesis, suggesting its involvement in a broad range of cancers.