How Do Proto Oncogenes Become Oncogenes

Proto-oncogenes are a class of genes encoded for the proteins that regulate the cell cycle. These proteins can be growth factor receptors, transcriptional regulators or signal transduction proteins. They serve as positive controls of the cell cycle, negatively regulating the apoptotic pathways. The activation of proto-oncogenes into oncogenes induces cancer formation. The conversion of proto-oncogenes into oncogenes occurs in three ways: through point mutations, high-level of gene amplification, fusions of genes or gene products. These three ways are described in this article.

Key Areas Covered

1. What are Proto Oncogenes
      – Definition, Features, Types
2. How Do Proto Oncogenes Become Oncogenes
     – Point Mutations, Gene Amplification, Gene Fusion

Key Terms: Gene Amplification, Gene Fusion, Oncogenes, Point Mutations, Proto-Oncogenes

What are Proto Oncogenes

Proto-oncogenes refer to a class of genes that promote the specialization and division of normal cells; they become oncogenes following mutations. Oncogenes are any genes that contribute to the conversion of a normal cell into a cancerous cell upon mutation or expressed at high levels. The gene products of proto-oncogenes are responsible for the positive regulation of the cell cycle. The role of proto-oncogenes in a cell is shown in figure 1.

Figure 1: Proto-Oncogenes

Approximately 100 different proto-oncogenes have been identified so far. Some of the well-characterized oncogenes are described in table 1.

Oncogenes

How Do Proto Oncogenes Become Oncogenes

Proto-oncogenes become oncogenes in three pathways: point mutations, high-level of gene amplification, fusions of genes or gene products. The conversion of proto-oncogenes into oncogenes are shown in figure 2.

Figure 2: Formation of Proto-Oncogenes

Point Mutations

Single nucleotide changes can occur either in protein-coding region or regulatory region of the proto-oncogene. Point mutations in the protein-coding region change the function of the proto-oncogene by means of activation, stability, and location of the protein. The changes in the regulatory sequences of the proto-oncogene change the gene expression by means of RNA splicing and altered amount of gene expression. However, point mutations introduce structural modifications, producing an oncoprotein. As an example, the conversion of the glycine residue at the number 12 amino acid of the Ras protein into a valine causes human bladder cancer. Moreover, some structural alterations may occur due to the deletions of parts of the protein.

Gene Amplification

Gene amplification causes increased levels of gene products. The high level of gene expression also leads to the gene products to serve as oncoproteins.

Gene Fusion

Gene fusion also causes the production of most structurally-altered proteins. The emergence of Philadelphia chromosome is an example of gene fusion. It is formed by a translocation between chromosome 9 and 22. This fuses bcr1 and abl genes. It causes chronic myelogenous leukemia (CML). The Brc1-Abl fusion protein serves as an oncoprotein.

The mutations of proto-oncogenes are passed to the next cell generation through cell division. Since the function of proto-oncogenes is to positively regulate the cell cycle, the mutated oncogenes cause uncontrolled cell division by bringing the cells into the malignant stage. This causes the formation of tumors or cancers in the body.

Conclusion

Proto-oncogenes are responsible for the specialization and division of cells. Following mutations, they become oncogenes that induce the formation of cancers. The three main methods involved in the conversion of proto-oncogenes into oncogenes are point mutations, gene amplification, and gene fusion. During point mutations, the nucleotide sequence of the proto-oncogene is altered forming a structurally-altered protein. In gene amplification, the amount of gene products is increased, inducing the cell division. In gene fusion, the fused genes by translocations form oncoproteins.

Reference:

1.“Cancer and the Cell Cycle.” Lumen: Boundless Biology, Available here.
2.Griffiths, Anthony JF. “Cancer: the Genetics of Aberrant Cell Control.” An Introduction to Genetic Analysis. 7th Edition., U.S. National Library of Medicine, 1 Jan. 1970, Available here.

Image Courtesy:

1. “Conversion of proto-oncogene flow chart” By Haywardlc – Own work (CC0) via Commons Wikimedia
2. “Oncogenes illustration” By Unknown Illustrator – released by the National Cancer Institute, an agency part of the National Institutes of Health (Public Domain) via Commons Wikimedia