Proto-oncogene

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The resultant protein may be termed as oncoprotein. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. The MYC gene is implicated in Burkitt's Lymphoma, which starts when a chromosomal translocation moves an enhancer sequence within the vicinity of the MYC gene. The MYC gene codes for widely used transcription factors. When the enhancer sequence is wrongly placed, these transcription factors are produced at much higher rates. Another example of an oncogene is the Bcr-Abl gene found on the Philadelphia Chromosome, a piece of genetic material seen in Chronic Myelogenous Leukemia caused by the translocation of pieces from chromosomes 9 and 22. Bcr-Abl codes for a receptor tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation. (More information about the Philadelphia Chromosome below)

Proto-Oncogene

Activation

The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:

1. A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causing
   • an increase in protein (enzyme) activity
   • a loss of regulation
2. An increase in the amount of a certain protein (protein concentration), caused by
   • an increase of protein expression (through misregulation)
   • an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell
   • gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
3. A chromosomal translocation (another type of chromosome abnormality)
   • There are 2 different types of chromosomal translocations that can occur:
   1. translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression
   2. translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this creates a fusion protein with increased cancerous/oncogenic activity)
      • the expression of a constitutively active hybrid protein. This type of mutation in a dividing stem cell in the bone marrow leads to adult leukemia
      • Philadelphia Chromosome is an example of this type of translocation event. This chromosome was discovered in 1960 by Peter Nowell and David Hungerford, and it is a fusion of parts of DNA from chromosome 22 and chromosome 9. The broken end of chromosome 22 contains the "BCR" gene, which fuses with a fragment of chromosome 9 that contains the "ABL1" gene. When these two chromosome fragments fuse the genes also fuse creating a new gene: "BCR-ABL". This fused gene encodes for a protein that displays high protein tyrosine kinase activity (this activity is due to the "ABL1" half of the protein). The unregulated expression of this protein activates other proteins that are involved in cell cycle and cell division which can cause a cell to grow and divide uncontrollably (the cell becomes cancerous). As a result, the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia (as mentioned before) as well as other forms of Leukemia.

The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes. Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.