oncogene

An oncogene is a gene that has the potential to cause cancer.^[1] In tumor cells, they are often mutated or expressed at high levels.^[2]

Most normal cells undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells that ought to die to survive and proliferate instead.^[3] Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.^[2][4][5][6]

Proto-oncogene

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The resultant protein may be termed an oncoprotein.^[7] 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.^[8] 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.

Activation

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

• A mutation within a proto-oncogene can cause a change in the protein structure, causing
  • an increase in protein (enzyme) activity
  • a loss of regulation
• An increase in 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
  • a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
• A chromosomal translocation (another type of chromosome abnormality), causing
  • an increased gene expression in the wrong cell type or at wrong times
  • the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult 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.^[9] Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes.^[10] Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.

Classification

There are several systems for classifying oncogenes,^[11][12] but there is not yet a widely accepted standard. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). There are several categories that are commonly used:

Conversion of proto-oncogenes

There are two mechanisms by which proto-oncogenes can be converted to cellular oncogenes:

Quantitative: Tumor formation is induced by an increase in the absolute number of proto-oncogene products or by its production in inappropriate cell types.

Qualitative: Conversion from proto-oncogene to transforming gene (c-onc) with changes in the nucleotide sequence that are responsible for the acquisition of the new properties.^[13]

History

The first oncogene was discovered in 1970 and was termed src (pronounced sarc as in sarcoma). Src was in fact first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr G. Steve Martin of the University of California, Berkeley demonstrated that the SRC was indeed the oncogene of the virus. The first nucleotide sequence of v-src was sequenced 1980 by A.P. Czernilofsky et al. (Nature Vol 287, pp 198-203).

In 1976 Drs. Dominique Stehelin, J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes, found in many organisms including humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989.^[14]

See also

• Tumor suppressor gene
• Apoptosis
• Cancer

References

External links

• Drosophila Oncogenes and Tumor Suppressors - The Interactive Fly
• List of web sites - oncogenes tables