oncogene

An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell.^[1]

Many cells normally undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells to survive and proliferate instead.^[2] 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 those DNA sequences and their products.^[3][4][5][6]

Proto-oncogene

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. 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.^[7] Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK.

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

Mutations in microRNAs can lead to activation of oncogenes.^[8] New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.^[9]Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.

Classification

There are several systems for classifying oncogenes,^[10][11] 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 which are responsible for the acquisition of the new properties.^[12]

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.

In 1976 Drs. J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were defective proto-oncogenes, found in many organisms including humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in 1989.^[13]

See also

• Tumor suppressor gene
• Apoptosis
• Cancer

References