Oncogenes

An oncogene is a gene that contributes to converting a normal cell into a cancer cell.

Cancer cells are cells that are engaged in uncontrolled mitosis.

Any gene whose product stimulates a cell to divide uncontrollably qualifies as an oncogene.

The signals for normal mitosis

• Normal cells growing in culture will not divide unless they are stimulated by one or more growth factors present in the culture medium. Example: PDGF (platelet-derived growth factor)
• The molecules of growth factor bind to molecules of its receptor, an integral membrane protein embedded in the plasma membrane with its ligand-binding site exposed at the surface of the cell. Example: the protein encoded by the proto-oncogene c-erbB forms part of the receptor for epidermal growth factor (EGF).
• Binding of growth factor to its receptor triggers a cascade of signaling events within the cytosol. Many of these involve protein kinases, enzymes that attach phosphate groups to the Tyr or Ser or Thr groups of other proteins. Examples: the proteins encoded by ras, abl, and the fusion protein encoded by bcr/abl found in chronic myelogenous leukemia (CML).
• In many cases, phosphorylation activates the protein and transfers the signal into the nucleus.
• Phosphorylation of kinases within the nucleus produces activated transcription factors that bind to promoters and enhancers in DNA, turning on their associated genes. Examples: the proteins encoded by jun and fos
• Some of the genes turned on by these transcription factors encode other transcription factors. Example: myc.
• Some of the genes turned on by these downstream transcription factors encode cyclins that prepare the cell to undergo mitosis.

• they become mutated so that their product becomes constitutively active (that is, active all the time even in the absence of a positive signal) or
• they produce their product in excess (because, for example, their promoter and/or enhancer has become mutated. Example: the oncomouse: a transgenic mouse that has both copies of its myc gene under the influence of extra-powerful promoters.

All these oncogenes act as dominants; if the cell has one normal gene (proto-oncogene) at a locus and one mutated gene (the oncogene), the abnormal product takes control.

No single oncogene can, by itself, cause cancer. It can, however, increase the rate of mitosis of the cell in which it finds itself. Dividing cells are at increased risk of acquiring mutations, so a clone of actively dividing cells can yield subclones of cells with a second, third, etc. oncogene. When a clone has accumulated several active oncogenes, it loses all control over its mitosis and the clone into which it develops becomes a cancer.

This graph (based on the work of E. Sinn et al, Cell 49:465,1987) shows the synergistic effect of two oncogenes. The fraction (%) of transgenic mice without tumors is shown as a function of age. Three groups are shown:

• those mice transgenic for a hyperactive myc alone (blue)
• those transgenic for ras alone (green)
• those transgenic for both myc and ras (red)

Another class of oncogenes

Mutations convert proto-oncogenes into oncogenes. Mutations arise from an unrepaired error in DNA. So any gene whose product participates in DNA repair probably can also behave as an oncogene when mutated.

Tumor-Suppressor Genes

Additional Reading