Oncogenes

An oncogene is a gene that

• when mutated or
• expressed at abnormally-high levels

Cancer cells are cells that are engaged in uncontrolled mitosis.

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), which is encoded by the gene PDGFB (also known as SIS).

• 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 gene ERBB2 encodes a receptor for epidermal growth factor (EGF). (In humans, ERBB2 is also known as HER2.)

• Binding of a growth factor to its receptor triggers a cascade of signaling events within the cytosol.

  Link to discussion.

  
  

  Many of these involve kinases — enzymes that attach phosphate groups to other proteins. Examples: the proteins encoded by SRC, RAF, ABL, and the fusion protein encoded by BCR/ABL found in chronic myelogenous leukemia (CML).

  or

  molecules that turn on kinases. Example: RAS, which activates RAF.

• In most cases, phosphorylation activates the protein and eventually transfers the signal into the nucleus.
• Here phosphorylation activates transcription factors that bind to promoters and enhancers in DNA, turning on their associated genes.

  Examples: AP-1, a heterodimer of 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 (sometimes called a 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 loses all control over its mitosis it is well on its way to developing into 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 cancer-promoting genes

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.

Example: ATM. ATM (="ataxia telangiectasia mutated") gets its name from a human disease of that name, whose patients — among other things — are at increased risk of cancer. The ATM protein is also involved in detecting DNA damage and interrupting the cell cycle when damage is found.

It is estimated that fully 1% of the 25,000 or so genes in the human genome are proto-oncogenes.

Tumor-Suppressor Genes