Tumor Suppressor Genes

• Their protein product inhibits mitosis.
• When mutated, the mutant allele behaves as a recessive; that is, as long as the cell contains one normal allele, tumor suppression continues. (Oncogenes, by contrast, behave as dominants; one mutant, or overly-active, allele can predispose the cell to tumor formation).

Example 1: RB - the retinoblastoma gene

Familial retinoblastoma

Multiple tumors in the retinas of both eyes occurring in the first weeks of infancy.

Sporadic retinoblastoma

A single tumor appears in one eye sometime in early childhood before the retina is fully developed and mitosis in it ceases.

Familial retinoblastoma

Familial retinoblastoma occurs when the fetus inherits from one of its parents a chromosome (number 13) that has its RB locus deleted (or otherwise mutated). Then random mutation of the remaining RB locus in any retinal cell removes the inhibition provided by the Rb protein (the Rb protein prevents mitosis by blocking cells from entering S phase of the cell cycle), and the affected cell grows into a tumor. So, in this form of the disease, a germline mutation plus a somatic mutation of the second allele leads to the disease.

Sporadic retinoblastoma

In this disease, both inherited RB genes are normal and a single cell must be so unlucky as to suffer a somatic mutation (often a deletion) in both in order to develop into a tumor. Such a double hit is an exceedingly improbable event, and so only rarely will such a tumor occur. (In both forms of the disease, the patient's life can be saved if the tumor(s) is detected soon enough and the affected eye(s) removed.)

Example 2: p53

The product of the tumor suppressor gene p53 is a protein of 53 kilodaltons (hence the name).

The p53 protein prevents a cell from completing the cell cycle if

• its DNA is damaged or
• the cell has suffered other types of damage.

• If the damage is minor, p53 halts the cell cycle — hence cell division — until the damage is repaired or
• if the damage is major and cannot be repaired, p53 triggers the cell to commit suicide by apoptosis.

These functions make p53 a key player in protecting us against cancer; that is, an important tumor suppressor gene. More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein.

Mice have been cured of cancer by treating them with a peptide that turns on production of the p53 protein in the tumor cells. However, there may be an inevitable tradeoff involved: excess production of the p53 protein leads to accelerated aging in mice [Link]. The converse appears also to be true: mice expressing high levels of the anti-aging protein Sirt1 [Link] have their production of p53 depressed and are more susceptible to cancer.

Loss Of Heterozygosity (LOH)

Because tumor suppressor genes are recessive, cells that contain one normal and one mutated gene — that is, are heterozygous — still behave normally.

However, there are several mechanisms which can cause a cell to lose its normal gene and thus be predisposed to develop into a tumor. These may result in a "loss of heterozygosity" or "LOH".

Mechanisms of LOH:

1. Deletion of
   • the normal allele;
   • the chromosome arm containing the normal allele;
   • the entire chromosome containing the normal allele (resulting in aneuploidy).
2. Loss of the chromosome containing the normal allele followed by duplication of the chromosome containing the mutated allele.
3. Mitotic recombination. The study of tumor suppressor genes revealed (for the first time) that crossing over — with genetic recombination — occasionally occurs in mitosis (as it always does in meiosis).

   External Link

   Animation showing the how mitotic recombination may lead to LOH.

   Please let me know by e-mail if you find a broken link in my pages.)

In #2 and #3, the resulting cell now carries two copies of the "bad" gene. This is called "reduction to homozygosity".

Mutation is not the only way to inactivate tumor suppressor genes.

• a similarly blocked promoter on the other allele (producing the same effect as #2 above);
• a loss of that locus on the other chromosome (like the LOH in #1 above);
• an inactivating mutation in the other allele.

Tumor suppressor genes = anti-oncogenes

Genes like RB and p53 are also called anti-oncogenes. They were first given this name because they reverse, at least in cell culture, the action of known oncogenes.

This image (courtesy of Moshe Oren, from Cell 62:671, 1990) shows petri dishes which were seeded with the same number of cells that had been transformed by two oncogenes: myc and ras. Many of those on the left have grown into colonies of cells. However, the cells plated on the right also contained the tumor suppressor p53 gene. Only a few have been able to grow into colonies.

Human Papilloma Viruses (HPV)

The name anti-oncogene may be even more appropriate than originally thought. Both the Rb protein and the p53 protein turn out to complex directly in the cell with an oncogene product of some human papilloma viruses.

Once inside the cells of their host, human papilloma viruses synthesize

• a protein designated E7 and
• another designated E6.

Result: E2F is now free to bind to the promoters of genes (like c-myc) that cause the cell to enter the cell cycle (right). Thus this version of E7 is an oncogene product.

The E6 protein of a second human papilloma virus implicated in cervical cancer binds the p53 protein targeting it for destruction by proteasomes and thus removing the block on the host cell's entering the cell cycle.

• the absence of activators of transcription and
• the presence of repressors of transcription.