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Familial retinoblastoma occurs when a baby inherits from one of its parents a chromosome (number 13) that has its RB locus deleted (or otherwise mutated). The normal Rb protein controls the cell cycle. It integrates the signals reaching the cell to determine whether it is safe for the cell to complete the passage from G1 of the cell cycle to mitosis.
Mechanism. The unphosphorylated Rb protein prevents cells from entering S phase of the cell cycle. It does this by binding to transcription factors called E2F. This prevents the E2Fs from binding to the promoters of such proto-oncogenes as c-myc and c-fos. Transcription of c-myc and c-fos is needed for mitosis so blocking the transcription factors needed to turn on these genes prevents cell division. However, if conditions are adequate for the cell to successfully complete mitosis, the Rb protein becomes phosphorylated, releases the E2Fs, and the cell can proceed through the cell cycle.The Rb protein also plays a role in mitosis itself: it is needed for proper chromosome condensation starting in prophase, as well as their proper attachment to the spindle. Failure of Rb function during mitosis can lead to aneuploidy and chromosome breakage.
A random mutation of the remaining RB locus in any retinal cell — which are nondividing cells and should not enter the cell cycle — completely removes the inhibition provided by the Rb protein, 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.
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.)
The product of the tumor suppressor gene p53 is a protein of 53 kilodaltons (hence the name). (You will find that the human gene is variously designated as P53, TP53 ["tumor protein 53"], and TRP53 ["transformation-related protein 53"])
The p53 protein prevents a cell from completing the cell cycle if
These functions make p53 a key player in protecting us against cancer; that is, it 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 a tradeoff involved: excess production of the p53 protein leads to accelerated aging in mice [Link].
The product of the tumor suppressor gene INK4a is a protein of 16 kilodaltons (hence the name).
Like p53, it blocks progression through the cell cycle — in this case by inhibiting the action of the cyclin-dependent kinase Cdk4.
As an animal ages, its cells produce increasing amounts of p16INK4a. This is probably a good thing in that it reduces the risk of the cell entering uncontrolled mitosis, i.e., becoming a cancer. However, again like p53, there is a tradeoff. As levels of p16INK4a rise in adult stem cells and progenitor cells, their ability to reproduce and thus replace lost or damaged tissue diminishes.p16INK4a is not simply a reflection of an aging cell but is actively involved in the process.
In humans, deletions and other mutations of p16INK4a are found in a variety of cancers.
Because tumor suppressor genes are recessive, cells that contain one normal and one mutated gene — that is, are heterozygous — still behave normally. (Exception: one X-linked tumor suppressor gene [WTX] has been found. In males, having only one X chromosome, a damaging point-mutation in WTX or its deletion is all that is needed to eliminate tumor-suppression. Females are also at risk if the mutation or deletion occurs on the X chromosome that is not inactivated.)
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:
In #3 and #4, the resulting cell now carries two copies of the "bad" gene. This is called "reduction to homozygosity".
(LOH can work both ways.)|
When LOH occurs by mitotic recombination (process #4 above), one daughter cell becomes homozygous for the mutant allele but the other becomes homozygous for the normal ("wild-type") allele. This is of no help when tumor-suppressor genes are involved but in other situations it can be.
A rare skin disease of humans called ichthyosis with confetti is an example. It is caused by the inheritance of a dominant mutation in one of the keratins (which make intermediate filaments). At birth, infants with the disease have uniformly reddened skin whose cells are heterozygous for the dominant mutant allele and a normal keratin allele. But as the years go by, an increasing number of patches of normal, whitened, skin appear (like "confetti"). Genomic analysis reveals that each patch develops from a skin stem cell that by mitotic recombination has undergone "reduction to homozygosity". In this case, the daughter cell that inherits two normal keratin alleles goes on to generate a patch of normal skin. This work is described in Choate, K.A., et al., Science 330:94-97 (1 October 2010).
|Link to description of the mechanism.|
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 mouse 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.
|Link to another illustration of the additive effect of myc and ras.|
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
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.Although the figure shows the "off" promoters as empty, it is now clear that being "off" involves both