Tumor Suppressor Genes

Tumor suppressor genes regulate mitosis and cell division. When their function is impaired, the result is a high rate of uncontrolled cell growth or cancer. Damage to tumor suppressor genes contributes to a large number of different types of tumors .

The Balancing Act of Regulating the Cell Cycle

The cell cycle is a fundamental process of life, regulated by a balance of positive and negative mechanisms that act at key points during cell growth and differentiation. Proto-oncogenes tend to "push" the cell cycle (in a positively acting manner) by activating various cell cycle pathways within the developing cell. By contrast, tumor suppressor genes normally repress, or "put the brakes on," the activation of the pathways.

Genetics of Tumor Suppressor Genes

Mutations in tumor suppressor genes can arise spontaneously by exposure to a mutagenic substance such as ultraviolet light or certain chemicals. In such cases, only the mutated cell and its descendants will be affected. Mutations can also be inherited from a parent or arise early in development. In these cases, almost all the cells of the body will inherit the same mutation.

A mutation in a single tumor suppressor gene is usually not enough to cause cancer. This is because each cell contains two copies of each gene, one inherited from each parent. Most cancer-causing mutations cause a loss of function in the mutated gene. Often, having even one functional copy is enough to prevent disease, and two mutations are needed for cancer to develop. This is known as the "two-hit" model of carcinogenesis.

This model was first described in retinoblastoma, a common cancer of the retina . The affected gene (called the retinoblastoma gene) is a tumor suppressor. Spontaneous (noninherited) mutations are rare, but since there are many millions of cells in the retina, several of them will develop the gene mutation over the course of a lifetime. It would be very unlikely, though, for a single cell to develop two spontaneous mutations (at least in the absence of prolonged exposure to carcinogens), and thus noninherited retinoblastoma is very rare. When it occurs, it almost always affects only one eye—the eye in which the unlucky doubly hit cell resides.

If, however, a person inherits one copy of an already mutated gene from one parent, every cell in the eye starts life with one "hit." The chances are very high that several cells will suffer another hit sometime during their life. The chances are thus very high that the person will develop retinoblastoma, almost always in both eyes, since the necessary second hit is common enough that cells in both eyes will be affected. Because inheriting a single copy of the mutated gene is so likely to lead to the disease, the gene is said to show a dominant inheritance pattern.

Generalized Tumor Suppressor Genes

There are a growing number of genes that have been identified as having some function as tumor suppressor genes. The table below lists genes and their associated tumor types. One of the most important tumor suppressor

genes is TP53 (more commonly known as p53 ). This gene was originally identified as a germ-line mutation in the rare inherited cancer called Li-Fraumeni Syndrome, but it has since been shown to be involved in a wide variety of cancer types. The p53 gene is lost (e.g., the gene is deleted from the chromosome) in about 50 percent of all cancerous cells.

The p53 protein is responsible for controlling the cell cycle checkpoint at the stage where the cell makes a decision to duplicate its genome, called the G2/S boundary. Along with p21 (another essential protein at this boundary), p53 protein monitors the state of the DNA to ensure that the genome is intact and not damaged. The S phase is where the genome is duplicated to get ready for cell division, so it is important that any damage and errors be repaired. If the cell is unable to repair the damage to its DNA, p53 can induce the programmed cell death pathway (called apoptosis) that kills off the cell, thus preventing division of a cell with damaged DNA. If p53 is not functional, the cell cycle is not arrested and any errors will be duplicated and passed on when the cell divides.

Mechanisms of Functional Tumor Suppressor Loss

There are three main ways in which a cell can lose the functionality of its tumor suppressor genes. Chromosomal aberrations, such as balanced reciprocal translocations, can occur. In such translocations, two unlike chromosomes switch segments. The most common such aberration is the chromosome 11 and 22 t(11;22) (q23;q11) translocation. It occurs in 10 to 15 of every 10,000 newborns and is the most common cause of childhood leukemia. The chromosome 9 and 22 t(9;22)(q34;q11) translocation gives rise to the characteristic derivative of chromosome 22, called the Philadelphia chromosome after the city where it was first found, and results in chronic myelogenous leukemia.

Constitutional chromosomal aberrations, which include deletions and aneuploidy , are sometimes associated with an increase in specific kinds of cancers. For example, a deletion on chromosome 13 band q14.1 is associated with retinoblastoma. Trisomy 21 in individuals with Down syndrome is associated with a 1 percent occurrence of leukemia.

Viral oncoproteins can interact with tumor suppressor gene proteins. The human papillomavirus (HPV) is a small DNA virus that causes warts. Various subtypes of HPV are associated with cervical cancer. The viral transforming protein E7 has the ability to interact with the retinoblastoma protein, thus interfering with the cell cycle checkpoint controlled by the retinoblastoma protein. Similarly, another HPV gene, E6, interacts with the p53 gene, causing the degradation of the p53 protein, thus allowing the cell cycle to go unchecked.

see also Apoptosis; Breast Cancer; Cancer; Cell Cycle; Chromosomal Aberrations; Colon Cancer; Oncogenes.

Giles Watts

Bibliography

Rosenberg, S. A., and B. M. John. The Transformed Cell: Unlocking the Mysteries of Cancer. New York: Putnam, 1992.

Weinberg, R. A. Racing to the Beginning of the Road: The Search for the Origin of Cancer. New York: W. H. Freeman, 1998.

———. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1999.