and their functions

Source: J. Marx, Learning how to suppress cancer, Science 261(1993):1 385.

Gene Cellular Location

NF1 Cytoplasm p53 Nucleus

RB Nucleus

WT-1 Nucleus


GTPase activator Transcription factor, regulates apoptosis

Transcription factor Transcription factor prevent their proliferation. Often these cells have mutations in genes that regulate apoptosis, and therefore they do not undergo programmed cell death. The ability of a cell to initiate apoptosis in response to DNA damage, for example, depends on a gene called p53, which is inactivate in many human cancers. Additional information about p53 and its role in cancer

DNA repair genes Cancer arises from the accumulation of multiple mutations in a single cell. Some cancer cells have normal rates of mutation, and multiple mutations accumulate because each mutation gives the cell a replica-tive advantage over cells without the mutations. Other cancer cells may have higher-than-normal rates of mutation in all of their genes, which leads to more frequent mutation of onco-genes and tumor-suppressor genes. What might be the source of these high rates of mutation in some cancer cells?

Two processes control the rate at which mutations arise within a cell: (1) the rate at which errors arise during and after replication; and (2) the efficiency with which these errors are corrected. The error rate during replication is controlled by the fidelity of DNA polymerases and other proteins in the replication process (see Chapter 12). However, defects in genes encoding replication proteins have not been strongly linked to cancer.

The mutation rate is also strongly affected by whether errors are corrected by DNA repair systems (see p. 000 in Chapter 17). Defects in genes that encode components of these repair systems have been consistently associated with a number of cancers. People with xeroderma pigmentosum, for example, are defective in nucleotide-excision repair, an important cellular repair system that normally corrects DNA damage caused by a number of mutagens, including ultraviolet light. Likewise, about 13% of colorectal, endometrial, and stomach cancers have cells that are defective in mismatch repair, another major repair system in the cell.

Some types of colon cancer are inherited as an autosomal dominant trait. In families with this condition, a person can inherit one mutated and one normal allele of a gene that controls mismatch repair. The normal allele provides sufficient levels of the protein for mismatch repair to function, but it is highly likely that this normal allele will become mutated or lost in at least a few cells. If it does so, there is no mismatch repair, and these cells undergo higher-than-normal rates of mutation, leading to defects in onco-genes and tumor-suppressor genes that cause the cells to proliferate. Additional information on DNA repair

Genes affecting chromosome segregation Most advanced tumors contain cells that exhibit a variety of chromosome anomalies, including extra chromosomes, missing chromosomes, and chromosome rearrangements. Aneu-ploidy in somatic cells usually arises when chromosomes do not segregate properly in mitosis. Normal cells have a checkpoint that monitors the proper assembly of the mitotic spindle; if chromosomes are not properly attached to the microtubules at metaphase, the onset of anaphase is blocked. Some aneuploid cancer cells contain mutant alleles for genes that encode proteins having roles in this checkpoint; in these cells, anaphase is entered into despite the improper or lack of assembly of the spindle, and chromosome abnormalities result.

The tumor-suppressor gene p53, in addition to controlling apoptosis, plays a role in the duplication of the centro-some, which is required for proper formation of the spindle and for chromosome segregation. Normally, the centrosome duplicates once per cell cycle. If p53 is mutated or missing, however, the centrosome may undergo extra duplications, resulting in the unequal segregation of chromosomes. In this way, mutation of the p53 gene may generate chromosome mutations that contribute to cancer. The p53 gene is also a tumor-suppressor gene that prevents cell division when the DNA is damaged.

Sequences that regulate telomerase Another factor that may contribute to the progression of cancer is the inappropriate activation of an enzyme called telomerase. Telomeres are special sequences at the ends of eukaryotic chromosomes (see p. 000 in Chapter 11). In DNA replication in somatic cells, DNA polymerases require a 3'-OH group to add new nucleotides. For this reason, the ends of chromosomes cannot be replicated, and telomeres become shorter with each cell division. This shortening eventually leads to the destruction of the chromosome and cell death; so somatic cells are capable of a limited number of cell divisions.

In germ cells, telomerase replicates the chromosome ends (see p. 000 in Chapter 12), thereby maintaining the telomeres, but this enzyme is not normally expressed in somatic cells. In many tumor cells, however, sequences that regulate the expression of the telomerase gene are mutated so that the enzyme is expressed, and the cell is capable of unlimited cell division. Although the expression of telom-erase appears to contribute to the development of many cancers, its precise role in tumor progression is still being investigated.

Genes that promote vascularization and the spread of tumors A final set of factors that contribute to the progression of cancer includes genes that affect the growth and spread of tumors. Oxygen and nutrients, which are essential to the survival and growth of tumors, are supplied by blood vessels, and the growth of new blood vessels (angiogenesis) is important to tumor progression. Angiogenesis is stimulated by growth factors and others proteins encoded by genes whose expression is carefully regulated in normal cells. In tumor cells, genes encoding these proteins are often overexpressed compared with normal cells, and inhibitors of angiogenesis-promoting factors may be inactivated or underexpressed. At least one inherited cancer syndrome— van Hippel-Lindau disease, in which people develop multiple types of tumors—is caused by the mutation of a gene that affects angiogenesis.

In the development of many cancers, the primary tumor gives rise to cells that spread to distant sites, producing secondary tumors. This process of metastasis is the cause of death in 90% of human cancer cases; it is influenced by cellular changes induced by somatic mutation. By using microar-rays to measure levels of gene expression (see Chapter 19), researchers have identified several genes that are transcribed at a significantly higher rate in metastatic cells compared with nonmetastatic cells. These genes encode components of the extracellular matrix and the cytoskeleton, which are thought to affect the migration of cells. Other genes that affect metastasis include adhesion proteins that help hold cells together. General information about cancer, the genetics of cancer, and telomerase

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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