Oncogenes

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Oncogenes

An oncogene is a gene that causes cancer. Oncogenes arise from normal cellular genes, often ones that help regulate cell division.

Early Oncogene Research

The first clues that cancer has a genetic basis came from several independent observations. In 1914 the German cell biologist Theodor Boveri viewed cancer cells through a microscope and noted that they often carried abnormal chromosomes. However, recognition that a specific chromosomal abnormality was routinely associated with a particular type of cancer did not come until 1973, when Janet Rowley showed that chronic myelogenous leukemia (CML) cells carried a chromosomal translocation in which the ends of chromosomes nine and twenty-two are exchanged. Several other studies showed that certain types of cancer can run in families, suggesting that cancer risk can be inherited. Then, in 1981 the laboratories of Robert Weinberg, Michael Wigler, Geoff Cooper, and Mariano Barbacid showed that DNA from a human bladder cancer cell line could cause nonmalignant cells in tissue culture to become cancerous.

Since the Weinberg and Wigler observations, dozens of oncogenes have been identified and characterized. It is clear that oncogenes represent certain normal cellular genes that are aberrantly expressed or functionally abnormal. Such normal cellular genes, or "proto-oncogenes," can be altered to become oncogenes through a variety of different molecular mechanisms.

RNA Tumor Viruses and Proto-Oncogenes

In 1911 Peyton Rous reported that a class of RNA viruses can cause tumors in animals. These RNA tumor viruses, called "retroviruses," carry an RNA genome that, once inside a cell, is copied into DNA, which then is inserted randomly into the genome of a host cell. Some retroviruses are slow to cause tumors. After infection and spread to a large number of cells, a DNA copy of the viral genome, by chance, integrates into a host cell's DNA next to a normal gene that plays an important role in cell growth. If this viral integration disrupts the expression or structure of the normal cellular gene, it induces abnormal growth signals that can lead to cancer.

Other retroviruses cause tumors to appear very quickly. In the process of copying viral RNA into DNA, RNA that is expressed from cellular genes can be mistakenly copied into the viral genome. The progeny of the virus transfer the cellular gene to many other cells. If this "captured" cellular RNA is from a gene that stimulates cell growth, it then causes abnormal growth stimulation, leading to cancer. This process is termed "gene capture."

Through molecular cloning, the genes that are activated or captured by retroviruses have been identified and characterized. Almost three dozen such retroviral oncogenes and their related cellular proto-oncogenes are now known.

Proto-Oncogene Activation without Retroviruses

The first human oncogene, called Ras, was identified in the Weinberg and Wigler experiments. The protein product of the Ras gene serves as a switch that turns growth signals on and off. Normally, the activity of this Ras switch is tightly regulated. However, single mutations (called point mutations) in critical sites of the Ras gene cause the Ras growth switch to remain constantly turned on, which contributes to cancer. Thus, some proto-oncogenes can become oncogenes by genetic point mutation. Such mutations are not dependent upon the presence of retroviruses. Instead, they can occur during normal cell division and can be caused by environmental factors such as chemicals, ultraviolet rays from the sun, and X rays. DNA repair mechanisms usually, but not always, correct such mutations.

Oncogenes also can be activated by structural changes, called "amplifications" or "translocations," that occur in the chromosomes. DNA amplification increases by several-fold a specific region of a chromosome. This can produce many copies of any genes that lie in the amplified region. If one of the genes in this region is important in driving cell growth, its over-expression due to amplification leads to uncontrolled proliferation.

In the case of chromosome translocations, a proto-oncogene on one chromosome might be moved to another chromosome, resulting in the gene's structural alteration and/or aberrant expression. For example, in the translocation between chromosomes 9 and 22 that is found in CML, a protooncogene on chromosome 9, called c-Abl, is moved to chromosome 22, where it is fused to another gene called Bcr. Normally, c-Abl is a nuclear enzyme called "tyrosine kinase," which adds a phosphate molecule to proteins at an amino acid called tyrosine. Phosphorylation regulates the function of certain proteins that play important roles in stimulating cell proliferation. The fusion of Bcr and c-Abl genes creates an oncogene, called Bcr/Abl, which makes a highly overactive tyrosine kinase variant that is found in the cytoplasm instead of the nucleus. These changes in the activity and cellular location of the c-Abl proto-oncogene lead to chronic myelogenous leukemia.

Short-Circuiting Normal Cell Growth Mechanisms

Normal cell growth is controlled by the availability of growth factors, which are hormone-like molecules that bind to specific receptors embedded in the surface membrane of cells. When this happens, the receptor stimulates a signaling cascade inside cells that ultimately tells the cells to divide. Many gene products in this signaling pathway are proto-oncogenes that can become oncogenes when activated by the different mechanisms described above. When a signaling proto-oncogene is activated, the signaling cascade becomes "short-circuited" and cells behave as if they are continually stimulated by their growth factor.

For example, the v-sis oncogene from a monkey cancer virus known as simian sarcoma retrovirus (SSV) comes from a gene that encodes platelet-derived growth factor, which stimulates growth of different cell types. Cells infected with SSV are, therefore, constantly bathed in the v-sis growth factor and stimulated to proliferate. Other oncogenes are mutated growth factor receptors where mutation leaves the receptor in the "on" status even in the absence of the growth factor. Two examples of mutated receptor onco-genes include v-erbB, found in a bird retrovirus that causes various cancers, and v-fms, which is carried by a mouse retrovirus that causes leukemia.

Inside the cell, components of the signaling cascade that connect cell surface growth receptors to the nucleus also can cause cancer when their activity is altered by mutation or overexpression. The Ras proto-oncogene is an example of a signal-transmitting molecule inside cells that can mutate into an oncogene. In the nucleus, these normal growth signals trigger other proteins, called transcription factors, that regulate gene expression needed for cell growth. Many transcription factors are proto-oncogenes. Two examples of proto-oncogene transcription factors are c-Fos and c-Jun, both of which were first identified as retroviral oncogenes.

Tumor Suppressor Genes

In 1983 Raymond White and Webster Cavanee, using a technique called chromosome mapping, learned that a loss of a small segment of human chromosome 13 was a recurring feature in retinoblastoma, a rare childhood cancer of the retina that can run in families. In this deleted region they discovered a gene called RB (for retinoblastoma), both copies of which are inactivated either by DNA deletion or by a mutation within the gene that destroys its function. Such inactivation of both copies of the RB gene occurs in about 40 percent of human cancers. The product of the normal RB gene functions as a brake to cell division, so that loss of this brake can lead to unregulated cell growth.

Another gene associated with cancer when both copies are affected by mutation is the p53 gene, which acts as a "guardian" of the genome. Normally, this gene product induces a cell suicide program called apoptosis in cells with damaged DNA. Loss of p53 activity allows cells with damaged DNA to grow and pass DNA mutations to their daughter cells. A third type of gene that plays a role in cancer when it is inactivated is NF1. This gene encodes a protein that turns off the Ras growth signal mentioned above. In this case, loss of NF1 function is another way that the Ras signal can be left constantly on.

Since the discovery of RB, researchers have identified several additional genes in which both copies are inactivated due to mutation or chromosomal deletion. These genes normally block cell growth; hence they are called tumor suppressor genes. Since both copies of these genes need to be inactivated in order to release cancer cells from growth inhibition, tumor suppressor genes act recessively. This contrasts to the oncogenes described above, where only one copy needs to be activated in order to promote cancer. Oncogenes, therefore, act in a dominant fashion.

Multiple Genetic "Hits"

In 1971 Alfred Knudson Jr. proposed that retinoblastoma resulted from at least two separate genetic defects. In families with a high risk of retinoblastoma, the first defect is inherited and the second occurs sometime during childhood. This came to be known as Knudson's "two-hit theory." Subsequent research has shown that most, if not all, cancer arises from multiple genetic events, or "hits."

In many cancers, more than two hits are required. Bert Vogelstein and coworkers first showed this in colon cancer in the late 1980s. Colon cancer begins with a precancerous stage, called a benign polyp. Left untreated, this will progress through successively more cancerous stages until it becomes an aggressive carcinoma. Vogelstein's group found that progression of colon cancer through these different stages was associated with the acquisition of genetic changes in oncogenes such as Ras, as well as in a number of different tumor suppressor genes, including p53. Together, sequential activation of different oncogenes along with inactivation of various tumor suppressor genes drive the step-wise progression of precancerous cells to highly malignant tumors.

see also Apoptosis; Breast Cancer; Cancer; Carcinogens; Cell Cycle; Colon Cancer; Inheritance Patterns; Mutation; Retrovirus; Signal Transduction; Tumor Suppressor Genes; Transcription Factors.

Steven S. Clark