Exposure routes: Inherited as genetic information
Where found: Proto-oncogenes are genes found within the chromosomes of all eukaryotic (nucleated) cells and organisms.
At risk: Proto-oncogenes are universal among all eukaryotic cells and organisms, which include humans and all animals. Congenital mutations in some of these genes are associated with a significantly increased risk for certain cancers.
Etiology and symptoms of associated cancers: More than one hundred proto-oncogenes have now been recognized in cells. Most are involved in regulating movement through the cell cycle (regulation of chromosome replication followed by cell division). The cell cycle is characterized as having four phases: G1, which regulates events leading to deoxyribonucleic acid (DNA) replication; S, in which cell chromosomes replicate; G2, which regulates events leading to cell division; and mitosis, the period in which the chromosomes separate and the cell divides. Each phase is regulated by specific enzymes, signals, and other molecules, as well as suppressors that prevent movement through the phase. Many of the regulatory proteins involved in these events are encoded by proto-oncogenes. Not all proto-oncogenes are expressed in every cell, and the type of cancer that potentially develops is related to the particular oncogene that has undergone a mutation.
Proto-oncogenes are subdivided into four categories, each of which represents a particular set of steps that regulate the cell cycle: growth factors, growth factor receptors, signal mechanisms, and tumor suppressors/regulators of apoptosis (cell death).
Growth factors are small proteins that bind specific cell surface receptors and set in motion events that will result in cell division. Overproduction of growth factors may result in repeated cell division, setting the stage for development of cancer. For example, the PDGFB (commonly known as sis) oncogene, originally isolated from the simian sarcoma virus, encodes one of the protein chains that make up the platelet-derived growth factor. PDGFB is secreted by platelets and binds receptors on certain fibroblast cells. Overproduction of PDGFB may induce uncontrolled cell division, resulting in a sarcoma.
Growth factor receptors are cell surface proteins that bind specific growth factors. Each cell type expresses a particular form or forms of receptors, and the ability of any growth factor to stimulate a cell depends on expression of these surface molecules. Some of these receptor proteins are actually enzymes that, when activated, begin a series of signals within the cell, resulting in cell division. Certain mutations in the genes that encode these receptors may, in effect, cause a “short circuit” in regulation, resulting in loss of control and continuous movement of the cell through the cell cycle.
One example of such a receptor mutation is that of the
HER2/neu (also known as ERBB2) receptor protein expressed on certain breast cells. The HER2/neu protein is similar in its amino acid sequence to the human epidermal growth factor receptor molecule and is an example of a transmembrane enzyme that begins the signal transmission in the cell. A mutation in the HER2/neu proto-oncogene converts it into the HER2/neu oncogene (named for the neuroblastoma in which it was first identified). Overexpression of the HER2/neu protein is associated with the aggressive nature of certain forms of breast cancer. The basis for the chemotherapeutic action of Herceptin is its ability to inhibit the activity of the HER2/neu protein.
Signal mechanisms represent a series or cascade of enzymatic reactions that move the cell through the cell cycle and regulate cell division. At the molecular level, intermediates in this pathway are enzymes that activate DNA-binding proteins (DBPs), inducing gene expression. The RAS supergene family and the greater than one hundred proteins its members encode are examples of such inducers. RAS proteins are also called G proteins, reflecting their utilization of guanosine triphosphate (GTP) for their activity. Mutations in these genes may result in a continuous activating signal within the cell and uncontrolled cell division. Certain forms of colon and bladder cancers are the result of such mutations, and some forms of mutations are associated with mutations in the DNA-binding protein substrates for these RAS proteins. RAS gene mutations have been observed in nearly one-third of all cancers.
Tumor suppressors/regulators of apoptosis control steps at the end of the cell cycle. The proto-oncogenes that regulate apoptosis can either promote or inhibit cell death. The BCL2 gene family produces proteins that are pro-apoptosis and anti-apoptosis (the BCL2 gene itself inhibits apoptosis, and its overexpression has been implicated in cancers such as lymphoma). Proto-oncogenes and tumor suppressors provide the cell with the means not only to block division if chromosome replication is incomplete or if a mutation has occurred that could cause the cell to become cancerous but also to actually cause the cell to die. Tumor suppressors promote apoptosis and therefore are usually inactivated in cancers.
The first of the tumor suppressors to be discovered was the retinoblastoma RB1 protein, isolated in the 1980s. The RB1 protein regulates the steps that allow DNA replication to begin in the cell. The TP53 protein, named for its size, detects mutations that have occurred in DNA and induces repair of the DNA site or, if the mutation is too extensive, induces steps that culminate in the death of the cell.
As is true for other genes that regulate cell division, mutations in the genes associated with tumor suppression are associated with certain forms of cancer. For example, mutations in the
RB1 gene seem to predispose people for retinoblastoma. Mutations in the TP53 gene have been found in more than 50 percent of all forms of cancer. The ability of oncogenic viruses such as hepatitis B, the etiological agent for hepatocarcinoma, or the human papillomavirus, the agent for cervical carcinoma, to initiate cancer is related to their abilities to inactivate tumor suppressors. At least two dozen types of tumor suppressors were identified in the first decade of the twenty-first century.
Mutations at these sites may be caused as a result of infection by certain viruses or by exposure to carcinogens, most of which are also mutagens, chemicals that induce DNA mutations. In some cases, the mutation is congenital, the individual having been born with that specific mutation. Childhood retinoblastoma, for example, results from congenital mutations in the RB1 gene.
In some cases, it is not “simply” a point mutation in a proto-oncogene that leads to a cancer. Certain forms of the disease are known to result from chromosomal breaks and translocations, the movement of pieces of chromosomes from one site to another in the cell chromatin. The DNA in patients suffering from chronic myelogenous leukemia was found to possess a specific type of translocation. What became known as the Philadelphia chromosome is characterized by translocation of the ABL1 oncogene, on chromosome 9, into the region of the BCR oncogene on chromosome 22. The combined gene product disrupts the normal signaling mechanism in these cells, resulting in uncontrolled cell division. Inhibition of this activity is the basis of action for at least one type of antileukemic drug, imatinib mesylate (Gleevec), lending further support to this mutation as being the actual cause of chronic myelogenous leukemia.
Cancer, however, generally is not the result of any individual mutation. The molecules previously described regulate cell division, The difference between a benign growth and a true malignancy is the result of accumulated mutations over time. For example, a malignancy would require not only a mutation in the signal pathway but also, at a minimum, additional mutations in tumor-suppressor genes or in steps that inhibit cell death.
History: The evidence for existence of oncogenes dates to the early history of retroviruses, viruses with genomes of ribonucleic acid (RNA), which are copied into DNA following infection and which were found to be etiological agents for some forms of cancer. In the late nineteenth century, leukemia in animals was demonstrated to be transmissible using extracts from cells. However, leukemia was not considered to be a true cancer at the time. It was only when Peyton Rous demonstrated in 1911 that solid tumors in chickens sarcomas could be transmitted using cell-free extracts that scientists began to believe cancer, at least in animals, was associated with infectious agents. Eventually what became known as the Rous sarcoma virus (RSV) was isolated and identified with this disease in chickens.
As an increasing number of such tumor viruses, in which RNA was shown to be the genetic material, were isolated by the 1950s, the question that followed was how these viruses could change, or transform, cells from normal to cancerous. In 1958, Howard Martin Temin and Harry Rubin demonstrated that single virus particles could transform chicken cells. Further work by Temin indicated that it was possible to disrupt viral replication and transformation by adding inhibitors acting at the level of DNA. Temin proposed that such viruses act using a DNA intermediate and that they encode an enzyme that copies RNA into DNA, allowing what has become viral DNA to integrate into the cell chromosome. By the late 1960s Temin and David Baltimore independently discovered an enzyme, popularly known as reverse transcriptase, that carries out this function. Viruses that encode the enzyme have become known as retroviruses and include the RNA tumor viruses. Temin and Baltimore were each awarded the Nobel Prize in Physiology or Medicine in 1975.
The seemingly simplistic genetic structure of the RNA tumor viruses lent itself to determining which viral genes are associated with cancers. The discovery of a temperature-sensitive mutation in one of these genes led to the identification of the SRC gene in the Rous sarcoma virus, the first such oncogene to be discovered.
The SRC gene was shown to be required for transformation by the Rous sarcoma virus. However, strains of the virus that lacked that gene were found to replicate normally, suggesting the SRC gene was superfluous for the virus and may even have originated as genetic material extraneous to the virus. In 1976, J. Michael Bishop and Harold Varmus provided the answer. Creating DNA probes from transformation defective mutants of the Rous sarcoma virus, they found that normal avian cells contained cellular homologs of the viral SRC gene that is, a cellular proto-oncogene. The proto-oncogene product of the gene was subsequently shown to be an enzyme critical in the signaling pathway that regulates cell division.
Through the 1980s, an increasing number of cellular proto-oncogenes were identified, and evidence for their association with cancers was increasingly demonstrated. When carcinogens were used to transform cells growing in laboratory cultures, mutations were found in proto-oncogenes carried by these cells. Indeed, the only difference found between proto-oncogenes in normal cells and oncogenes expressed in cancer cells was often a mutation at a single site. For example, the RAS oncogene found in cases of bladder cancer differed from its counterpart in a normal cell at only one amino acid position, suggesting the origin of the cancer was a mutation at that site. The RAS product, as was the SRC product described above, was shown to be involved in the signaling pathway within the cell.
Bishop, J. Michael. How to Win the Nobel Prize. Cambridge: Harvard UP, 2003. Print.
Coffin, John, et al. Retroviruses. Plainview: Cold Spring Harbor Laboratory, 1997. Print.
Cooper, Geoffrey. Oncogenes. 2nd ed. Boston: Jones, 1995. Print.
Mitri, Zahi, Tina Constantine, and Ruth O'Regan. “The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy." Chemotherapy Research & Practice (2012): 1–7. Academic Search Complete. Web. 8 Dec. 2014.
Panno, Joseph. Cancer: The Role of Genes, Lifestyle, and Environment. Rev. ed. New York: Facts On File, 2011. Print.
Pecorino, Lauren. Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics. 3rd ed. Oxford: Oxford UP, 2012. Print.
Pelengaris, Stella, and Michael Khan. The Molecular Biology of Cancer. Malden: Blackwell, 2006. Print.
Vogelstein, Bert, and Kenneth Kinzler. The Genetic Basis of Human Cancer. New York: McGraw, 2002. Print.
Weinberg, Robert A. The Biology of Cancer. 2nd ed. New York: Garland Science, 2014. Print.
No comments:
Post a Comment