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Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in Tumor Suppressor Genes1. In 1997, Kinzler and Bert Vogelstein grouped these cancer susceptibility genes into two classes: the caretakers and gatekeepers18. In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa, and Martin Nowak, the landscaper genes.
Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes².
In contrast to caretaker genes, Gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation5,15.
The third classification of genes, the landscapers, encode products that, when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation13.
Genes in context
Pathways to Cancer via the Caretakers
The process of DNA replication inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome15. Caretaker genes provide genome stability by preventing the accumulation of these mutations.
Pathways to cancer via the Gatekeepers
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death5. When tissue damage occurs, for example, products of gatekeeper genes ensure that balance of cell growth over cellular death remains in check11. In the presence of competent gatekeeper genes, mutations of other genes do not lead to on-going growth imbalances.
Pathways to cancer via the Landscapers
Gatekeepers, Caretakers, and Cellular Aging
It has been suggested that gatekeeper genes confer beneficial anti-cancer affects but may provide deleterious affects that increase aging15. This is because young organisms experiencing times of rapid growth necessitate significant anti-cancer mechanisms. As the organism ages, however, these formerly beneficial pathways become deleterious by inducing apoptosis in cells of renewable tissues, causing degeneration of the structure15. Studies have shown an increased expression of pro-apoptotic genes in age-related pathologies19. This is because the products of gatekeeper genes are directly involved in coding for cellular growth and proliferation.
It is interesting to note, however, that dysfunctional caretaker genes does not always lead to a cancerous phenotype19. For example, defects in nucleotide excision repair pathways are associated with premature aging phenotypes in diseases such as Xeroderma pigmentosum and Trichothiodystrophy. These patients exhibit brittle hair, nails, scaly skin, and hearing loss – characteristics associated with simple human aging. This is important because the nucleotide excision repair pathway is a mechanism thought to be encoded by a caretaker gene. Geneticists studying these premature-aging syndromes propose that caretaker genes that determine cell fate also play a significant role in aging 19.
Similarly, gatekeeper genes have been identified as having a role in aging disorders that exhibit mutations in such genes without an increased susceptibility to cancer. Experiments with mice that have increased gatekeeper function in the p53 gene show reduced cancer incidence (due to the protective activities of products encoded by p53) but a faster rate of aging19.
Cellular senescence, also encoded by a gatekeeper gene, is arrest of the cell cycle in the G1 phase. Qualitative differences have been found between senescent cells and normal cells, including differential expression of cytokines and other factors associated with inflammation19. It is believe that this may contribute, in part, to cellular aging.
In sum, although mechanisms encoded by gatekeeper and caretaker genes to protect individuals from cancer early in life, namely induction of apoptosis or senesence, later in life these functions may promote the aging phenotype19.
Mutations in context
It has been proposed that mutations in gatekeeper genes could, to an extent, offer a sort of selective advantage to the individual in which the change occurs. This is because cells with these mutations are able to replicate at a faster rate than nearby cells5. This is known as increased somatic fitness7. Caretaker genes, on the other hand, confer selective disadvantage because the result is inherently decreased cellular success5. However, increased somatic fitness could also arise from a mutation in a caretaker gene if mutations in tumor suppressor genes increase the net reproductive rate of the cell7.
Although mutations in gatekeeper genes may lead to the same result as those of caretaker genes, namely cancer, the transcripts that gatekeeper genes encode are significantly different from those encoded by caretaker genes.
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death5. In cases of tissue damage, for example, gatekeeper genes would ensure that balance of cell growth over cellular death remains in check11. In the presence of competent gatekeeper genes, mutations of other genes would not lead to on-going growth imbalances.
Whether or not mutations in these genes confer beneficial or deleterious effects to the animal depends partially on the environmental context in which these changes occur, a context encoded by the landscaper genes. For example, tissues of the skin and colon reside in compartments of cells that rarely mix with one another5. These tissues are replenished by stem cells. Mutations that occur within these cell lineages remain confined to the compartment in which they reside, increasing the future risk of cancer5. This is also protective, however, because the cancer will remain confined to that specific area, rather than invading the rest of the body, a phenomenon known as metastasis.
In areas of the body compartmentalized into small subsets of cells, mutations that lead to cancer most often begin with caretaker genes5. On the other hand, cancer progression in non-compartmentalized or large cell populations may be a result of initial mutations in gatekeepers5.
These delineations offer a suggestion why different types of tissue within the body progress to cancer by differing mechanisms5.
Although the classification of tumor suppressor genes into these categories is helpful to the scientific community, the potential role of many genes cannot be reliably identified as the functions of many genes are rather ill-defined 18. In some contexts, genes exhibit discrete caretaker function while in other situations gatekeeper characteristics are recognized. An example of one such gene is p53. Patients with Li-Fraumeni syndrome, for example, have mutations in the p53 gene that suggest gatekeeper function. p53 has an identified role, however, in regulating the cell cycle as well, which is an essential caretaker function 18.
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|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Caretaker_gene". A list of authors is available in Wikipedia.|