Genetics: Tumor Suppression
GENETICS: TUMOR SUPPRESSION
Long-lived organisms have had to evolve mechanisms to suppress the development of cancer. These mechanisms are termed tumor suppression mechanisms, and the genes that control them are termed tumor suppressor genes. Tumor suppressor genes promote the development of cancer when they are lost or inactivated.
Many genes have been shown to function as tumor suppressors. Most participate in normal cellular and developmental processes, where the proteins they encode act to inhibit cell proliferation or promote differentiation or apoptosis. Tumor suppressors also play important regulatory and functional roles in the sensing and repairing of DNA damage, and in the responses to DNA damage; namely, cellular senescence and apoptosis.
Proteins encoded by tumor suppressor genes include growth-inhibitory cytokines and their receptors, such as some members of the TGF-β (transforming growth factor-beta) family and their transmembrane receptors. They also include transmembrane proteins such as E-cadherin, which organizes cells in epithelial tissues and promotes their differentiation. Some nuclear receptors, such as some of those that bind retinoic acid (retinoic acid receptors, or RARs), can also act as tumor suppressors. In addition, proteins that transduce growth-inhibitory signals, such as those that transduce TGF-β and related signals, as well as transcriptional regulators that respond to growth-inhibitory signals, such as the retinoblastoma susceptibility protein (pRB), can be tumor suppressors. Pro-apoptotic proteins comprise another class of tumor suppressors—one example is BAX, which stimulates the opening of the mitochondrial permeability pore, a prelude to apoptosis. Finally, proteins that sense or regulate the repair of DNA damage or that control the cellular response to DNA damage can be tumor suppressors. Examples include ATM (ataxia telangiectasia mutated), a protein kinase that transduces damage signals to p53, and p53 itself, a transcription factor that induces either cellular senescence, apoptosis, or cell-cycle arrest and DNA repair.
Loss or inactivation of tumor suppressor genes can occur by genetic (necessarily hereditary) or epigenetic (not necessarily hereditary) mechanisms. Genetic mechanisms include deleterious mutations or deletion of all or part of the gene. Epigenetic mechanisms include gene silencing, as well as any change in synthesis, degradation, localization, or interaction that prevents the gene product from functioning. Because cancer phenotypes generally result from loss of tumor suppressor gene functions, oncogenic mutations in these genes tend to be recessive, that is, both gene copies must be inactivated before cell behavior is affected.
Because many tumor suppressors function in normal cellular and developmental processes, they tend to be key participants in pathways that control cell growth, death, differentiation, and/ or repair.
Two of the most important tumor suppressor pathways are those controlled by the RB and TP53 genes, which encode the pRB and p53 proteins, respectively. Most, if not all, cancers harbor mutations in either the pRB or p53 pathway, or in both.
Both pRB and p53 regulate the transcription of other genes; pRB does so indirectly by binding and regulating transcription factors or transcription modulators. It also inhibits cell-cycle progression, largely by repressing the activity of E2F, a transcription factor that induces the expression of genes needed for DNA replication. By contrast, p53 is a direct transcription factor that induces the expression of cell-cycle inhibitors in response to DNA damage. Consistent with their key roles in tumor suppressor pathways, pRB and p53 are controlled by upstream regulators, and their activities are mediated by downstream effectors. Examples of upstream regulators are p16, which inhibits the cyclin-dependent protein kinase that phosphorylates and inactivates pRB; and ATM, which phosphorylates and activates p53. Examples of downstream mediators are E2F, the transcription factor that is blocked by pRB; and p21, the cyclin-dependent kinase inhibitor whose transcription is induced by p53.
Oncogenic mutations in pRB tend to be deletions, typical for tumor suppressor genes. By contrast, although some p53 mutations are deletions, many cancer cells harbor point mutations in p53. These point mutations alter its functions as a transcription factor, and are dominant.
Tumor suppressor genes are generally identified by their ability to increase the incidence of cancer when one or both copies are defective in the germline, and by their consistent absence in malignant tumors.
Germ-line tumor suppressor gene mutations are rare, and generally heterozygous (only one allele is mutant). This is because, although homozygous mutations favor the growth and/or survival of cancer cells, they are often lethal during embryogenesis. For example, mice lacking both RB genes do not survive to birth, whereas mice carrying one mutant and one wild-type (normal) RB allele develop normally but die of cancer at an early age. The tumors invariably show loss of the wild-type allele, indicating that once development is complete, loss of pRB results in cancer. This is also true in humans—children with one defective and one normal RB allele are normal at birth. However, they have a high incidence of childhood retinoblastoma and other tumors, and the tumors inevitablty have lost the wild-type allele.
Most cancers, of course, develop in organisms with a genetically normal germ line. Nonetheless, tumors generally harbor loss or inactivation of both copies of tumor suppressor genes. One reason that most cancers develop relatively late in life is that it takes time for mutations to develop in both tumor suppressor genes within a single cell.
Not all tumor suppressor genes are critical for normal development. Rather, some tumor suppressors appear to act primarily to suppress the development of cancer during adulthood. For example, genetically engineered mice that completely lack p16 develop normally, but die of cancer during young adulthood. Similarly, mice completely deficient in p53 develop normally, but develop cancer at an early age. When only one p16 or p53 gene is deleted, cancer incidence is lower than in animals that lack both genes, but higher than in wild-type animals. Tumors that develop in these animals invariably lose the remaining gene or, in the case of p53, acquire a dominant mutation in it. Tumor suppressor genes of this type, then, appear to act as longevity assurance genes. That is, they act to prevent the development of cancer during young adulthood or the peak of reproductive fitness. It is not surprising that tumor suppressors of this type also tend to be critical regulators of apoptosis and/or cellular senescence. Cellular senescence and apoptosis are potent tumor suppression mechanisms in mammals that also appear to play important role in the development of aging phenotypes.
See also Cancer, Biology; Cellular Aging: Cell Death; Cellular Aging: Telomeres; Genetics: Longevity Assurance; Molecular Therapy; Mutation.
Kaelin, W. G. "The p53 Family." Oncogene 18 (1999): 7701–7705.
Mcleod, K. "pRb and E2f-1 in Mouse Development and Tumorigenesis." Current Opinion in Genetics and Development 9 (1999): 31–39.
Oren, M. "Tumor Suppressors Review Issue." Experimental Cell Research 264 (2001): 1–192.
Death is an inevitable fact of life for organisms. Increasingly, biologists have come to realize that death is also, in many cases, an important and predestined fate of individual cells of organisms. Apoptosis is a process by which cells in a multicellular organism commit suicide. While cells can die as a result of necrosis , apoptosis is a form of death that the cell itself initiates, regulates, and executes using an elaborate arsenal of cellular and molecular machinery. For this reason, the term apoptosis is often used interchangeably with the term "programmed cell death," or PCD (although technically, apoptosis is but one particular form of programmed cell death). There is some disagreement on the origins of the word. The word apoptosis has ancient Greek origins, referring to the falling of leaves, or possibly "dropping of scabs" or "falling off of bones." There is even less agreement on its proper pronunciation, and even specialists in the field seem to use every possible way to say the word. "A-pop-TOE-sis" and "AP-oh-TOE-sis" are both common.
Why Cells Commit Suicide
Why do cells commit apoptosis? There seem to be two major reasons. First, apoptosis is one means by which a developing organism shapes its tissues and organs. For instance, a human fetus has webbed hands and feet early on its development. Later, apoptosis removes skin cells, revealing individual fingers and toes. A fetus's eyelids form an opening by the process of apoptosis. During metamorphosis, tadpoles lose their tails through apoptosis. In young children, apoptosis is involved in the processes that literally shape the connections between brain cells, and in mature females, apoptosis of cells in the uterus causes the uterine lining to slough off at each menstrual cycle.
Cells may also commit suicide in times of distress, for the good of the organism as a whole. For example, in the case of a viral infection, certain cells of the immune system, called cytotoxic T lymphocytes, bind to infected cells and trigger them to undergo apoptosis. Also, cells that have suffered damage to their DNA, which can make them prone to becoming cancerous, are induced to commit apoptosis.
The Regulatory Mechanism
The cellular mechanisms that regulate and cause apoptosis were first elucidated by genetic studies of the roundworm, Caenorhabditis elegans. Normally, in the development of a C. elegans worm, one out of every eight body cells produced is eliminated by programmed cell death. By studying mutants in which either too many or too few cells died, worm geneticists identified many of the proteins that control apoptosis. Subsequently, the critical medical relevance of apoptosis became clear when biologists discovered that mammals contain many of the same genes that control apoptosis in worms. More strikingly, they found that many of these genes were mutated in tumors from cancer patients. Other genes often found to be mutated in cancers are those which regulate the cell cycle, which is the complex set of processes controlling how and when cells divide. These two findings led cancer researchers to recognize that cancer, a disease of uncontrolled cell proliferation, can result either from too much cell division or not enough apoptosis. Because of this important finding, apoptosis has become the subject of intense medical research, and molecules that regulate apoptosis are being studied as potential targets for anti-cancer drug therapies.
A cell can be triggered to undergo apoptosis either by external signaling molecules, such as so-called "death activator" proteins, or through molecules that reside within the cell and monitor events that might commit the cell to suicide, such as damage to DNA. There are several biochemical pathways that lead to apoptosis. One of the major pathways involves inducing mitochondria to leak one of their proteins, cytochrome c, into the cystosol. This in turn activates a set of related proteases (enzymes that degrade proteins) called caspases. Ultimately, the caspases degrade proteins in the cell and activate enzymes that degrade other cell constituents, such as the DNA. Cells undergoing apoptosis exhibit characteristic morphological and biochemical traits, which can be recognized by microscopic examination or biochemical assays. Apoptosis can occur in as little as twenty minutes, after which the cell "corpse" typically becomes engulfed and completely degraded by neighboring phagocytic cells that are present in the tissue and attracted to the apoptotic cell.
see also Cancer; Cell Cycle; Roundworm: Caenorhabditis Elegans ; Signal Transduction.
Paul J. Muhlrad
Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.
Nature 407, no. 12 (Oct., 2000). (Issue devoted to review articles on apoptosis).
The WWW Virtual Library of Cell Biology. "Apoptosis." <http://vlib.org/Science/Cell_Biology/apoptosis.shtml>.
APOPTOSIS GENES IN C. ELEGANS
Much of our understanding of what causes apoptosis comes from genetic studies in Caenorhabditis elegans. Several cell death proteins (CED) proteins were identified in C. elegans by studying apoptosis-defective mutants. The main executioner is CED-3, a caspase, which becomes activated by CED-4, another caspase. The central guardian protecting cells against apoptosis is CED-9, which inhibits the actions of CED-4 and CED-3. CED-9 has a mammalian homolog, called BCL-2, which serves a similar role in mammals.
Caspase inhibitors are being investigated as a possible means to slow the progress of Huntington's disease, a degenerative brain disease.