Tumor suppressor gene

(cell and molecular biology) A class of genes which, when mutated, predispose an individual to cancer by causing the loss of function of the particular tumor suppressor protein encoded by the gene.

Tumor suppressor genes regulate mitosis and cell division. When their function is impaired, the result is a high rate of uncontrolled cell growth or cancer. Damage to tumor suppressor genes contributes to a large number of different types of tumors.

The Balancing Act of Regulating the Cell Cycle

The cell cycle is a fundamental process of life, regulated by a balance of positive and negative mechanisms that act at key points during cell growth and differentiation. Proto-oncogenes tend to "push" the cell cycle (in a positively acting manner) by activating various cell cycle pathways within the developing cell. By contrast, tumor suppressor genes normally repress, or "put the brakes on," the activation of the pathways.

Genetics of Tumor Suppressor Genes

Mutations in tumor suppressor genes can arise spontaneously by exposure to a mutagenic substance such as ultraviolet light or certain chemicals. In such cases, only the mutated cell and its descendants will be affected. Mutations can also be inherited from a parent or arise early in development. In these cases, almost all the cells of the body will inherit the same mutation.

A mutation in a single tumor suppressor gene is usually not enough to cause cancer. This is because each cell contains two copies of each gene, one inherited from each parent. Most cancer-causing mutations cause a loss of function in the mutated gene. Often, having even one functional copy is enough to prevent disease, and two mutations are needed for cancer to develop. This is known as the "two-hit" model of carcinogenesis.

This model was first described in retinoblastoma, a common cancer of the retina. The affected gene (called the retinoblastoma gene) is a tumor suppressor. Spontaneous (noninherited) mutations are rare, but since there are many millions of cells in the retina, several of them will develop the gene mutation over the course of a lifetime. It would be very unlikely, though, for a single cell to develop two spontaneous mutations (at least in the absence of prolonged exposure to carcinogens), and thus noninherited retinoblastoma is very rare. When it occurs, it almost always affects only one eye—the eye in which the unlucky doubly hit cell resides.

If, however, a person inherits one copy of an already mutated gene from one parent, every cell in the eye starts life with one "hit." The chances are very high that several cells will suffer another hit sometime during their life. The chances are thus very high that the person will develop retinoblastoma, almost always in both eyes, since the necessary second hit is common enough that cells in both eyes will be affected. Because inheriting a single copy of the mutated gene is so likely to lead to the disease, the gene is said to show a dominant inheritance pattern.

Generalized Tumor Suppressor Genes

There are a growing number of genes that have been identified as having some function as tumor suppressor genes. The table below lists genes and their associated tumor types. One of the most important tumor suppressor genes is TP53 (more commonly known as p53). This gene was originally identified as a germ-line mutation in the rare inherited cancer called Li-Fraumeni Syndrome, but it has since been shown to be involved in a wide variety of cancer types. The p53 gene is lost (e.g., the gene is deleted from the chromosome) in about 50 percent of all cancerous cells.

Table 1

The p53 protein is responsible for controlling the cell cycle checkpoint at the stage where the cell makes a decision to duplicate its genome, called the G2/S boundary. Along with p21 (another essential protein at this boundary), p53 protein monitors the state of the DNA to ensure that the genome is intact and not damaged. The S phase is where the genome is duplicated to get ready for cell division, so it is important that any damage and errors be repaired. If the cell is unable to repair the damage to its DNA, p53 can induce the programmed cell death pathway (called apoptosis) that kills off the cell, thus preventing division of a cell with damaged DNA. If p53 is not functional, the cell cycle is not arrested and any errors will be duplicated and passed on when the cell divides.

Mechanisms of Functional Tumor Suppressor Loss

There are three main ways in which a cell can lose the functionality of its tumor suppressor genes. Chromosomal aberrations, such as balanced reciprocal translocations, can occur. In such translocations, two unlike chromosomes switch segments. The most common such aberration is the chromosome 11 and 22 t(11;22) (q23;q11) translocation. It occurs in 10 to 15 of every 10,000 newborns and is the most common cause of childhood leukemia. The chromosome 9 and 22 t(9;22)(q34;q11) translocation gives rise to the characteristic derivative of chromosome 22, called the Philadelphia chromosome after the city where it was first found, and results in chronic myelogenous leukemia.

Constitutional chromosomal aberrations, which include deletions and aneuploidy, are sometimes associated with an increase in specific kinds of cancers. For example, a deletion on chromosome 13 band q14.1 is associated with retinoblastoma. Trisomy 21 in individuals with Down syndrome is associated with a 1 percent occurrence of leukemia.

Viral oncoproteins can interact with tumor suppressor gene proteins. The human papillomavirus (HPV) is a small DNA virus that causes warts. Various subtypes of HPV are associated with cervical cancer. The viral transforming protein E7 has the ability to interact with the retinoblastoma protein, thus interfering with the cell cycle checkpoint controlled by the retinoblastoma protein. Similarly, another HPV gene, E6, interacts with the p53 gene, causing the degradation of the p53 protein, thus allowing the cell cycle to go unchecked.

Bibliography

Rosenberg, S. A., and B. M. John. The Transformed Cell: Unlocking the Mysteries of Cancer. New York: Putnam, 1992.

Weinberg, R. A. Racing to the Beginning of the Road: The Search for the Origin of Cancer. New York: W. H. Freeman, 1998.

———. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1999.

—Giles Watts

It has been suggested that Caretaker gene be merged into this article or section. (Discuss)

A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.

Contents 1 Two-hit hypothesis 2 Functions 3 Examples 4 See also 5 References 6 External links

Two-hit hypothesis

Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor suppressors alleles are usually recessive whereas mutant oncogene alleles are typically dominant. The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma.^[1] Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain of function mutations. There are notable exceptions to the 'two-hit' rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a 'dominant negative', meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele.^[2] Other tumor-suppressor genes that are exceptions to the 'two-hit' rule are those which exhibit haploinsufficiency. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.^[3]

Functions

Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following:^[4]

1. Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle will not continue, effectively inhibiting cell division.
2. Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue.
3. If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organism.
4. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors.^[5][6]

Examples

The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor.

Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Homozygous loss of p53 is found in 70% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome (LFS), which increases the risk of developing various types of cancers.

PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic Akt activation.

Other examples of tumor suppressors include APC and CD95.

See also

• Metastasis suppressor
• Adenomatosis polyposis coli
• Oncogene
• Cancer
• DNA repair
• Signal transduction
• Von Hippel Lindau Binding protein 1
• BRCA1

• p53

References

1. ^ Knudson AG (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad of Sci 68 (4): 820–3. doi:10.1073/pnas.68.4.820. PMID 5279523. 
2. ^ Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. (1990). "Suppression of human colorectal carcinoma cell growth by wild-type p53.". Science 249 (4971): 912–5. doi:10.1126/science.2144057. PMID 2144057. 
3. ^ Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (1998). "The murine gene p27Kip1 is haplo-insufficient for tumour suppression". Nature 396 (6707): 177–80. doi:10.1038/24179. PMID 9823898. 
4. ^ Sherr CJ (January 2004). "Principles of tumor suppression". Cell 116 (2): 235–46. doi:10.1016/S0092-8674(03)01075-4. PMID 14744434. 
5. ^ Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW (November 2000). "Metastasis-suppressor genes: a review and perspective on an emerging field". J. Natl. Cancer Inst. 92 (21): 1717–30. doi:10.1093/jnci/92.21.1717. PMID 11058615. 
6. ^ Hirohashi S, Kanai Y (2003). "Cell adhesion system and human cancer morphogenesis". Cancer Sci 94 (7): 575–81. doi:10.1111/j.1349-7006.2003.tb01485.x. PMID 12841864. 

External links

• TCF21 gene discovery at Ohio State University

v • d • e Pathology: Tumor, Neoplasm, Cancer, and Oncology (C00-D48, 140-239) Benign tumors Hyperplasia · Cyst · Pseudocyst · Hamartoma Malignant progression Dysplasia · Carcinoma in situ · Cancer · Metastasis Topography Oral · Head/Neck · Nasopharyngeal · Digestive system · Respiratory system · Bone · Skin · Blood · Urogenital · Nervous system · Endocrine system Histology Carcinoma · Sarcoma · Papilloma · Adenoma Misc. Tumor suppressor genes/oncogenes · Staging/grading · Carcinogenesis · Carcinogen · Research · Precancerous condition · Paraneoplastic syndrome · List of oncology-related terms

v • d • e Neoplasm: Tumor suppressor genes/proteins Cell membrane MAPK/ERK pathway (Neurofibromin 1) Wnt signaling pathway (CDH1) Hedgehog signaling pathway (PTCH1) TGF beta signaling pathway (TGF beta receptor 2) other/unknown (Maspin) Cytosol/cytoskeleton Wnt signaling pathway (APC) TGF beta signaling pathway (SMAD2, SMAD4) Akt/PKB signaling pathway (PTEN) other/unknown: (Neurofibromin 2/Merlin) Mitochondria SDHB - SDHD Nucleus Cell cycle regulation: pRb - CHEK2 - p14arf/p16 - cip/kip (p21, p27, p57) - p53 p63 p73 family (p53, p63, p73) - WT1 DNA repair/Fanconi: BRCA1 - BRCA2 other: KLF6 - VHL see also oncogenes

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