Tumor suppressor gene
Encyclopedia
A tumor suppressor gene, or anti-oncogene, 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.
whereas mutant oncogene alleles are typically dominant
. The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma
. 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 unnoble 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. Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency
for example PTCH in medulloblastoma. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.
s 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:
(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 VHL, APC
, CD95, ST5
, YPEL3
, ST7
, and ST14
.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that protects a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
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.
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 because 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 recessiveDominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
whereas mutant oncogene alleles are typically dominant
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
. The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
. 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
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
mutations, in contrast, generally involve a single allele because they are gain-of-function mutations. There are unnoble 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. Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency
Haploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
for example PTCH in medulloblastoma. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.
Functions
Tumor-suppressor genes, or more precisely, the proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s for which they code, either have a dampening or repressive effect on the regulation of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
or promote apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following:
- Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressedProtein expressionProtein expression is a subcomponent of gene expression. It consists of the stages after DNA has been translated into polypeptide chains, which are ultimately folded into proteins...
, the cell cycle does not continue, effectively inhibiting cell divisionCell divisionCell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. - CouplingCouplingA coupling is a device used to connect two shafts together at their ends for the purpose of transmitting power. Couplings do not normally allow disconnection of shafts during operation, however there are torque limiting couplings which can slip or disconnect when some torque limit is exceeded.The...
the cell cycle to DNA damage. As long as there is damaged DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue. - If the damage cannot be repaired, the cell should initiate apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(programmed cell death) to remove the threat it poses for the greater good of the organism. - Some proteins involved in cell adhesionCell adhesionCellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
prevent tumor cells from dispersing, block loss of contact inhibitionContact inhibitionContact inhibition is the natural process of arresting cell growth when two or more cells come into contact with each other. Oncologists use this property to distinguish between normal and cancerous cells....
, and inhibit metastasisMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. These proteins are known as metastasis suppressorMetastasis suppressorA metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal attributes of cancer. This attribute is responsible for about ninety percent of human cancer deaths...
s. - DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
proteins are usually classified as tumor suppressors as well, as mutations in such their genes increase the risk of cancer, for example mutations in HNPCC, MEN1MEN1Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
and BRCABRCA mutationA BRCA mutation is a mutation in either of the genes BRCA1 and BRCA2. Harmful mutations in these genes produce a hereditary breast-ovarian cancer syndrome in affected families...
. Furthermore, increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes.
Examples
The first tumor-suppressor protein discovered was the Retinoblastoma proteinRetinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(pRb) in human retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
; however, recent evidence has also implicated pRb as a tumor-survival factor.
Another important tumor suppressor is the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
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
Li-Fraumeni syndrome
Li-Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. It is named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome. Li-Fraumeni syndrome greatly increases susceptibility to cancer...
(LFS), which increases the risk of developing various types of cancers.
PTEN
PTEN
PTEN may mean:* Patterson-UTI Energy, Inc., which trades on the NASDAQ stock market under the symbol 'PTEN'* Prime Time Entertainment Network* PTEN , a human tumour suppressor gene on chromosome 10...
acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
activation.
Other examples of tumor suppressors include VHL, APC
APC (gene)
Adenomatous polyposis coli also known as deleted in polyposis 2.5 is a protein that in humans is encoded by the APC gene. Mutations in the APC gene may result in colorectal cancer....
, CD95, ST5
ST5 (gene)
Suppression of tumorigenicity 5 is a protein that in humans is encoded by the ST5 gene. ST5 orthologs have been identified in nearly all mammals for which complete genome data are available.-Further reading:...
, YPEL3
YPEL3
Human YPEL3 is a recently discovered protein encoded by the YPEL3 gene, shown to have growth inhibitory effects in normal and tumor cell lines. One of five family members , YPEL3 was named in reference to its Drosophila melanogaster orthologue...
, ST7
ST7
See also ST6/ST7 microcontrollerSuppressor of tumorigenicity protein 7 is a protein that in humans is encoded by the ST7 gene.. ST7 orthologs have been identified in all mammals for which complete genome data are available.-Interactions:...
, and ST14
ST14
Suppression of tumorigenicity 14 , also known as ST14, is a human gene. ST14 orthologs have been identified in most mammals for which complete genome data are available.-Further reading:...
.
See also
- Metastasis suppressorMetastasis suppressorA metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal attributes of cancer. This attribute is responsible for about ninety percent of human cancer deaths...
- Adenomatosis polyposis coliAPC (gene)Adenomatous polyposis coli also known as deleted in polyposis 2.5 is a protein that in humans is encoded by the APC gene. Mutations in the APC gene may result in colorectal cancer....
- OncogeneOncogeneAn oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
- CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
- DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
- Signal transductionSignal transductionSignal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
- Von Hippel Lindau Binding protein 1Von Hippel Lindau Binding protein 1von Hippel–Lindau binding protein 1 , also known as "prefoldin 3", is a chaperone protein that binds to von Hippel–Lindau protein and transports it from perinuclear granules to the nucleus or cytoplasm inside the cell...
- BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
- p53P53p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...