If the p53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of p53 will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. More than 50 percent of human tumors contain a mutation or deletion of the p53 gene. In health p53 is continually produced and degraded in the cell.
The degradation of p53 is, as mentioned, associated with MDM-2 binding. In a negative feedback loop MDM-2 is itself induced by p However mutant p53s often don't induce MDM-2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 Blagosklonny, In-vitro introduction of p53 in to pdeficient cells has been shown to cause rapid death of cancer cells or prevention of further division. It is more these acute effects which hopes rest upon therapeutically McCormick F, The rationale for developing therapeutics targeting p53 is that "the most effective way of destroying a network is to attack its most connected nodes".
P53 is extremely well connected in network terminology it is a hub and knocking it out cripples the normal functioning of the cell. Restoring its function would be a major step in curing many cancers Vogelstein et al Various strategies have been proposed to restore p53 function in cancer cells Blagosklonny, A number of groups have found molecules which appear to restore proper tumour suppressor activity of p53 in vitro.
These work by altering the conformation of mutant conformation of p53 back to an active form. So far, no molecules have shown to induce biological responses, but some may be lead compounds for more biologically active agents.
A promising target for anti-cancer drugs is the molecular chaperone Hsp90, which interacts with p53 in vivo. Adenoviruses rely on their host cells to replicate, they do this by secreting proteins which compel the host to replicate the viral DNA. Adenoviruses have been implicated in cancer-causing diseases, but in a twist it is now modified viruses which are being used in cancer therapy.
Without functioning p53, cell proliferation is not regulated effectively and DNA damage can accumulate in cells. Additional genetic, environmental, and lifestyle factors contribute to a person's cancer risk; in lung cancer, the greatest risk factor is being a long-term tobacco smoker. Somatic TP53 gene mutations are common in ovarian cancer, occurring in almost half of ovarian tumors. These mutations result in a p53 protein that is less able to control cell proliferation.
Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. In addition to the cancers described above, somatic TP53 gene mutations have been identified in several types of brain tumor, colorectal cancer, liver cancer, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands small hormone-producing glands on top of each kidney.
Most TP53 mutations change single amino acids in the p53 protein, which leads to the production of an altered version of the protein that cannot control cell proliferation and is unable to trigger apoptosis in cells with mutated or damaged DNA.
Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. TP53 gene tumor protein p From Genetics Home Reference. Normal Function The TP53 gene provides instructions for making a protein called tumor protein p53 or p Health Conditions Related to Genetic Changes Breast cancer Inherited changes in the TP53 gene greatly increase the risk of developing breast cancer, as well as several other forms of cancer, as part of a rare cancer syndrome called Li-Fraumeni syndrome described below.
More About This Health Condition. Bladder cancer Somatic TP53 gene mutations have been found in some cases of bladder cancer. Head and neck squamous cell carcinoma Somatic mutations in the TP53 gene have been found in nearly half of all head and neck squamous cell carcinomas HNSCC.
Li-Fraumeni syndrome Although somatic mutations in the TP53 gene are found in many types of cancer, Li-Fraumeni syndrome appears to be the only cancer syndrome associated with inherited mutations in this gene.
Lung cancer Somatic mutations in the TP53 gene have been found in nearly half of all lung cancers. Ovarian cancer Somatic TP53 gene mutations are common in ovarian cancer, occurring in almost half of ovarian tumors.
Other cancers Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. Comprehensive molecular profiling of lung adenocarcinoma. They also suppose that this base pair DNA sequence may not be the only sequence that has the ability to bind specifically to the p53 in humans; however, it can help people better understand the function of p Rotter V et al.
For example, a high level of p53 protein was detected in several key steps during B-cell differentiation. Elevated p53 can also be detected during spermatogenesis. Meanwhile, only a very low level of p53 protein can be detected in some organs of adult mice.
In , a useful tool was discovered occasionally. It is a temperature-sensitive mutant of p53 , called p53val It can act as a real wild-type p53 at the temperature of Additionally, for transformed cells expressing p53val , its proliferation is controlled at the permissive temperature, and this kind of control is reversible. After reactivation of p53val for a few days, all cells died, and this death exhibits some properties of apoptosis.
A wild type p53 was transfected into a human colon tumor-derived cell line EB. The cells were examined under light and electron microscopes, and found to exhibit some properties of apoptosis. In , a key protein MDM2 was discovered because it binds tightly with p53, and it inhibits the transactivation mediated by p The molecular mass of MDM2 is 90kDa, and it forms a complex with both mutated and wild-type p Gene amplification was detected mostly in transformed cells but not in the normal fibroblasts.
The result showed that cells losing one copy of the p53 alleles act as wild-type p53, while cells losing both copies of the wild type p53 alleles exhibit a higher frequency of amplification.
It encodes the protein p21 which is a cyclin-dependent kinase inhibitor that inhibits cyclin-CDK2 and CDK1 by binding to them. A 66 amino acid long peptide is responsible for the formation of complex EBNAp53, point mutations of p53 did not affect its binding ability to EBNA However, it inhibits its formations of complexes with other molecules. This DNA binding domain was also called the core domain. It contains residues , and consists of a beta sandwich. They also demonstrated the detailed structure of the core domain.
They found that HBX can inhibit the ability of p53 to bind to other sequence-specific DNA after it is bound to p53 and it can also inhibit the association of p53 with transcription factors. In , Honda R et al. The location is deleted frequently in neuroblastoma and other tumors. Like p73, p63 can transactivate p53 target genes significantly, it can also induce apoptosis. One characteristic of p63 is that the majority of p63 lack an N-terminus.
These findings suggest that p53 plays a role in cellular senescence. When cells come into the proliferation phase, the telomeres at the end of each chromosome would shorten after each round of DNA replication due to incomplete replication of single strand DNA at the end of the DNA stand. Wynford TD 35 found that with the loss of the function of wild-type p53 , all fibroblasts escape from apoptosis.
Also, the transactivation function of p53 can be turned on by apoptosis. The first one is post-translational modification by phosphorylation, the second one is up-regulates the transcritional cofactors like p33ING1, the last one is down-regulates the p53 inhibitors like MDM2. In , Brodsky MH et al.
There is evidence to show Drosophila eyes display a severe rough eye phenotype under the expression of human p53 that will induce apoptosis of eye imaginal disc cells, causing the loss of pigment cells, finally inhibiting eye development of Drosophila , 35 so Drosophila can be a model animal for studying the function of p Brodsky found that the gene rpr contains a consensus p53 binding site that is located in the cis-regulatory region of rpr , and it also is an activator of apoptosis.
With other evidence, Brodsky claimed that rpr is one transcriptional target of the p This C. In , Tyner and co-workers proposed that p53 plays a role in regulating the aging of organisms. It act as wild-type p53 and has enhanced resistance to spontaneous tumors better than wild type p This is a symbol of osteoporosis and osteoporosis is a marker of aging in humans and mice. In , it was found that p53 has the ability to induce apoptosis, while in ; Mihara and other scientists found that p53 also has an apoptosis role in the mitochondria.
After that the caspase recruitment domain CARD of Apaf-1 exposed in the apoptosome, recruit procaspase-9, and then autoactivate themselves. The final complex then cleaves and activates other caspases such as caspase-3 which in turn subsequently cleave important molecules in the cell, causing chromatin condensation, DNA fragmentation and finally leading to apoptosis.
Figure 2 The cytochrome c-induced caspase activation pathway. Mihara M et al. In the experiment, they found that some stress-induced wild-type p53 protein has the ability to translocate to the mitochondria of thymocytes in human or mouse cells after apoptosis due to DNA damage and hypoxia.
Then these wild-type p53 proteins induce permeabilization of mitochondria and cause a series of changes that occur in mitochondria like releasing cytochrome c by forming complex with Bcl2 and BclXL. As a good clinical result with little side effect, gene therapy is popular. By the end of , there were gene therapy trials in the database of Journal of Gene Medicine.
In April , a recombinant human adenovirus-p53 injection Gendicine was launched formally. Gendicine is used to treat head and neck squamous cell carcinoma and it was approved by the State Food and Drug Administration of China on Oct. It became the first gene therapy product in the world to be approved by the Chinese government. The gene p53 was discovered to regulate metabolism in In order to transfer from G1 to S phase, cells must have sufficient raw materials support for DNA, organelles and protein synthesis.
To regulate this process, some checkpoints are necessary. When glucose is exhausted, AMPK can phosphorylate protein p53, which in turn induces cell arrest, and avoids cell death. Cells which encounter the pdependent arrest will reenter the cell cycle when glucose is sufficient. It is known that inactivation of p53 is necessary for the formation of tumors. Bykov et al. VJ and Snydel EL et al. They restored the function of endogenous p53 in primary autochthonous tumors to examine the consequence of p53 reactivation.
The result showed that p53 reactivation was responsible for regression of autochthonous tumors. That means inactivated p53 protein can lead to tumor development. In the experiment, doxycycline Dox is used to reactivate p53 , as the expression of p53 is totally suppressed when Dox is missing and rapidly restored when Dox is added. When treated with Dox, p53 miRNA was shut off which in turn causes increased expression of p The result showed that the tumors in Dox-treated mice become undetectable after 12 days, while tumors in untreated mice grew rapidly.
To test the consequence of transient reactivation of p53 , they treated mice with Dox for 4 days and then stopped. The result showed that even a two-day treatment can cause regression of tumors and 4 days of treatment can cause the tumors to completely regress.
They also pointed out that during tumor regression, transiently-reactivated p53 can trigger cellular senescence, not apoptosis. The LIF is a secreted cytokine and is important for blastocyst implantation. The gene coding LIF is identified as the p53 target gene and the p53 binding site is located in intron 1 in both humans and mice. The protein p53 is encoded by the TP53 gene in humans. TP53 spans about 20 kb and is located on the p arm of the chromosome 17 17p Figure 3 shows the location of the p53 gene family p53, p63, p73 and other regulator genes in human chromosome Then, using in situ hybridization, they confirmed that p53 was located on the most distal band of the short arm of chromosome Figure 4 shows that the gene TP53 contains 11 exons in which the first one is a non-coding exon and is kb away from exon 2.
Figure 4 shows the structure of the human p53 gene. Figure 3 Location of gene TP Transcription of the p53 gene can be initiated from two different sites: P1 and P1' is located at the upstream of exon 1, and P2 is located in intron 4.
The transcript from P2 will synthesize a protein lacking an N-terminal. Therefore, the human p53 gene can encode at least nine different p53 proteins and fifteen different mRNA due to alternative splicing locations and alternative promoters. They have similar DNA binding domain with gene p53 , and thus share the same properties that can cause apoptosis and cell cycle arrest. However, transgenic knockout mice that contain one of the p53, p63 and p73 exhibit distinct phenotypes, indicating that each of them contain specific functions.
Figure 5 shows the human p63 and p73 gene structures. In the gene p63 , P1 and P2 are alternative promoters. In the gene p73, P1 and P2 are alternative promoters. Figure 4 Human p53 gene Structure. Figure 5 The schema of human p53 gene and p73 gene structure. Most diseases are related to incorrect expression of the gene p53 and the dysfunction of the p53 protein.
The protein p53 contains three domains. Figure 6 shows the structure of the human protein p53 and its domains. NTD consists of the acidic N-terminus transcription activation region and a proline-rich region.
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