Specifically, it is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.
Compared with breast cancers without TP53 gene mutations, tumors with these genetic changes tend to have a poorer prognosis: They are more likely to be aggressive, to be resistant to treatment with certain anti-cancer drugs and radiation, and to come back recur after treatment. Somatic TP53 gene mutations have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.
Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer NMIBC and muscle-invasive bladder cancer MIBC , based on where in the bladder the tumor is located. Most of these mutations change single amino acids in p This altered p53 protein cannot regulate cell growth and division and is unable to trigger apoptosis in cells with mutated or damaged DNA.
If such cells continue to divide in an uncontrolled way, they can lead to the formation of bladder cancer. This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. Without functioning p53, cell proliferation is not regulated. As a result, cells accumulate DNA damage and continue to divide in an uncontrolled way, leading to tumor growth.
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. This condition greatly increases the risk of developing several types of cancer, including breast cancer; bone cancer; and cancers of soft tissues such as muscle called soft tissue sarcomas, particularly in children and young adults.
At least different mutations in the TP53 gene have been identified in individuals with Li-Fraumeni syndrome. Many of the mutations associated with Li-Fraumeni syndrome change single amino acids in the part of the p53 protein that binds to DNA. Other mutations delete small amounts of DNA from the gene. These mutations result in an altered p53 protein that cannot regulate cell proliferation effectively and is unable to trigger apoptosis in cells with mutated or damaged DNA.
Such cells may continue to divide in an uncontrolled way, leading to the growth of tumors. Somatic mutations in the TP53 gene have been found in nearly half of all lung cancers. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Signs and symptoms may not occur in early stages of the disease. Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope.
Small cell lung cancers nearly always have TP53 gene mutations; however, these mutations may also occur in non-small cell lung cancer.
TP53 gene mutations change single amino acids in p53, which impair the protein's function. 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.
Model depicting the mechanism by which activated p53 induces apoptosis through the BCLregulated pathway. Fat arrows indicate pinduced targets that are essential for pinduced apoptosis. Thin arrows indicate pinduced targets that are constituents of the BCLregulated apoptotic pathway but are still expressed at levels sufficient for apoptosis induction in the complete absence of p53; that is, their induction by p53 may make the pathway work more efficiently, but this induction is not a sine qua non for pinduced apoptosis, at least in haematopoietic cells.
The broken arrow indicates that p53 may also activate BIM expression indirectly. The possible scenario that activation of targets that are not constituents of the apoptosis machinery per se can impact on apoptosis indirectly is also depicted. Studies using cell lines with enforced expression of WT p53 or temperature-sensitive p53 revealed that overexpression of anti-apoptotic BCL-2 could prevent pinduced apoptosis. Thus, p53 must induce cell cycle arrest and apoptosis through distinct pathways, and BCL-2 or other pro-survival BCL-2 family members inhibit pinduced apoptosis at a downstream point in apoptosis signalling Figure 2.
The caveat with the aforementioned experiments is that the levels of p53 used to induce apoptosis were abnormally high. Hence, it was not yet proven that p53 could induce apoptosis under physiological conditions, that is, when expressed at normal levels. The demonstration that pinduced apoptosis can be blocked by BCL-2 overexpression launched the hunt to identify the pactivated initiators of the cell death pathway that is regulated by BCL Many candidates were identified by searching for genes that were upregulated in response to overexpression of p53 at highly nonphysiological levels.
Perhaps predictably, most of these candidates have still not been proven to have roles in apoptosis. However, evidence for direct activation of Bim transcription by p53 has also been reported. It is also noteworthy that two additional constituents of the BCLregulated apoptotic pathway, the pro-apoptotic effector BAX and APAF-1 the scaffold protein for caspase-9 activation have been convincingly shown to be transcriptionally regulated by p This may relate to the observation that the levels of BAX, APAF-1 and other constituents of the apoptosis machinery are much lower in many tissues e.
This may account for the reduced sensitivity to apoptotic stimuli of cells from these tissues in adults compared with newborns. For many years p53 was thought to have no relatives, but then within a short time frame, two closely related proteins, called p63 81 and p73, 82 were discovered. P63 and p73 share similarity with p53 in their DNA-binding and transactivation domains and it is therefore widely assumed that many recognised p53 target genes, and hence the cellular processes they control, can also be regulated by p63 and p Even very low dose 0.
This cell death is completely prevented by loss of p63, but loss of p53 has no protective effect. Of note, the nematode C. Importantly, p53 can also regulate the expression of components of the extrinsic apoptotic pathway. In striking contrast, complete loss of the death receptor apoptotic pathway e. This would allow for paracrine killing by cytotoxic T cells or NK cells and such a process may contribute to the effectiveness of cancer therapy in certain cancers.
To further add to the complexity of pmediated control of apoptosis, p53 also drives the expression of several genes whose functions do not lie within the two apoptotic pathways per se but may modulate the cellular response to cell death-inducing insults. For example, p53 drives expression of a number of microRNA species, including miR, 94 that is known to target the pro-survival Bcl-2 gene. Another well-characterised transcriptional target of TP53 is Zmat3 96 that has a poorly defined function but has been shown to impact on the response of cells to apoptotic stimuli.
This may well be pertinent to tumour development and cancer therapy. Although the role of p53 and p63 in the induction of apoptosis is widely accepted, there are also reports that p53 can regulate additional non-apoptotic cell death pathways. For example, p53 was reported to open the mitochondrial permeability transition pore to thereby induce necrotic cell death.
For example, p53 activation by nutlin-3a results in apoptosis in some cells but cell cycle arrest and senescence in others both malignant and nontransformed. For example, cells within the gastrointestinal tract and the haematopoietic system 54 , 55 , 91 are particularly vulnerable to pinduced apoptosis that underlies their prominent involvement in toxicity associated with DNA damage-inducing chemotherapy.
We can speculate on factors that may differentiate the p53 response: post-translational modifications on the p53 protein e. These are all fascinating possibilities that require much further investigation. The finding that p53 can induce apoptosis led to the widely accepted assumption that out of all the cellular effector processes activated by p53 Figure 3 this is the most critical, possibly even the sole, process by which p53 suppresses tumour development reviewed in Vousden and Lane 9.
This made sense: after all, if cells during the early stages of neoplastic transformation are killed through pinduced apoptosis, no fully transformed malignant cells will emerge from this clone. However, matters are not that simple. The CDK inhibitor p21 is essential for cell cycle arrest and also a major contributor to cellular senescence. Moreover, combined loss of PUMA and p21 or mutations in the two transactivation domains of p53 that are critical for the transcriptional induction of Puma , Noxa and p21 accelerate c-MYC-driven lymphoma development and mutant RAS-driven lung cancer development to a much lesser extent than loss of p53 Figure 4.
The relative importance of the induction of apoptosis to overall TPmediated tumour suppression is likely to vary depending on the type of cell undergoing neoplastic transformation and the nature of the oncogenic lesions that drive tumorigenesis.
P53 activates a multitude of cellular effector processes. Model showing a selected cellular effector processes that can be activated by p Some, but not all, of the p53 target genes that are critical for the execution of these processes are indicated.
The challenge remains to understand of which of these processes are critical for tumour suppression in which setting; that is, cell of origin undergoing neoplastic transformation and nature of the oncogenic lesions driving their transformation.
Impact of pinduced apoptosis on tumour development. Important insight into the mechanisms that are critical for TPmediated tumour suppression also came from experiments using an elegant genetically engineered mouse model in which p53 activity can be turned on or off at will. Instead, p53 function was required during the later recovery phase. The very rapid proliferation of progenitor cells bearing oncogenic lesions, which is likely to also be the basis of the development of many other cancers, may facilitate the acquisition of mutations in oncogenes or suppressor genes that further drive neoplastic transformation.
Some initially paradoxical findings are consistent with this. The p53 is unusual among tumour suppressors. In tumours that are driven by mutations in the tumour suppressors PTEN or RB, the expression of these proteins is usually lost completely because of the nature of the mutations selected for during tumorigenesis reviewed in Knudsen and Knudsen and Yin and Shen In contrast, many tumours that are driven by mutations in TP53 express high levels of the mutant p53 protein and show a loss of the other allele of TP53 reviewed in Vousden and Lane 9 and Freed-Pastor and Prives In fact, the high-level mutant p53 protein expression can be used as a diagnostic marker for cancers driven by mutations in the TP53 gene reviewed in Liu and Gelmann The highly expressed mutant p53 protein can promote tumorigenesis in three ways: 1 loss of the WT p53 activity, 2 DNEs over the WT p53 protein early in transformation before loss of the WT TP53 allele, through the formation of mixed tetramers containing both wild-type and mutant p53 proteins and 3 de novo GOFs that are mediated through interactions of mutant p53 protein with other transcription factors and tumour suppressors e.
As early in transformation, mutant p53 levels are often variable and low, it appears likely that the GOF effects may only come into play at a late stage of transformation. It is obvious how loss of the WT p53 function contributes to the tumour promoting action of mutant p53 but the mechanisms by which the DNE and GOF effects of mutant p53 drive tumour development are not established.
A detailed understanding of the role of these processes in the development as well as the sustained growth of tumours is anticipated to identify targetable vulnerabilities for the development of novel cancer therapies. Impact of mutant p53 proteins on tumour development. Model depicting the mechanisms by which mutant p53 proteins, which are frequently highly overexpressed compared with the wild-type p53 protein , on tumour development.
In conclusion, TP53 is arguably one of the most important if not the most important genes in human cancer. It appears that p53 is critical for tumour suppression not during the acute response to cellular stress, such as DNA damage e. The p53 transcription factor activates several effector processes, apoptotic cell death being one of them. Thus, additional cellular processes, either by themselves or in a manner overlapping with the aforementioned mechanisms, must account for the potent tumour suppressive action of p Identifying these signalling pathways and how they are integrated will provide exciting research opportunities for several years.
A better understanding of pmediated apoptosis and pmediated tumour suppression more generally holds promise for various potential clinical applications. These include improving the efficacy of anticancer therapies that rely on p53 activation, reducing the toxicities associated with chemotherapy and radiotherapy and improving haematopoietic stem cell transplant conditioning regimens and perhaps also in nonmalignant settings where abnormal induction of cell death pathways that may in part be driven by p53 contributes to tissue damage, such as myocardial infarction and cerebral ischaemia.
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Apoptosis is the "last resort" to avoid proliferation of cells containing abnormal DNA. The cellular concentration of p53 must be tightly regulated. While it can suppress tumors, high level of p53 may accelerate the aging process by excessive apoptosis. The major regulator of p53 is Mdm2 , which can trigger the degradation of p53 by the ubiquitin system. Some important examples are listed below.
As mentioned above, p53 is mainly regulated by Mdm2. The regulation mechanism is illustrated in the following figure. Figure 1. Regulation of p In normal cells, these three residues are not phosphorylated, and p53 is maintained at low level by Mdm2.
The roles of p53 in growth arrest and apoptosis are illustrated in Figure 4-H One of its transcriptional target gene, p53R2, encodes ribonucleotide reductase, which is important for both DNA replication and repair. Figure 2. The roles of p53 in growth arrest and apoptosis. The latter can then stimulate the release of cytochrome c from mitochondria see Mitochondria, Apoptosis and Aging.
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".
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