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. 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.
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Adolescents and Young Adults with Cancer. Emotional Support for Young People with Cancer. Cancers by Body Location. Late Effects of Childhood Cancer Treatment. Pediatric Supportive Care. Rare Cancers of Childhood Treatment. Childhood Cancer Genomics. In an undamaged cell, p53 is complexed with Mdm2 and targeted for ubiquitin-dependent proteolysis.
DNA damage induces phosphorylation of p53 at serine and serine, displacing Mdm2. In addition to revealing the transactivation domain of p53, displacement of Mdm2 results in p53 no longer being efficiently targeted for degradation, leading to an increase in the levels of cellular p Activated p53 is then capable of inducing the transcription of genes that lead to cell cycle arrest, apoptosis, or enhanced DNA repair.
As mentioned above, one mechanism to rapidly and effectively regulate p53 in response to DNA damage is by post-translational modification. Although recent advances have been made in our understanding of the post-translational modifications that occur to p53 in vivo , much of the initial studies of how p53 is covalently modified and regulated came from studies in vitro.
These studies have lead to the discovery of two major mechanisms of p53 modification, namely phosphorylation and acetylation.
Phosphorylation of p53 in response to DNA damage is one mechanism by which its activity may be modulated. This assumption is supported by the observations that incubation of cell lines expressing p53 with the phosphatase inhibitor okadaic acid results in an increase in p53 phosphorylation state and increased levels of p53 protein Zhang et al.
Indeed, p53 has been shown to be phosphorylated in vitro on both the N-terminal and C-terminal regulatory domains by a number of different kinases, including cyclin dependent kinases Cdks at serine Bischoff et al.
In support of some of these phosphorylation events being involved in regulating p53 activity, phosphorylation of the p53 C-terminal regulatory domain by CKII, PKC or Cdks has been shown to activate p53 sequence-specific DNA binding in vitro Hupp et al. Furthermore, phosphorylation of serine of p53 has been shown to inhibit the interaction of p53 with Mdm2 in vitro Shieh et al. In light of the above, an attractive hypothesis is that phosphorylation of p53 at multiple sites in vivo regulates p53 function in several ways.
Thus, phosphorylation at N-terminal sites could inhibit interactions with Mdm2, leading to elevated p53 levels and elevated p53 transcriptional activity, whereas phosphorylation at C-terminal sites could trigger the sequence-specific DNA binding potential of the protein.
Such models have been tested extensively by a number of different laboratories through expressing recombinant p53 derivatives containing mutations in specific phosphorylation sites and then ascertaining the activity of the resulting proteins.
However, several other reports have illustrated that mutation of specific phosphorylation sites in p53 results in no abrogation of either p53 functional activity or up-regulation of p53 levels in response to DNA damage for example Slingerland et al. One interpretation of these data is that multiple, functionally overlapping, phosphorylation events control p53 activity. However, one recent report revealed that mutation of all known phosphorylation sites in the N-terminus and C-terminus of p53 has no dramatic effect on the ability of mutant p53 to activate transcription of receptor genes nor on its ability to be stabilized in response to DNA damage Ashcroft et al.
Although the above data provide a confused picture of the relevance of phosphorylation regulating p53 activity, certain caveats have to be introduced into the interpretation of the results.
For example, variability in these experiments could be due to cell-type differences and the fact that, in many experiments, mutant p53 is being over expressed in cell lines.
Moreover, it is possible that further regulatory phosphorylation sites that regulate p53 activity in vivo have yet to be identified. Thus, although phosphorylation of p53 is likely to play an essential role in regulating its activity, more extensive and subtle studies are required to elucidate the precise molecular mechanisms by which this may be achieved.
Acetylation of lysine residues present in histones has long been implicated in the regulation of transcription. The mechanism by which this regulation occurs is now beginning to be elucidated. Furthermore, and consistent with the fact that these acetylation events occur within the C-terminal region of p53 implicated in regulating its DNA binding potential, acetylation of these residues has been found to activate p53 sequence-specific DNA binding.
This may therefore explain, in part, how acetylation activates p53 transcriptional activity Gu and Roeder, ; Sakaguchi, ; Liu et al. The possibility exists, therefore, that activation of p53 by increasing its ability to bind to and activate promoters is regulated by a combination of phosphorylation and acetylation events.
As described above, it is evident from in vitro studies that p53 is capable of undergoing a number of covalent post-translational modifications. However, whether these modifications have direct relevance in vivo remains controversial. Although post-translational modification of p53 has been known for many years, it is only relatively recently that the effects of DNA damage on these has begun to be clearly defined.
Initially, sites on p53 phosphorylated in response to DNA damage were identified by phospho-peptide mapping. For example, using this approach Milne et al. However, although these types of experiments have proved informative, certain caveats must be maintained with this approach.
For example, labelling cellular proteins using radioactive phosphate will itself cause DNA damage and activate pathways that signal to p One major tool that has overcome some of these problems is the development of phospho- or acetylation-specific antibodies that can detect modifications at specific p53 residues. Indeed, studies using these reagents have implied that a number of the modifications of p53 that have been identified in vitro are used to regulate p53 activity in vivo see Figure 2.
Post-translational modifications of p53 in vivo. Serine residues 15, 20, 33, 37 and are phosphorylated in response to DNA damage. Furthermore, serine is dephosphorylated in response to IR. In addition, p53 is acetylated at lysine residues , and after DNA damage. Kinases and HATs that have been reported to modify these sites in vitro are illustrated.
One of the first demonstrations that p53 is phosphorylated in vivo was provided by Wang and Eckhart who, by a phospho-peptide mapping approach, demonstrated that cellular mouse p53 is phosphorylated at serine residues 7, 9, 18 and Using a similar approach, Siliciano et al. Subsequently, by using phospho-specific antibodies, serine was identified as a site on p53 phosphorylated in response to DNA damage induced by UV or IR Siliciano et al, ; Shieh et al.
These data, taken together with in vitro experiments addressing the importance of serine phosphorylation in regard to modulating the interaction between p53 and Mdm2 see above , provide an attractive model as to how p53 half-life and transcriptional activity may be increased in response to DNA damage.
In this model, p53 is targeted for ubiquitin-mediated degradation in the undamaged cell by interacting with Mdm2. Upon DNA damage, however, p53 becomes phosphorylated on serine in vivo and no longer interacts with Mdm2 effectively Siliciano et al. The half-life of p53 is therefore prolonged due to the fact that it is no longer degraded in a Mdm2-dependent fashion. In support of this model, it was recently shown that substitution of serine with glutamic acid a residue that sometimes mimics serine phosphorylation , results in a slight stabilization of p53 in vivo Ashcroft et al.
Finally, phosphorylation of the p53 N-terminal region could trigger modifications elsewhere in the protein, including acetylation in the C-terminal domain that activates sequence-specific DNA binding Sakaguchi et al. In addition to the above studies, two recent reports have illustrated that other phosphorylation events at the N-terminus of p53 can also affect the interaction of p53 with Mdm2.
Thus, Shieh et al. These observations are particularly interesting given that serine resides in the region of p53 that binds to Mdm2 Picksley et al. Consistent with this, Unger et al. Thus, is would appear that DNA damage induced phosphorylation of p53 at serine also contributes to the regulation of p53 via its interaction with Mdm2.
It is clear from these studies that a number of different, possibly overlapping, modifications of the N-terminus of p53 can regulate the interaction of Mdm2 with p53 and that further experiments are required to establish the precise mechanisms by which these modifications impinge on the regulation of p53 by Mdm2. Further studies using phospho-specific antibodies have indicated that DNA damage also influences phosphorylation events at other sites on the p53 polypeptide.
Thus, both serine and, to a lesser extent, serine have been shown to be phosphorylated in response to DNA damage Sakaguchi et al. Nevertheless, the role of CAK in the regulation of p53 in vivo , and specifically the idea that CAK may provide a mechanism to couple p53 phosphorylation with DNA damage, remain to be demonstrated. Recent work has suggested that overlapping but distinct mechanisms of p53 regulation are invoked by different forms of DNA damage.
This phosphorylation event is of particular interest, because phosphorylation of this site in vitro activates sequence-specific DNA binding of p Consistent with this, Kapoor and Lozano have reported data consistent with a model in which p53 DNA binding is activated in response to UV. However, these particular experiments do not rule out the possibility that this activation could be performed by phosphorylation of p53 at other sites apart from, or in addition to, serine In addition to phosphorylation of p53 occurring in response to DNA damage, Waterman et al.
These studies revealed that, in response to IR, p53 is dephosphorylated on serine, a residue lying in the C-terminal regulatory region of p Interestingly, dephosphorylation of serine induces the interaction of p53 with proteins that, in turn, activate its DNA binding potential.
These studies have lead to the proposition that dephosphorylation is a key regulatory mechanism for p53 in response to DNA damage.
Recently, by the use of acetylation-specific antibodies raised against these acetylation sites, Sakaguchi et al. Furthermore, a similar study by Liu et al. Additional experiments, however, are required to establish the physiological functions of these modifications in regulating p53 activity in vivo. In particular, it will be of interest to determine whether mutations of the various acetylation sites influences the ability of p53 to be modulated in response to DNA damage.
Identifying the specific residues modified in vivo on p53 in response to DNA damage has allowed a greater understanding of the molecules that may signal to p53 in vivo. In contrast, under genomic stress P53 can activate AMPK via sestrin 1 and sestrin 2, leading to inhibition of mTOR and thus arrest of cell growth and proliferation [ ].
P53 also regulates amino acid metabolism via transcriptional regulation of GLS2. Overall, many of the P53 related metabolic functions rest on the capability of the cells to handle metabolic stress and survive the stress. Various mouse models have shown that restoration of wild-type P53 function in cancer cells results in the induction of tumour cell death and tumour eradication. Thus, P53 reactivation can be a crucial strategy to fight cancer, and various small molecules identified to rescue and reactivate missense-mutant P53 protein as well as by induction of mutant P53 degradation Fig.
These small molecules bind and stabilize mutant P53, but the accurate and precise mechanism of the refolding of mutant-P53 is not entirely clear. Strategies to target mutant P53 in cancer cells [ ]. In Table 1 , we have provided an overview of small molecules that directly target mutant P53 via reactivation of its tumour-suppressive transcriptional activity.
Another method to target oncogenic mutant P53 is via compounds that particularly deplete mutant P53 with minimal effect on wild-type P In Table 2 , we have provided an overview of small molecules that directly target and degrade mutant P Currently, there are more than a dozen of HSP90 inhibitors under preclinical and clinical studies.
Blagosklonny et al. Ubiquitination and degradation of P53 is induced by MDM2, which acts as a unique E3 ubiquitin ligase protein. Small molecules that block the MDM2-P53 interaction and reactivate the P53 function seem to be a promising strategy for cancer treatment retaining wild-type P Many of these small molecules have also entered clinical trials. The autoregulatory feedback loop of MDM2 and P53 controlling their cytological levels [ ]. P53 influences the onset of various lifestyle-related diseases like type 2 diabetes and obesity by altering the regulation of metabolism at the individual level [ 26 ].
Proper regulation of the MDM2-P53 axis is essential to prevent tumorigenesis and various metabolic diseases. Increased P53 levels resulted in increased sensitivity of neurons to various stressors and underwent apoptotic death [ ]. This increased levels, and activity of P53 was associated with neuronal death and enhanced inflammatory cytokine levels [ ].
A similar phenomenon observed in AD and PD that increased P53 levels was associated with DNA damage, activated cellular stress response, and apoptosis [ ]. An important observation was that the deletion of P53 from other renal tubules segments was ineffective [ ]. The above studies altogether suggest a pathological role of renal tubular cell P53 in IRI.
Various studies indicate that P53 plays a protective role against various systemic autoimmune diseases by inhibiting the production of cytokine and reducing the number of pathogenic cells. Conversely, Macchioni et al. Also, Chen et al. The precise mechanisms of how P53 protects against the development of autoimmune diseases remains unclear.
In this review, we have attempted to present a comprehensive overview of some of the P53 functions by discussing the various mechanism of P53, focusing on Pmediated DNA damage response, and P53 role in different cellular processes like DNA repair mechanism, apoptosis, autophagy, and metabolism. We have also put some light on various Preactivation strategies that hold great importance in cancer therapy in the future as many small molecules are under investigation.
We have also discussed how P53 levels change in various diseases. In addition to its function as guardian of the genome under various cellular stress, numerous studies suggest that P53 is allied with many other physiological processes and also different pathological processes.
Following several decades of research, the complete role of P53 remains unclear. Owing to a vast and variety of P53 regulatory mechanisms and their collaboration in triggering specific responses remains an open area for research.
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