Helicobacter pylori, a bacterial pathogen that commonly infects the human stomach and is strongly linked to gastric cancer. Besides H. pylori, a number of other bacterial species were recently discovered to inhibit p53. These findings provide novel insights into host–bacteria interactions and tumorigenesis associated with bacterial infections.p53 tumor suppressor has been identified as a protein interacting with the large T antigen produced by simian vacuolating virus 40 (SV40). Subsequent research on p53 inhibition by SV40 and other tumor viruses has not only helped to gain a better understanding of viral biology, but also shaped our knowledge of human tumorigenesis. Recent studies have found, however, that inhibition of p53 is not strictly in the realm of viruses. Some bacterial pathogens also actively inhibit p53 protein and induce its degradation, resulting in alteration of cellular stress responses. This phenomenon was initially characterized in gastric epithelial cells infected with  Helicobacter pylori infection, which is currently the strongest known risk factor for adenocarcinoma of the stomach. This phenomenon, however, is not limited to H. pylori, and many other bacterial pathogens inhibit p53 using various mechanisms. Inhibition of p53 by bacteria is linked to bacterial modulation of the host cellular responses to DNA damage, metabolic stress, and, potentially, other stressors. This is a dynamic area of research that will continue to evolve and make important contributions to a better understanding of host–microbe interactions and tumorigenesis. These studies may offer new molecular targets and opportunities for drug development.This review focuses on a novel aspect of host–bacteria interactions: the direct interplay between bacterial pathogens and tumor suppression mechanisms that protect the host from cancer development. Recent studies revealed that various pathogenic bacteria actively inhibit the major tumor suppression pathway mediated by p53 protein that plays a key role in the regulation of multiple cellular stress responses and prevention of cancerogenesis. Bacterial degradation of p53 was first discovered in the context of  This interest originates from the protein’s prominent role in tumor suppression that was eloquently paraphrased in the scientific literature as “the guardian of the genome” . p53 is tp53) the most mutated gene in human tumors. p53 can also be inhibited by mutation-independent mechanisms. Inhibition of wild-type p53 by the SV40 virus was one of the first reported examples. SV40 is a small DNA tumor polyomavirus that induces cellular transformation in cell culture and an array of different tumors in animals. In infected cells, viral protein (SV40 large T antigen [T-Ag]) binds p53 and inhibits p53-dependent transcription, resulting in accumulation of inactivated p53 protein [Inactivation of p53 is a hallmark of tumorigenic changes. More than half of all tumors carry p53 mutations, rendering the p53 gene  has classified this bacterium as a Group 1 carcinogen. H. pylori infection is considered to be the strongest known risk factor for gastric cancer, and epidemiological studies have estimated that, in the absence of H. pylori, 75% of gastric cancers would not occur [Recent studies have found that it is not only viruses, but also some pathogenic bacteria, that actively inhibit p53 and induce its degradation. This phenomenon was initially described in gastric cells co-cultured with r pylori . H. pyloot occur .H. pylori infection is determined by interactions between bacterial factors and host cells. The most well characterized bacterial virulence determinants are the vacuolating cytotoxin A (vacA) and the cag pathogenicity island (cag PAI). The cag PAI is a 40 kb region of DNA that encodes a type IV secretion system (T4SS) that forms a syringe-like pilus structure used for the injection of a bacterial protein CagA (cytotoxin-associated gene A) into gastric cells. Following the delivery, intracellular CagA is localized to the plasma membrane and triggers complex alterations of the host signaling pathways [Pathogenesis associated with pathways , includipathways ,24. Oncopathways ,26.H. pylori infection results in conditions of cellular stress because the bacteria induce DNA damage and disturb normal cellular homeostasis (including aberrant activation of multiple oncogenic pathways), all of which are conditions that typically activate p53 [H. pylori is able to dampen activity of p53 protein by inducing its rapid degradation [H. pylori to suppress the p53 response was also demonstrated when DNA damage was experimentally induced by DNA-damaging agents [H. pylori but rather induced [H. pylori strains, with CagA-positive bacteria being more potent [vate p53 ,28. Howeradation . The abig agents ,29,30. T induced . The abie potent ,29. Althe potent ,30. Recee potent . Among oe potent –35. DownH. pylori infection, expression of p53 was changed in a bimodal fashion, with an accumulation after initial infection that was followed by a rapid down-regulation of p53 protein in gastric epithelial cells. A second peak of p53 was observed later, when gastritis (inflammation of the lining of the stomach) developed. These findings led to a hypothesis that, at a certain time, levels of p53 reflect a balance between p53 degradation induced by the bacteria and p53 induction caused by cellular stress [H. pylori-infected mice [The kinetics of p53 in infected cells in vivo appears to be complex. In infected Mongolian gerbils, which are commonly used for studies of r stress . A down-ted mice .H. pylori takes advantage of host mechanisms normally regulating p53 [H. pylori in vitro and H. pylori-infected animals and humans in vivo [H. pylori [H. pylori-infected cells [In contrast to small DNA tumor viruses, ting p53 ,35. The  in vivo ,35,37. I in vivo ,35,38. Aed cells . It remaH. pylori efficiently degrades p53 [H. pylori, may be particularly vulnerable to degradation of p53 [p14ARF tumor suppressor (termed p19ARF in rodents and p14ARF in humans), which functions upstream of p53, was found to be a critical modulator of p53 protein stability in infected cells , as ARF ades p53 . Loss ofades p53 . Given tn of p53 .H. pylori-infected cells [Among other cellular factors, ASPP2 protein (apoptosis-stimulating protein of p53), which normally activates p53, was identified to regulate p53 in ed cells . Buti etH. pylori varied greatly in their ability to degrade p53, but that, generally, isolates associated with a higher gastric cancer risk more strongly affect p53 when compared to low-risk counterparts [Recent studies suggest that bacterial degradation of p53 may contribute to gastric tumorigenesis. It was reported that clinical isolates of terparts .H. pylori inhibits p53 through multiple mechanisms, implying that inhibition of p53 activity is an important factor for successful infection. The bacteria not only induce degradation of p53, but also alter the expression profile of p53 isoforms [H. pylori with gastric epithelial cells, mediated via the cag PAI, induces N-terminally truncated Δ133p53 and Δ160p53 isoforms, which inhibit transcriptional and proapoptotic activities of p53, resulting in activation of NFkB. Induction of proinflammatory cytokine Macrophage Migration Inhibitory Factor (MIF) by H. pylori was suggested to inhibit p53 by decreasing its phosphorylation [H. pylori can facilitate mutagenesis of the p53 gene. Infection with H. pylori leads to aberrant induction of activation-induced cytidine deaminase (AID), which deaminates cytosine residues, leading to accumulation of p53 mutations in gastric tissues [isoforms . Interacrylation . It was  tissues . Interes tissues –48. SV40 tissues ,50.H. pylori  and blinding trachoma. Similar to H. pylori, C. trachomatis activates the PI3K/Akt pathway and increases phosphorylation of HDM2 (Ser166), leading to activation of HDM2 and proteasomal degradation of p53. Down-regulation of p53 allows Chlamydia to enhance activity of the PPP that provides bacteria with necessary metabolites, such as nucleotides precursors, and protects against oxidative stress by increasing the cellular NADPH pool [Chlamydia interferes with the host’s response to genotoxic stress and may contribute to cancerogenesis in the female genital tract [A new and exciting development in this area is that other bacteria induce degradation of p53 using a similar mechanism to that of . pylori . Two res protein ,52. C. tal tract ,52.Shigella flexneri, which causes bacillary dysentery in humans. Infection with Shigella is accompanied by strong genotoxic stress and cellular damage [Shigella causes rapid degradation of p53 using two distinct mechanisms. During the early phase of infection, the bacterial virulence effector IpgD promotes activation of the host PI3K/Akt pathway and phosphorylation of HDM2 at serines 166 and 186, causing activation of HDM2 and degradation of p53. The second mechanism for p53 inhibition comes into play during the late phase of infection. p53 is proteolytically cleaved by the calpain protease system, in which activation is facilitated by the Shigella virulence effector VirA. The VirA activates calpain by promoting proteolysis of the calpain inhibitor calpastatin. Bergounioux et al. suggested that Shigella inhibits p53 to prevent apoptotic cells death that saves energy and preserves its own epithelial niche [Salmonella typhimurium infection [Enterobacteriaceae family, down-regulation of p53 protein was reported in studies of Neisseria gonorrhoeae, which is responsible for the sexually transmitted gonorrhea that may increase the risk of genital neoplasms [N. gonorrhoeae causes strong genotoxic stress and induces both single and double strand DNA breaks. The mechanism of p53 down-regulation is not fully understood, but Vielfort et al. reported that the bacteria can inhibit transcription of the p53 gene [Inhibition of p53 through the HDM2-dependent mechanism is also employed by enteropathogen nfection . Outsideeoplasms . Similarp53 gene .H. pylori, expression of the CagA virulence factor is sufficient to inhibit p53 and extend short and long term survival of gastric epithelial cells that underwent DNA damage [Chlamydia. As described above, degradation of p53 allows C. trachomatis to release inhibition of the PPP elicited by p53. When bacterial degradation of p53 was experimentally inhibited, the development and formation of infectious progeny was blocked, suggesting that metabolic control of p53 provides antibacterial protection. It is possible to draw a parallel between Chlamydiae and viruses since both are obligatory intracellular pathogens, which strictly rely on the host resources. Similar to viruses, inhibition of p53 allows Chlamydia to reprogram the host cell signaling to create a metabolic environment necessary for chlamydial survival and growth. To some extent, this may also be applied to obligate parasitic Mycoplasma bacteria, which inhibit activity of p53 [H. pylori. One proposed possibility is that inhibition of p53 helps H. pylori to compromise the gastric epithelial barrier, allowing the bacteria to acquire nutrients from the host or get access to the lamina propria. This concept is supported by recent findings showing that H. pylori inhibits activation of p53 induced by disruption of the adherens junctions, which stabilize cell–cell adhesion [H. pylori adapt during the early phase of infection and prevent the host immune response [Inhibition of p53 may provide certain benefits to bacteria. One particular mechanism that may be targeted by bacteria is the p53 DNA damage response. Inhibition of p53 may allow bacteria to subvert the host cell cycle control and apoptosis mechanisms, resulting in inhibition of cell death and survival of host cells damaged by infection. This is in agreement with the findings of antiapoptotic and prosurvival effects produced by bacterial pathogens, which inhibit p53 ,29,52,53A damage . Besidesy of p53 . A more adhesion . It was response . The p53response . Among ds of the bacterial regulation of p53 hold the promise of a better understanding of pathogenesis and tumorigenesis associated with bacterial infections.Interaction of bacterial pathogens with the host cells induces DNAdamage, alters intracellular signaling, and profoundly affects normal cellular homeostasis. To prevent the cellular stress response, which may be detrimental to a successful infection, some bacteria have evolved to inhibit p53, a key component of the stress response machinery. Bacteria inhibit p53 through multiple mechanisms, including protein degradation, transcriptional inhibition, and post-translational modifications. Current research revealed that p53 has a role in controlling the bacterial infections and that inhibition of p53 may confer certain selective advantages to bacteria. Unfortunately, this may have grave consequences for the hosts, increasing the risk of tumor development. It is particularly relevant to prolonged chronic infections. Initial experiments with inhibition of protein degradation of p53 demonstrate that p53 activities can be restored in infected cells using specific chemical inhibitors. These findings may offer new and exciting opportunities for therapeutic targeting of p53 in infected cells. Future studie


Ictidomys tridecemlineatus during multiple stages of the torpor-arousal cycle. Transcript and protein levels of p53 were both elevated in the skeletal muscle during early and late torpor stages of the hibernation cycle. Nuclear localization of p53 was also increased during late torpor, and this is associated with an increase in its DNA binding activity and expression of p53 transcriptional targets p21CIP, gadd45α, and 14-3-3σ. The increase in p53 transcriptional activity appears to be independent of its phosphorylation at Ser-15, Ser-46, and Ser-392, consistent with an absence of checkpoint kinase activation during torpor. Sequence analysis revealed unique amino acid substitutions in the ground squirrel p53 protein, which may contribute to an increase in protein stability compared to nonhibernators. Overall, the study results provided evidences for a potential role of p53 in the protection of the skeletal muscle during torpor.The transcription factor p53 is located at the centre of multiple pathways relating the cellular response to stress. Commonly known as a tumor suppressor, it is responsible for initiating diverse actions to protect the integrity of the genome, ranging from cell cycle arrest to apoptosis. This study investigated the regulation of p53 protein in hibernating 13-lined ground squirrel Ictidomys tridecemlineatus). I. tridecemlineatus, an inhabitant of the central North American grasslands, typically hibernates from October to April, when seasonal changes that increase metabolic demand are met with a restriction on food supply. Hibernation in I. tridecemlineatus is characterized by cyclic arousal and reentry into a low metabolic state , 2019, 2 of MDM2 . Myotis brandtii bats contains unique amino acid substitutions at the highly conserved single-transmembrane domain, and this is thought to be associated with an altered expression of insulin-associated genes in the bats that is similar to those observed in the long-lived GHR−/− mice [The cellular levels of p53 are typically determined by the rate at which it is degraded through the ubiquitin-mediated pathway, rather by the rate at which it is synthesized . While M−/− mice . Sequenc−/− mice .In this study, we reported the activation of the p53 transcriptional response during the torpor stages in the 13-lined ground squirrels. Increase in p53 activity appeared to be independent of the select posttranslational modifications examined in this study but rather a result of an increased p53 protein expression. We also identified two amino acid substitutions in the ground squirrel p53 protein sequence that were unique compared to other nonhibernating mammals; the K290R and S364P substitutions are of particular interest as these two residues contribute to the ubiquitin mediated degradation of p53 in human. In conclusion, our results show that the activation of p53 transcriptional response is mediated by its upregulation at the transcriptional and translational level, and further experiments will be needed to elucidate the significances of the ground squirrel specific amino acid substitutions, and whether these alterations contribute to changes in p53 stability compared to nonhibernating mammals.


The tumor suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these corrective powers, but counterproductively acquire new capacities that drive cancer. A newly emerging manner in which mutant p53 executes its cancer promoting functions is by harnessing key proteins, which normally partner with its wild type, tumor-inhibiting counterpart. In association with the subverted activities of these protein partners, mutant p53 is empowered to act across multiple fundamental cellular pathways (regulating cell division and metabolism) and corrupt them to become cancer promoting. Reliance on the tumor suppressive capacity of p53 is profoundly emphasized by its near universal malfunction in all cancers. P53 is the most altered gene in cancer. More than 50% of human cancers are afflicted with a p53 mutation. Severe consequences of p53 mutation include the failure to protect against cancer stimuli, compounded by the acquisition of new cancer promoting, “neomorphic” properties, referred to as “Gain of function” (GOF), covered by other reviews in this series [reviewed in Ref. ].A particularly sinister GOF constitutes the subversion by mutant p53, of molecular partners of wild type (wt) p53, and this strategy forms the focus of this review. Specifically, mutant p53 conscripts proteins that normally partner with wt p53. This new association divests them of their anticancer activities and in place, they are corrupted to act as promoters of tumorigenesis . A numbProper cell cycle regulation is vital for normal cell function. Equally critical is the capacity to sense DNA damage and to interrupt the cycle to instigate repair or eliminate cells with irreparable damage, as appropriate. Wt p53 is a key dictator of cellular fate in response to DNA damage resulting from cellular stresses. Partnership with the tumor suppressor promyelocytic leukemia (PML) protein facilitates p53 stress responses. Specifically, wt p53 stabilization and activation in response to stress is promoted by PML, through temporal co-recruitment of post-translational modifiers of p53 , to fSignificantly, mutant p53 enslavement of PML defines a paradigm for mutant p53 disruption of tumor suppressive partners of wt p53. We identified that when p53 is mutated in cancer cells, its association with PML is constitutive, unlike the transient association with its wt p53 counterpart in response to stress. Importantly, PML facilitates mutant p53 to aberrantly transcribe targets in the context of hijacked transcription factor NF-Y . One trAt a higher level, cell cycle control is coordinated by the Circadian clock , and wt At a molecular level, the clock is comprised of at least nine interplaying proteins, and we will discuss only those pertinent to this review. The clock is positively activated in a cyclic fashion through the combined activities of the two transcription factors: CLOCK and BMAL1 Figure . As heteWt p53 controls the clock through negative regulation of Per2 expression Figure . In normPhosphatase and Tensin homolog (PTEN) is also a vital cell cycle regulator that has achieved its reputation as a tumor suppressor in the context of wild type (wt) p53. Pten curbs cell cycle progression and cell survival by suppressing PI3K–AKT/PKB cell survival pathway . PTEN fuIn the context of mutant p53, in a diametrically opposing function, Pten promotes tumor growth . PTEN, iPolo-like kinase-2 (PLK2) is also a wt p53 target that contributes to cell cycle control. PLK2 is transcriptionally induced by wt p53 in response to the stress of DNA damage . PLK2 inRapid cell proliferation inherent in cancer growth is utterly dependent on the ready supply of “molecular building blocks.” Recent studies have identified that fundamental metabolic processes normally regulated by wt p53 are extensively disrupted by mutant p53 to facilitate the supply of these necessities.Proper repair of DNA damage is orchestrated by wt p53, which not only temporally halts cell cycle progression to allow repair, but also actively facilitates the supply of constituents for the repair. Specifically, in response to DNA damage, wt p53 transcriptionally activates the small subunit of the ribonucleotide reductase (RRM2b) in a temporary manner, to facilitate the catalytic conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which is an essential step for DNA synthesis. In contrast, when p53 is mutated, it constitutively upregulates RRM2b expression. Importantly, the mechanism of transcriptional activation of RRM2b is dependent on the status of p53: where wt p53 engages its REs in the intronic region and in contrast mutant p53 localizes to the promoter. Further, it has emerged that mutant p53 transcriptionally drives additional nucleotide metabolic genes, both in the salvage and new synthesis pathways, through co-recruitment with the transcription factor ETS2, to its target gene promoters. ETS2 engagement by mutant p53 is a recurring theme, as we discuss below for epigenetic regulation. Overall, mutant p53 upregulates nucleotide biosynthesis, which contributes to meeting the voracious demands of rapidly proliferating and invading cancers .Regulated glucose metabolism is vital for maintaining healthy, normal cell homeostasis, in contrast to the voracious consumption of glucose that feeds cancer cell proliferation and is inherent in the “Warburg effect.” Proper glucose regulation is then an important tumor suppressive capacity of wt p53. Wt p53 regulates glucose metabolism by restricting cellular glucose at three levels through : (1) supProfoundly, when p53 is mutated, not only are these points of regulating glucose metabolism lost but further glucose uptake is accentuated through a novel GOF. This disastrous mutant p53 GOF is the shunting of the glucose transporter, Glut1, to the cell membrane surface where it stokes glucose uptake by cancer cells . ElevateReliance on a mutant p53-dependent enhanced supply of glucose to foster cell proliferation defines a unique point of vulnerability in cancer cells. This appetite for glucose identifies a potential therapy target which is currently being extensively investigated . SpecifReactive oxygen intermediates perform important cellular functions including signaling; however, they are seriously damaging to normal cells if not properly contained and are linked to cancer [review in Ref ]. A mastA novel GOF of mutant p53 is its capacity to reduce Nrf2 protein levels (without impacting its mRNA), in response to oxidative stress. The consequence is low levels of Nrf2 target detoxifying genes and elevated levels of reactive oxygen species (ROS). Remarkably, in contrast to growth inhibition imposed on wt p53 cells subject to oxidative stress, those with mutant p53 tolerate elevated ROS, survive, and proliferate .When p53 is mutated, a radical shift in transcriptional activity occurs, which is conducive to cancer promotion. An altered repertoire of transcription factor engagement is emerging for mutant p53. While mutant p53 is not able to directly engage wt p53 response elements, it may instead directly bind its wt counterpart and impose a dominant negative effect over wt p53 functions, including depriving it of capacity to regulate transcription. Mutant p53 may also engage transcription factors that wt p53 does not, including the family members p63 and p73 and disrupt their functions. More specifically, the presence of arginine at codon 72 dictates the capacity of mutant p53 to sequester p73, where mutants with proline are incapable of this inactivation , 50.Beyond this negative regulation of wt p53 and its family members, mutant p53 may hijack transcription factor partners and disrupt their normal transcriptional activity (as mentioned above). Mutant p53 has been reported to engage NF-Y, NF-kappa B, SP1, E2F1, ETS1, ETS2, and SREBP. The outcome may be altered target engagement, or a change in the rate of transcription relative to a wt p53 context. These features of mutant p53 have been comprehensively reviewed recently , so we wAt a higher level, mutant p53 disruption of chromatin regulation is also now emerging. In order for wt p53 to access specific DNA responsive elements in the regulatory regions (upstream promoters or introns) of its target genes, it must coordinate with numerous chromatin regulators to expose appropriate regulatory elements and associated DNA to be transcribed . Wt p53 Mutant p53 can also alter transcriptional machinery, through distinct interactions from its wt counterpart. Wt p53 is able to physically interact through its core domain with the RNA polymerase II  and limit target gene expression . In contCorruption of the normal interactions between wt p53 and its molecular partners appears to lie at the heart of significant tumor promoting mutant p53 GOFs. Intriguingly, p53 mutations, which eliminate its function , are rare, in contrast to the frequent activating missense mutations. To an extent, which appears unequaled by any other gene, mutation of p53 confers an exceptionally wide range of fundamental new properties that promote deregulated cell growth. These findings provide new insights directing innovative and rational approaches to therapeutically targeting cancers with mutant p53, which have proven particularly resistant to treatment. The polarized functions of these key p53 partners, would also caution that p53 status be an important criteria to consider prior to adoption of therapies directed toward these targets.SH wrote the paper and prepared the figures. DR contributed to writing the paper and to preparing a figure. YH contributed to discussion and editing the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The management of increased intracranial pressure (ICP) and monitoring of ICP is an important part of neurosurgery, but reference values for ICP have not been established differentiating between children and adults. The same estimated reference of 7-15 is used indiscriminately for children and adults, and does not take in to account that adults and children differ physiologically. The effect on ICP of a postural change from a supine to a upright standing position has been established, though the association between height and ICP in upright position has not been studied. The purpose of this study is to address if ICP values could depend on height.Patients having a shunt were excluded from the study in order to avoid the influence of mechanical siphoning. Forty-one patients undergoing diagnostic ICP monitoring for a suspicion of hydrocephalus or idiopathic intracranial hypertension (IIH) were included in this study. Data were consecutively and prospectively collected. Nine were children (age 7-17) and thirty-two were adults (age 23-85). ICP was measured in parenchyma by either a cable-based or a telemetric probe. Measurements included both a supine and a upright standing position, and changes in ICP were calculated.Mean height was 152.3 cm (range 122-180) for children and 169.4 cm (range 155-188) for adults. Height did not appear to have an impact on measured ICP in either supine (p = 0.15) or upright standing position (p = 0.28). Changing body position from supine to upright caused a significant decrease in ICP in both children  and adults median decrease 12.5 mmHg; p<0.001).In the entire group there was borderline significance between patient height and the calculated postural decrease in ICP occurring when the patient changed from a supine to a upright standing position (p = 0.053). When dividing into children and adults, the change in ICP correlated to height was significant in children (p = 0.022), but not in adults (p = 0.34).We did not establish a direct correlation between ICP and height. However, in children we found a relationship between height and ICP decrease going from supine to upright. A similar correlation was not found in adults. Our results may be important for approaches to physiological risks of overdrainage caused by shunting.


Scientific Reports6: Article number: 19222; 10.1038/srep19222 published online: 01122016; updated: 05132016.The authors of this Article have requested that it is retracted. In the western blotting analysis, the rabbit monoclonal antibody to human mutant p53 rather than wild type p53  was used. While in the immunohistochemistry detection, the mouse monoclonal antibody to both wild-type and mutant forms of human p53  was used. The authors believe that the use of antibodies for both wild type p53 and mutant p53 is not appropriate because it cannot reflect the overexpression status of mutant TP53. The results as described in the manuscript stated that the number of patients with overexpression of mutant p53 was 84/241 (34.9%), using the mouse monoclonal antibody to both wild-type and mutant forms of human p53 . Ninety (37.3%) pancreatic ductal adenocarcinomas (PDACs) showed a virtual absence of p53 immunolabeling compared with the adjacent normal tissues. These patients were also considered to be “abnormal” in p53 immunolabeling. In contrast, the normal immunolabeling of p53 was detected in 67 (27.8%) of the 241 PDACs. However, the authors later found that the number of patients with overexpression of mutant p53 was actually 113/241 (46.9%) in these same specimens when using the specific anti-mutant p53 antibody . This inconsistency could impact the subsequent analyses and the previous conclusion of this study could not be drawn. Therefore, the authors feel they cannot guarantee the accuracy of the results and conclusions described in this paper, and believe it is necessary to retract it.


Gamma-glutamylcyclotransferase (GGCT) is one of the major enzymes involved in glutathione metabolism. However, its gene locus was unknown for many years. Recently, the gene for GGCT was found to be identical to C7orf24, which is registered as a hypothetical protein. Orthologs have been found in bacteria, plants, and nematodes as well as higher organisms, and the GGCT gene is highly preserved among a wide range of species. GGCT (C7orf24) was also reported as an upregulated protein in various cancers. Although the function of GGCT in cancer cells has not been determined, the following important activities have been reported: (1) high expression in various cancer tissues and cancer cell lines, (2) low expression in normal tissues, (3) inhibition of cancer cell proliferation via anti-GGCT RNAi, (4) inhibition of cancer cell invasion and migration via anti-GGCT RNAi, (5) an epigenetic transcriptional regulation in cancer cells, and (6) an antitumor effect in cancer-bearing xenograft mice. Therefore, GGCT is promising as a diagnostic marker and a therapeutic target for various cancers. This review summarizes these interesting findings. The existence of human gamma-glutamylcyclotransferase (GGCT) has been known since around 1970. However, its amino acid sequence and gene locus were unknown for many years . RecentlMasuda et al. reported that C7orf24 is identical to cytochrome c-releasing factor (CRF21), which is a substance released into the cytoplasm when human leukemia cells U937 are treated with geranylgeraniol, an apoptosis inducer . They prAs mentioned above, a number of relationships between cancer and GGCT have been reported by some researchers and the role of this molecule in cancer has attracted attention. This minireview summarizes the role of GGCT in cancer cells and the possibility of using GGCT in cancer diagnosis and targeting treatment.GGCT is one of the major enzymes comprising the gamma-glutamyl cycle proposed by Orlowski et al.  2]. GGC. GGC2]. Glutathione is a tripeptide consisting of glutamate, cysteine, and glycine. Glutathione is found in cells at a relatively high concentration of 0.5–10 mM and has a number of important functions such as an antioxidant and a detoxifying agent. Adequate amounts of glutamate, cysteine, and glycine are essential to maintain glutathione at proper levels . MeisterAlthough GGCT was isolated more than 40 years ago –3, its gSeveral studies concerning the distribution of GGCT in normal tissues were reported. Oda et al. examined the mRNA expression of GGCT in rats . They reThe intracellular distribution found by immunohistochemistry was in the cytoplasm and nucleus and these findings were almost consistent with a few other reports –14. CytoWe conducted proteome analysis with two-dimensional electrophoresis in bladder cancer to search for diagnostic markers for urothelial carcinomas , 16. FifAfter our report, other groups reported similar results using clinical samples , 17, 18.n = 30 in each cancer), and they reported significant decreased expressions were observed in renal and urothelial tumors [On the other hand, the results obtained by IHC were inconsistent in several types of cancers. Amano et al. examined 13 types of cancer specimens obtained by surgery  inhibitory concentration) with GGCT siRNA at a low concentration of 5 nM in each cell line resulted in an additional 25–41% inhibition of proliferation over coadministration of docetaxel and control siRNA (manuscript in submission). The combined use of a functional inhibitor of GGCT with chemotherapy may become a promising treatment.We first reported that the administration of anti-GGCT siRNA inhibited cell proliferation in some cell lines, including bladder, prostate, lung, breast, and cervical cancers . SimilarA study of treatment targeting GGCT using an animal model was reported by Hama et al. . They prRecently, Yoshiya et al. developed probes “LISA-4” and “LISA-101,” which produce fluorescence as the result of an enzymatic reaction , 24. TheIt has only been a few years since the existence of GGCT was shown and accumulation of research results has not been sufficient. However, GGCT is a very attractive target molecule because its high expression has been observed in a wide range of cancer types. Inhibition of GGCT expression suppresses the proliferation of cancer cells, and mild adverse events are expected from a recent study. Further investigations are needed in the future.


To date, a total of 75 different disease-causing mutations have been published for the CTSC gene. A summary of recurrent mutations identified in Hungarian patients and a review of published mutations is presented in this update. Comparison of clinical features in affected families with the same mutation strongly confirm that identical mutations of the CTSC gene can give rise to multiple different phenotypes, making genotype–phenotype correlations difficult. Variable expression of the phenotype associated with the same CTSC mutation may reflect the influence of other genetic and/or environmental factors. Most mutations are missense (53%), nonsense (23%), or frameshift (17%); however, in-frame deletions, one splicing variant, and one 5′ untranslated region (UTR) mutation have also been reported. The majority of the mutations are located in exons 5–7, which encodes the heavy chain of the cathepsin C protein, suggesting that tetramerization is important for cathepsin C enzymatic activity. All the data reviewed here have been submitted to the CTSC base, a mutation registry for PLS at http://bioinf.uta.fi/CTSCbase/.Papillon–Lefèvre syndrome  is an autosomal recessive condition characterized by palmoplantar hyperkeratosis and periodontitis. In 1997, the gene locus for PLS was mapped to 11q14-21, and in 1999, variants in the  Papillon–Lefèvre syndrome  is a rare form of palmoplantar keratodermas. It was first described by Papillon and Lefèvre . The maiKeratoderma in PLS can present in the first 3 months of life, although palmoplantar hyperkeratosis generally first appears in years 1–4 Haneke . HoweverPeriodontitis and gingivitis result in the loss of primary and permanent teeth  was independently identified by two groups , this gene has nine splice variants. Of these, five occur in protein coding regions; the remaining four are noncoding transcripts.PLS is transmitted as an autosomal recessive condition affecting males and females equally. PLS was independently mapped to chromosome 11q14-21 by three groups , a lysosomal exo-cysteine proteinase belonging to the peptidase C1 family. Cathepsin C is an oligomeric enzyme composed of four identical subunits , also characterized by palmoplantar hyperkeratosis and periodontal inflammation, as well as arachnodactly, acroosteolysis, pesplanus, and onychogryposis , which is characterized by severe periodontal inflammation leading to tooth loss without the presence of skin symptoms  were reported in PLS cases, while only a few mutations (3%) were reported in HMS or AP1 cases. Note that some mutations were detected in two different disease entities: c.1040A>G p.Tyr347Cys was reported for AP1 and also for classic PLS families  literature search was performed to identify all known CTSC mutations. In addition, Hungarian pedigrees with PLS were screened for CTSC mutations and added to this article. All available information about mutation carriers have been uploaded to the CTSCbase, a mutation registry for PLS  list of locus-specific databases. The database can be visited at http://bioinf.uta.fi/CTSCbase/ and has been updated with data from the literature as well as unpublished variants identified in Hungarian PLS pedigrees.A PubMed , the sisters were found to carry the c.901G>Ap.Gly301Ser missense mutation in a homozygous form (data not published). The family was not aware of consanguinity. This mutation has also been previously published for a German patient with typical PLS skin symptoms , we have identified the c.748C>Tp.Arg250X homozygous nonsense mutation (data not published). Unfortunately, both of these patients were reared in state care and have no known relatives; therefore, investigation of the family was not possible. The fact that both individuals carry the same mutation raises the possibility that these patients are relatives. This mutation has also been previously published in the literature in a Turkish PLS family  and numbered with respect to the CTSC gene reference sequence (ENSG00000109861 corresponding to the CTSC gene transcript ENST00000227266). The 75 unique mutations – point mutations, small deletions, and insertions – are summarized in Figure To date, a total of 75 mutations have been identified for the n = 40), 23% are nonsense (n = 17) and 17% are frameshift (n = 13) variants. There are two in-frame deletions, one intronic splice-site variant and one point mutation in the 5′ untranslated region (UTR) of the CTSC gene. The majority  of the mutations has only been reported once. Among these, 65% (n = 36) were present in homozygous form in the investigated patients, while 35% (n = 20) occurred in a compound heterozygous form. Recurrent mutations  occurred both in homozygous and in compound heterozygous forms and were detected in geographically distant, unrelated families, suggesting mutational clustering on the CTSC gene. However, there are reports suggesting that an initial founder effect and subsequent migration of carriers can lead to the presence of the same mutation in geographically distant and unrelated families  are located within exons 5–7, encoding amino acids 231–394 in the heavy-chain region. Of the remaining half, 16% (n = 12) are located within exons 1–3 encoding amino acids 25–134 in the exclusion domain, 12% (n = 9) are located within the second half of exon 7 encoding amino acids 395–463 in the light-chain region, 13% (n = 10) are located within exon 4 and the first half of exon 5 encoding amino acids 135–230 in the propeptide region, 3% (n = 2) are located in the 5′ end of exon 1 encoding amino acids 1–24 in the signal peptide region and 3% (n = 2) are located within UTRs. Note, not all mutations have been identified by DNA sequencing.Known mutations that have been sequenced are unequally distributed on the CTSC mutations (n = 75) were reported in a homozygous form in PLS patients. Of these mutations, 85% (n = 64) were present only in homozygous form in PLS patients, while 15% (n = 11) were also detected in a compound heterozygous state. Among the homozygous mutations, 50% (n = 32) were missense, 25% (n = 16) nonsense, 23% (n = 15) frameshift mutations, and 2% (n = 1) were other types of mutations  of all CTSC gene mutations identified to date. Missense mutations occur in all coding regions of the gene; however, the majority occurs in exons 5–7, encoding the heavy-chain region of the cathepsin C protein  of the pathogenic mutations identified for the CTSC gene to date. Nonsense mutations occur in all coding regions of the gene; however, the majority is located in exons 5–7, encoding the heavy-chain region of the cathepsin C protein  of the mutations identified to date. Frameshift mutations occur in all coding regions of the gene; however, the majority is located in exons 4–5 encoding the propeptide region of the cathepsin C protein  of all identified CTSC mutations (n = 75) were detected in a compound heterozygous form. The most frequent  compound heterozygotes involved two heterozygous missense mutations. The combination of a heterozygous missense and a heterozygous nonsense mutation occurred in 22% (n = 5) of the cases, a heterozygous missense and a heterozygous frameshift mutation in 16% (n = 4), a heterozygous nonsense and a heterozygous frameshift mutation in 11% (n = 3), and two heterozygous nonsense mutations in 5% (n = 1)  of the mutations have been reported twice or more in different ethnic groups. One of the most frequently reported missense mutation, the c.815G>Cp.Arg272Pro variant, has been detected in Lebanese, Turkish, Saudi, Holland, Russian and French PLS patients , an exclusion domain (110 amino acids), a propeptide (96 amino acids), as well as heavy-(164 amino acids) and light-(69 amino acids) chain regions  search, the cathepsin C protein is highly conserved in vertebrates: the human cathepsin C shows 82% sequence similarity with the sequence from dog, 70% with turkey, and 63% with frog and zebrafish  of all CTSC gene mutations affect the heavy-chain domain and result in different positioning of its N-terminus. As the N-terminal region is involved in oligomer contacts with the N-terminal region of the light chain, the mutation may interfere with tetramer formation  affect this domain  of all CTSC mutations affect the exclusion domain, which blocks access to the active site and prevents substrates from binding any part except their N-termini. Thirteen mutations were detected in the exclusion domain; of these, six are nonsense variants, four are missense mutations, and three are deletions (two resulting in frameshift and one in an in-frame deletion).Sixteen percent (n = 10) of all CTSC gene mutations affect the propeptide fragment, which plays a pivotal role in the activation of the cathepsin C precursor. The majority of frameshift mutations are located in this domain  of all mutations affect the light-chain domain, which is important for tetramerization of the mature enzyme: four are missense mutations, two are nonsense variants and one is an in-frame deletion. Three common missense variants, rs151269219, rs28937571, and rs3888798 are also located in this domain  of all mutations are located in the signal peptide region, presumably affecting the translocation or secretion of the protein: one nonsense mutation and one frameshift variant  of the all 75 mutations are located within exons 5–7, encoding the heavy-chain region of the cathepsin C protein. Three types mutations accounted for 93% (n = 61) of CTSC gene mutations: missense 53% (n = 41), nonsense 23% (n = 17), and frameshift 17% (n = 13). In addition, the majority of missense, nonsense, and frameshift mutations occur in exons 5–7.Analysis of data reported for Hungarian PLS patients revealed 75 CTSC mutation location  suggested that mutations located outside coding regions are more likely to be associated with transgression of the lesions (Hart et al. CTSC gene mutations with little functional consequences are putative causes of more common types of early-onset periodontal disease (Hart et al. In general, no strict genotype–phenotype correlations have been identified for PLS. Analysis of CTSC gene can lead to the development of HMS or AP1 as well as PLS. The common characteristic of these three entities is periodontal inflammation (Hart et al. Mutations in the CTSC gene can give rise to multiple different phenotypes: the c.1040A>G p.Tyr347Cys missense mutation can lead either PLS or AP1 (Toomes et al. CTSC mutation may reflect the influence of other genetic and/or environmental factors (Hart et al. Several reports indicate that identical mutations of the CTSC gene mutations has not yet resulted in the identification of genotype–phenotype correlations. Future efforts might provide insight into these correlations and elucidate the mechanism of the different phenotypic variants – PLS, HMS, and AP1 – of the disease. We believe that, to improve molecular analysis of the CTSC gene, it is necessary to promote both better awareness of the PLS, HMS, and AP1 phenotypic variants of the same disease and better understanding of the underlying molecular mechanisms. The availability of the extended clinical findings from CTSC mutation carriers, as provided by the CTSCbase, is critical for furthering both our understanding of the disease and the development of causative therapies that will be more specific and effective than the symptomatic treatments currently available for patients with PLS, HMS, and AP1 variants.To date, the comparison of


Adjuvant chemotherapy was administered for the uterine corpus cancer and the patient remains healthy 48 months after the surgery. These tumors may have become malignant due to the presence of p53 mutations.A malignant solitary fibrous tumor arising from the omentum is extremely rare. To our knowledge, this is the first case of a malignant solitary fibrous omentum tumor coexisting with uterine corpus cancer. A 62-year-old woman presented to our hospital with vaginal discharge. Endometrioid adenocarcinoma was diagnosed by endometrial curettage. In addition, a solid tumor in front of the uterus was detected following computed tomography and/or magnetic resonance imaging, which was suspected to be a primary (or secondary) malignant tumor arising from the omentum. Hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymphadenectomy were performed. A malignant solitary fibrous tumor of the omentum and grade 3 endometrioid adenocarcinoma of the uterus were diagnosed by pathohistological analysis. Interestingly, the tumor cells were immunoreactive for  We present here the clinical course and immunohistological findings.A solitary fibrous tumor (SFT) is a rare neoplasm mainly originating in the pleura; however, extrathoracic SFTs have been increasingly described, such as those in the meninges, liver, upper respiratory tract, orbit, thyroid, salivary gland, and female genital tract . SFT of  p53. Tumor in the peritoneal cavity was hypercellular and exhibited a patternless arrangement of fibroblastic spindle cells. It was composed of markedly atypical cells with a high mitotic activity (>10 mitotic figures/10 high power fields (HPF);  p16  were administered for the uterine corpus cancer. The patient remains healthy 48 months after the surgery.A 62-year-old menopausal woman presented to our hospital with vaginal discharge. The uterus, which was slightly larger than a hen's egg, along with a movable goose-egg-sized hard tumor in front of the uterus, was palpable during the internal examination. Grade 3 endometrioid adenocarcinoma of the uterus was detected by endometrial curettage. Computed tomography (CT) and/or magnetic resonance imaging (MRI) detected 2 solid tumors in both the uterus and the peritoneal cavity, measuring approximately 4 cm and 10 cm, respectively. Bilateral ovaries could also be detected . The tumF);  p16 , and p5316  and are summarized in  p53 tumor suppressor gene plays an important role in the regulation of cell growth. Mutations in this gene have been reported in various malignant tumors and are thought to be involved in pathogenesis and progression [ p53 mutations are known to be associated with uterine corpus cancer development  [ p53 expression in SFT [ p16 and weakly positive for p53. Mosquera and Fletcher suggested that p53 and p16 overexpression in the anaplastic component of SFT are in keeping with their potential role in the dedifferentiation process previously identified in some sarcomas and carcinomas [ de novo occurrence of malignant SFT [ de novo due to p53 mutations.Thegression . In relarcinoma) . Howeverrcinoma) . There hn in SFT , 7. In orcinomas . Yokoi e


The protective function of p53 (in its homotetrameric form) as a tumor suppressor is lost in more than 50% of human cancers.Despite considerable experimental evidence suggesting the presence of multiple p53 states, it has been difficult to correlate the status of p53 with cancer response to treatments and clinical outcomes, which suggest the importance of complex but essential p53 regulatory pathways.TP53 gene encodes at least 12 p53 isoforms, which are produced in normal tissue through alternative initiation of translation, usage of alternative promoters, and alternative splicing. Furthermore, some researchers have suggested that the formation of mutant p53 aggregates may be associated with cancer pathogenesis due to loss-of function (LoF), dominant-negative (DN), and gain-of function (GoF) effects.Recent studies have indicated that the expression pattern of p53 isoforms may play a crucial role in regulating normal and cancer cell fates in response to diverse stresses. The human As different isoforms or the aggregation state of p53 may influence tumorigenesis, this review aims to examine the correlation of p53 isoforms and aggregation with cancer. In particular, p53, as a transcription factor, is responsible for the induction or inhibition of gene expression by specific binding to p53-responsive elements (p53REs). These interactions usually occur as a tetramer to finely control proteins related to apoptosis, DNA repair, and cell cycle arrest, and serve to block the transformation of normal cells to cancerous cells by maintaining genetic stability. The p53 evidently is known active as a tetrameric form, and it binds with high affinity to DNA or interacts more efficiently with various other proteins in this conformation. The ability of p53 to distinguish various signals allows it to influence delicate and complex regulatory processes.p53 protein, named after its molecular weight, was discovered by David Lane in 1979 as a protein that is bound to the simian virus (SV40) large T antigen. A few years later, p53 was called “the guardian of the genome” due to its ability to inhibit cancer by maintaining various cellular functions.In humans, p53 is composed of 393 amino acids, which can be classified into 6 domains: the transcription activation domain (TAD) (residues 1–67), which interacts with a variety of proteins and can be further subdivided into TAD I (residues 1–40) and TAD II (residues 41–67); the proline-rich region (residues 67–98), which is conserved in the majority of p53s; the central core domain (residues 98–303), which includes the DNA-binding domain wherein more than 90% of cancer-causing p53 mutations are found in humans; a nuclear localization signal located at residues 303 to 323; and the tetramerization domain, located at residues 323 to 363; and the C-terminal basic domain (residues 363–393), which contains a nonspecific DNA-binding domain that recognizes and binds to damaged DNA.TP53 gene. Furthermore, more than 90% of TP53 point mutations are located in the central core domain. Inactivation of p53-regulated pathways through point mutations dramatically increases susceptibility to cancer. Cancer can occur even when no p53 mutations are present, but the p53 pathway is disrupted. Many studies were conducted to elucidate the mechanisms underlying the above mentioned phenomena. Recently, numerous researchers have focused on the potential importance of different isoforms and the aggregation states of p53, which we will discuss as follows.The importance of p53 as a tumor suppressor is clearly evident, considering that more than 50% of all malignant tumors are caused by mutations in the 1.21.2.1TP53 gene is composed of 11 exons  through alternative initiation of translation, usage of alternative promoters, and alternative splicing.–13Figure p53 gene. The most abundant p53 isoform, the canonical p53 protein (p53α or p53), has the full TAD sequence and the longest C-terminal domain. In addition, depending on the translation initiation site, 3 ΔN variants, Δ40p53, Δ133p53, Δ160p53, can be expressed. These 4 N-terminal variants can be combined with 3 different C-terminal domains . p53 isoforms are not only expressed differently for different cancer types but they also have different transcriptional activities and tumor-suppressor functions that can affect various other biological functions. Currently, researchers reported the existence of various isoforms of p53, but their biological functions have not been fully investigated. In short, p53β was reported to enhance the transcriptional activity of p21 through p53(α) pathway and through BCL2-associated X protein (BAX) promoters. p53β can also lead to apoptosis through p53-independent manner. On the contrary, p53γ could enhance the transcriptional activity of only through BAX promoter. Interestingly, Δ40p53α could influence the dominant-negative effect to p53(α), interfering transcriptional activities. In addition, interactions between Δ133p53α and p53(α) could regulate the gene expressions by arresting apoptosis, G1 cell-cycle arrest, and replicative senescence, and enhancing blood vessel formation, metastasis formation, and endothelial cell migration. Hence, the functions of various p53 isoform could strengthen or interfere the tumor suppressor activity. Recently, the expression patterns of p53 isoforms were investigated for their importance in regulating gene expression in cancer cells compared with that in normal cells. Hence, the expression of abnormal p53 isoforms, regardless of the mutation, may contribute to the development of cancer.The 1.2.2,17–25 Collectively, results from these clinical studies suggest that specific expression patterns of p53 isoforms may be associated with tumor progression, clinical response, and prognoses. The expression patterns of p53 isoforms were studied in various cell lines, such as colorectal adenoma, renal cell carcinoma, mucinous ovarian cancer, serous ovarian cancer, breast cancer, cholangiocarcinoma, acute myeloid leukemia (AML), squamous cell carcinoma of the head and neck (SCCHN), and melanoma cell lines. Fujita et al showed that the progression of colorectal adenoma to carcinoma could be predicted by the ratio of p53β to Δ133p53α. In renal cell carcinoma, p53β was evaluated as a potential progression marker at both the mRNA and protein levels, and p53β overexpression appeared to be associated with tumor progression. In addition, the expression of Δ40p53α in mucinous ovarian cancer was found to improve recurrence-free survival rates. Δ133p53α and Δ40p53α isoforms were assessed in serous ovarian cancer cases as potential biomarkers. p53α, p53β, and p53γ isoforms are expressed in normal breast cells, but following the expression pattern of the p53γ isoform alone may be sufficient to predict good prognosis. In a subsequent study, the expression patterns of p53 isoforms were analyzed in 30 cases of primary breast tumors. In 18 cases, loss of p53β and p53γ expression was seen, whereas in 12 cases, overexpression of the isoform Δ133p53 was seen. The expression patterns of isoforms in tumors differed from those in normal tissue, and could differ even between each tumor case. The expression of Δ133p53 in cholangiocarcinoma correlated with poor clinical outcomes. In contrast, overexpression of p53β and p53γ was correlated with improved responses to chemotherapy in AML. In SCCHNs, elevated levels of the p53β isoform were found in a large number of samples. In a study on melanoma, elevated levels of mRNA for p53β and Δ40p53 were detected in tumor cells but not in melanocytes or fibroblasts. The expression patterns of p53 isoforms in the various tumors mentioned above are summarized in Table p53 plays an important role in the growth and progression of cancer and its response to chemotherapy. Despite many studies, it was difficult to predict these factors with only p53 status. Many institutions have independently performed clinical studies trying to correlate the expression patterns of p53 isoforms, at the mRNA and protein levels, with various types of cancers. and Marcel et al suggested to measure the changes in p53 mRNA levels by using nested RT-PCR and quantitative real-time RT-PCR and p53 protein quantification by using western blotting, immunoprecipitation, and luciferase reporter gene assays.p53 isoforms could be found in various cancers and their compositions may vary. These dynamic changes of p53 isoforms may affect the main known function of p53 as tumor suppressor. Hence, understanding and monitoring p53 isoforms at the level of mRNA and changes in transcription landscape will pave the directions of future studies of p53 isoforms. In addition, Khoury et alAlthough diverse p53 isoforms were studied clinically by using various types of cancer models with mRNA and protein expression levels, the challenges in correlating p53 expression patterns with cancer prognosis and treatment outcomes may result from investigating only individual isoforms instead of profiling for all isoforms. Hence, further investigation of various aberrant p53 isoforms may help in understanding cancer development and progression, and may ultimately provide novel targets for more effective cancer therapies and tumor markers.1.31.3.1,29 Over the past 2 decades, many neurodegenerative diseases such as Alzheimer disease , Parkinson disease (α-synuclein), Huntington disease (polyglutamine-huntingtin), familial amyloid polyneuropathy (transthyretin), prion diseases , amyotrophic lateral sclerosis (superoxide dismutase 1), and type II diabetes (islet amyloid polypeptide) have been investigated to understand how misfolding or aggregation of their respective proteins induces pathological features. The fundamental paradigm that explains transmission of these aggregates in their respective diseases was pioneered by Stanley Prusiner in the 1980s and is now referred to as the prion hypothesis. Recent research trends in p53 aggregation are based on the prion hypothesis, which will be discussed as follows.Protein misfolding and aggregation occur in several human disorders, which are commonly referred to as protein misfolding diseases (PMDs). PMDs are characterized by the formation of protein oligomers, protofibrils, and mature fibrils, which can accumulate intra- or extracellularly in several tissues.1.3.2 At that time, aggregated p53 was incorrectly considered to be a quaternary structure, which might be produced in order to prevent rapid degradation. However, recently, research on the p53 aggregation has been actively conducted in the motif obtained prion concept. As noted above, many in vitro aggregation studies focused on the central core domain (hot spot mutation with more than 90% genetic modification), and transactivation and tetramerization domains. Ishimaru et al confirmed the formation of various aggregates, which were due to physical interactions of the central domain of p53 (p53C), by using AFM and thioflavin T binding. Later, similar amyloid aggregates formed by the transactivation and tetramerization domains were reported.–35 In particular, the p53 hotspot mutant R248Q appeared to self-aggregate more than wild-type p53. p53 mutant (R248Q) seemed to be located in the hotspot of the protein, influencing self-aggregation. In addition, p53 mutant (R248Q) could be influenced by various environment factors, pH, temperature, and pressure. It was reported that p53 mutant (R248Q) could become a seed for the p53 aggregations, including with wild-type p53. The immunofluorescence colocalization assay of breast tissue from biopsy revealed the deposition of p53 aggregates that such aggregates could alter and decrease the normal function of p53 of tumor suppressor function. Aggregation might be due in part to a decrease in the thermodynamic stability of protein conformations in the mutants, which might compensate for this instability by aggregating. A variety of techniques such as electron microscopy, X-ray diffraction, Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), cell viability assays, and anti-amyloid immunoassays could be used to accurately determine the underlying physical mechanisms.Recently, interest in p53 aggregation has grown among researchers. In fact, the high-molecular weight form of p53 was already detected in 1991. It was also shown that full-length and N-terminally truncated protein (p53C) aggregates could be internalized by cells into the cytosol and induce coaggregation with endogenous p53 protein, further supporting the possibility of the prionoid nature of p53 aggregates. Other in vivo evidence has revealed the accumulation of p53 aggregates, which were detected using an amyloid oligomer specific antibody (A11) or a fibrillar-specific antibody (OC), in paraffin-embedded breast tumor biopsy sections and basal cell carcinoma (BCC) cancer samples.,39,40 A summary of the above-mentioned results can be found in Table Furthermore, it was shown that p53 aggregates may act as seeds for coaggregation with other p53 family proteins such as p63 and p73.Together, these results implicate p53 misfolding and aggregation in cancers and support the hypothesis of prion-like activity of p53 aggregates. As p53 aggregates could coaggregate with wild-type p53, they may have a cytotoxic effect on mammalian cells by hindering the normal functions of p53.1.4The tumor-suppressor protein p53 is inarguably important for cancer development and progression and the response to chemotherapy. Despite many studies, it is difficult to predict the therapeutic response and clinical outcome based on p53 alone. Indeed, the p53 pathway can be regulated  in a number of ways. As a result, considerable efforts were made to uncover the mechanisms of inactivation, for example, by p53 protein isoforms and aggregation. Two independent mechanisms have been proposed regarding the isoforms and aggregation of p53. Most of the in vitro methods used to induce p53 aggregation use a partial peptide of the p53C domain, which is similar to the N-terminal truncated p53 isoform . In addition, robust aggregation of p53 could be induced at low pH, which is thought to simulate the tumor environment.,41 The formation of this complex could be due to native functional interactions or non-native interactions, which might arise from the formation of aggregates or be due to other causes that inactivate p53. Moreover, in recent studies, the presence of p53 aggregation affected the response of ovarian cancer cells to chemotherapy, which agrees with earlier studies that showed an association between chemoresistance and the presence of shorter p53 isoforms.,42 These results strongly suggest a more robust relationship between p53 isoforms and aggregation. In Fig. TP53 gene or other proteins in the downstream pathways in the transcription or tranalation mechanisms could alter the expressions of mp53 or Ip53, resulting aggregations of wp53 and suppressing the normal functions of p53.Furthermore, p53 isoforms were found to form a complex with FLp53 in several studies.–48Breaking p53 aggregations similar with prion-like behavior could be the novel therapeutic target in the anti-cancer therapy, as well as other PMDs from protein aggregations, such as Alzheimer disease and Parkinson disease.We also propose that further investigations are required to determine the relationship between p53 isoforms and aggregation, especially to clarify their contributions to the regulation of the normal functions of p53. These studies could provide a comprehensive understanding of p53 regulation and functions, and could contribute to the future development of cancer biomarkers and pharmaceutical therapies.


ExIII knockout mice which still express the short isoform of p75NTR. To scrutinize the role of p75NTR in the hippocampus, we analyzed adult and aged p75NTRExIV knockout mice, in which both, the short and the full-length isoform are deleted. Deletion of these isoforms induced morphological alterations in the adult dentate gyrus (DG), leading to an increase in the thickness of the molecular and granular layer. Based on these observations, we next determined the morphological substrates that might contribute to this phenotype. The cholinergic innervation of the molecular and granular layer of the DG was found to be significantly increased in the knockout mice. Furthermore, adult neurogenesis in the DG was found to be significantly altered with increased numbers of doublecortin (DCX) positive cells and reduced numbers of apoptotic cells in p75NTRExIV knockout mice. However, cell proliferation as measured by phosphohiston H3 (PH3) positive cell numbers was not affected. These morphological alterations (number of DCX-positive cells and increased cholinergic fiber densities) as well as reduced cell death in the DG are likely to contribute to the observed thickening of the granular layer in p75NTRExIV knockout mice. In addition, Sholl-analysis of DCX-positive neurons revealed a higher dendritic complexity and could thus be a possible morphological correlate for the increased thickness of the molecular layer in p75NTR deficient animals. Our data clearly demonstrate that deletion of both, the short and the full-length isoform of p75NTR affects DG morphology, due to alterations of the cholinergic system and an imbalance between neurogenesis and programmed cell death within the subgranular zone.Analyses of mice carrying a deletion of the pan-neurotrophin receptor p75NTR have allowed identifying p75NTR as an important structural regulator of the hippocampus. Most of the previous analyses were done using p75NTR Neurotrophins exert many of their specific actions through tyrosine kinase (trk) receptors that bind the neurotrophins with high affinity and, in addition, all neurotrophins can signal through a low-affinity receptor, known as p75NTR  are viable and fertile; however they display several defects in the nervous system, including, among others, deficits in the peripheral sensory nervous system . Deletion of Exon IV results in a loss of both, the full-length and the short isoform of p75NTR  in both mutants is unaffected  the neurotransmitter supply in the hippocampus is affected, whether (2) spine densities of DG granule cells are altered, and (3) whether changes in adult hippocampal neurogenesis can be observed in p75NTRExIV mice.However, it can be speculated that deletion of p75NTR has also an impact upon the DG, since proNGF can signal via p75NTR and since proNGF seems to be capable of inhibiting adult neurogenesis in the DG  were analyzed in comparison to littermate controls (p75NTRExIV+/+) that were both obtained by crossing heterozygous p75NTRExIV mice.p75NTRFor the subsequent analysis, mice with an age of 4–6 months (“adult”) as well as with an age between 20 and 23 months (“aged”) were used. All animal experiments were performed in accordance with German animal rights regulations and with permission of the Landesamt für Landwirtschaft, Lebensmittelsicherheit und Fischerei (LALLF) Mecklenburg-Vorpommern, Germany.2PO4, 10.73 g Na2HPO4 and 9.0 g NaCl in 1,000 ml distilled water, pH 7.2) followed by perfusion with 4% paraformaldehyde . Brains were removed and immersed in the same fixative for at least 5 days.Animals were killed with an overdose of ether and transcardially perfused with phosphate-buffered saline  stained 30 μm thick coronal serial sections, sampled at a random start position  and cut at 120 μm. Analysis of dendritic spines was conducted in a blinded procedure. Only one segment per individual dendritic branch and neuron was chosen for the analysis. Spines were analyzed in the dorsal, but not ventral, leaf of the DG because spine densities are different in these locations and no subdivision into different types of spines [filopodia, stubby, thin, and mushroom, which reflect temporal snapshots of a dynamic phenomenon . For statistical evaluation of two groups unpaired two-sided p ≤ 0.05. Data in figures were expressed as mean ± SEM; significant changes in the figures were indicated by an asterisk.For the analysis of more than two groups one-way ANOVA followed by a Tukey’s multiple comparisons test was used. In case of the HPLC analysis, a two-way ANOVA followed by a Bonferroni post-test was used. Significance levels for all tests were set at ExIII knockout) causes a significant increase of the DG resulting from an increased width of the granular, but not the molecular layer in adults  as well as the granular layer  in adult p75NTRExIV knockout mice  nor in the molecular layer (p = 0.735).We have previously shown that functional deletion of the long isoform of the p75 receptor  and subgranular (p = 0.041) layer of the DG in p75NTRExIV knockout mice were significantly increased by more than 32%, as compared with age-matched controls  as well as subgranular layer (p = 0.0003) of the DG.We next examined whether and to what extent deletion of p75NTRs Figure . Thus, ds Figure . The ince Figure , in contExIII knockout mice are reduced as compared to controls . Aged p75NTRExIV−/− mice also showed reduced rates of apoptosis, but due to the great variance observed in older animals, the difference was not significant from age-matched controls .We have recently shown that the rates of cell death in the hippocampus of p75NTRExIV−/− mice was not different from the number determined in control mice . Thus, neither deletion of Exon III  as a marker Figure . In adulExIV−/− mice harbor significantly more DCX positive cells within the DG than age-matched p75NTRExIV+/+ mice . This is in contrast to mice with a deletion of Exon III  as a marker for both mitotically active and postmitotic young neurons Figure . As showExIII−/− mice  was not statistically different (t-test: p = 0.83) from the numbers determined in the respective controls  during aging from 17.33 to 14.81 spines per 10 μm and in p75NTRExIV−/− mice an age-related decline in spine densities from 17.93 to 13.71 spines per 10 μm (p = 0.011) was found. Concerning the mean length of dendritic spines, subtle alteration in mean spine length was noted by comparing p75NTRExIV−/− mice with age-matched controls; however, these effects were not significant  and neurogenin 3, which might contribute to the phenotypes observed. Activation of p75NTR was shown to up-regulate the expression of Hes1/5 and increased expression of these genes is sufficient to decrease the number of dendrites . However, due to hind limb ataxia p75NTRExIV−/− mice are not well-suited for those behavioral tests  expressing cells, a lasting increase in the number of cholinergic neurons was observed (Boskovic et al., In summary, our data show that deletion of both, the short and the full-length isoform of p75NTR causes altered DG morphology with an overall thickening of the involved cell layers.Consequently, alterations in morphogenic substrates such as the quantity of cholinergic innervation as well as the amount of active neurogenesis and programmed cell death were evident. Thus, p75NTR is likely to play a role in regulating the cholinergic system and modulating adult neurogenesis by balancing neuronal differentiation and apoptotic cell death within the DG.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Humans have an impressive ability to augment their creative state . Though this “thinking cap” phenomenon is commonly experienced, the range of its potential has not been fully explored by creativity research, which has often focused instead on creativity as a trait. A key question concerns the extent to which conscious augmentation of state creativity can improve creative reasoning. Although artistic creativity is also of great interest, it is creative reasoning that frequently leads to innovative advances in science and industry. Here, we studied state creativity in analogical reasoning, a form of relational reasoning that spans the conceptual divide between intelligence and creativity and is a core mechanism for creative innovation. Participants performed a novel Analogy Finding Task paradigm in which they sought valid analogical connections in a matrix of word-pairs. An explicit creativity cue elicited formation of substantially more creative analogical connections . Critically, the increase in creative analogy formation was not due to a generally more liberal criterion for analogy formation . The use of an online sample provided evidence that state creativity augmentation can be successfully elicited by remote cuing in an online environment. Analysis of an intelligence measure provided preliminary indication that the influential “threshold hypothesis,” which has been proposed to characterize the relationship between intelligence and trait creativity, may be extensible to the new domain of state creativity. Creativity research has frequently followed the form of intelligence research, treating creativity as a trait, i.e., a stable attribute of which some people have more and other people have less –3. A somOf particular importance to efforts aimed at augmenting creativity and innovation is state creativity in the context of reasoning. Creative reasoning, especially in the form of analogical reasoning, is frequently the basis of innovation in science and industry –26. AnalThis initial evidence suggests that the dynamism of state creativity can be channeled to improve reasoning, but important questions remain. Valuable creative insights in the sciences and industry cannot often be gained by simply assessing the validity of an already-formed analogy as in the study by Green et al.  or by chA further question concerns the relationship between state creativity and intelligence. The creativity-intelligence relationship has been a target of inquiry in the trait creativity literature. Much of this work has surrounded the “threshold hypothesis,” originally proposed by Guilford . The thrAn additional unexplored question concerns the effectiveness of state creativity augmentation via remote online communication. This question is timely as online communication becomes an increasingly common medium for education, work, and research –47. StudTo contribute to the developing understanding of state creativity, and state creative reasoning in particular, we sought to address these questions. We employed a novel Analogy Finding Task devised to be sufficiently open-ended to detect individual differences in creative performance yet sufficiently constrained to enable sensitivity to inappropriate responding. The Analogy Finding Task tests participants’ ability to find analogical connections among a large matrix of word pairs while avoiding combinations of word pairs that form invalid analogies. State creativity was measured, as in prior state creativity research  in April of 2015 and paid $2.00 for participation. Data were quality controlled to identify responses not indicative of appropriate attention to task instructions. Exclusion of a substantial number of participants is common for online data collection via Mturk and was anticipated for the present study. Thirty-seven Participants who did not complete the entirety of the survey were removed. Completion times were reviewed and 17 participants with times greater than two standard deviations above the mean  or less than one standard deviation below the mean  were considered to be potentially affected by inappropriate attention to the tasks and were removed. Note that two standard deviations below the mean would have been 0 minutes and thus not a meaningful exclusion criterion. IP Addresses were reviewed. In one case, multiple participants had the same IP address, and only the first completed survey from this IP address was included for analysis. Two participants who participated in the pilot phase of the study, described below, were also removed. A question to “prove you are human” appeared at the end of the survey. Three ostensible participants who did not accurately complete this question were removed. Lastly, quality control analogies were embedded within the Analogy Finding task itself. The task was broken into two matrices of word pairs (described below), and each matrix included 5 quality control analogies that were determined via a pilot study (described below) to be the most readily identifiable analogies in the matrices. In order to eliminate participants who were either not properly following instructions or not giving appropriate attention to task performance, seven participants who did not identify at least three quality control analogies in each matrix were removed from further analysis. The fully quality-controlled dataset included 90 participants . Written informed consent from all participants (main study and pilot study) was obtained according to Institutional Review Board guidelines. Study procedures were approved by the Georgetown University Institutional Review Board.One hundred and fifty seven participants were recruited online via Amazon Mechanical Turk . Second, we sought to confirm that a set of quality control analogies embedded in each matrix would be the most readily identifiable analogies in each matrix .A total of 296 participants were recruited for the pilot study. Based on similar exclusion criteria to the ones described above, the sample was cut down to a final N of 178 . Since we were interested in confirming that the quality control analogies would be the most readily identified items in the matrices, participants were not initially excluded for failing to identify quality control analogies.The Analogy Finding task consisted of two matrices of word-pairs . Each mahttp://lsa.colorado.edu). We used the LSA topic space of “general reading up to first year college (300 factors)” and term-to-term comparison type. This measure of semantic distance corresponds to the cosine of the angle between vectors corresponding (in our usage) to the terms of each analogy within a given semantic space, which is derived through analyses of all of the contexts in which each word tends to be present or absent in that topic space ) Participants in the pilot study completed the two Analogy Finding Task matrices used in the main study, with the order of the matrices fully counterbalanced between subjects. Participants were randomly assigned to one of two conditions: they were either cued to be creative for both matrices (Cued condition), or were not cued to be creative in either matrix (Uncued condition).Creativity was assessed via the following outcomes measures: (1) the total semantic distance of valid analogies identified, (2) the number of valid analogies identified, which is related but not informationally identical to the total semantic distance, and (3) the number of invalid analogies identified. The change in these measures from the first/uncued matrix to the second/cued matrix was taken to measure the effect of the creativity cue in the main study. The total, rather than the average, semantic distance was used because averages were deemed likely to provide misleading representations of the ability to formulate creative analogies. For example, it was possible to identify very few analogies (as few as one) and yet to have a high average semantic distance.X2 = 99.10, p < 0.001, r = 0.75), and the least frequently identified quality control item was identified more often than the most frequently identified non-quality control analogy .The pilot study revealed that a set of analogies intended to be used as quality control analogies in the main study were, as hoped, the most frequently identified analogies. On average, participants (N = 178) identified 8.17 out of a possible 10 quality control analogies compared with 5.73 out of a possible 24 cross-domain analogies. This difference in frequency of identification was significant , 29 participants who failed to identify at least three quality control analogies in each matrix were removed. The reduced sample , showed no practice effect of performing a second Analogy Finding Task matrix after performing a first matrix. That is, there was no significant change on any outcome measure from the first matrix to the second in either condition  were more semantically distant than those identified by participants in the Uncued condition .M = 565.33 ± SD = 305.96) than in the first/pre-cue matrix (M = 457.69 ± SD = 247.09), t(89) = 5.48, p < .001, d = 0.39 (M = 8.38 ± SD = 3.52) than on the first/uncued matrix (M = 7.12 ± SD = 2.91), t(89) = 5.90, p < .001, d = 0.39. Critically, this increase in finding valid analogies was not accompanied by a greater number of “false alarm” invalid analogies identified in the second/cued matrix (M = 2.23 ± SD = 3.22) than in the first/uncued matrix (M = 1.98 ± SD = 3.42), t(89) = .97, p = .334. A repeated measures ANCOVA model taking number of false alarm analogies as a covariate demonstrated that the effect of the creativity cue on semantic distance was independent of false alarms, F = 31.08, p < .001, η2 = .25. There was no main effect of false alarms in this model (p = .752), and no interaction of cue by false alarms (p = .266). Additionally, a linear regression model confirmed that pre-cue vs. post-cue change in the number of false alarm analogies was not predictive of the change in total semantic distance, β = .10, t(88) = .965, p = .337.Consistent with our primary hypothesis, participants showed notable improvement on creativity measures following the creativity cue. Participants identified analogies that were more creative (greater semantic distance) in the second/post-cue matrix  of 39.54% ± SD = 22.89%. Verbal IQ was strongly correlated with the change in semantic distance from the pre-cue to the post-cue matrix . MRT score also showed a correlation with change in semantic distance that approached significance . A model in which change in semantic distance (effect of cue) was regressed on both Verbal IQ and MRT indicated that Verbal IQ remained significantly predictive, β = .35, t(87) = 3.27, p = .002, whereas MRT was not significantly predictive in this model β = .08, t(87) = .77, p = .441. First-order correlations of the two intelligence measures with all creativity outcome measures are reported in Participants showed an average estimated Verbal IQ of 114.19 ± SD = 4.24. The lower IQ group included 55 participants with average Verbal IQ = 106.22 ± SD = 10.72. A 2 X 2 ANOVA indicated an expected main effect of the creativity cue on semantic distance  = 39.43, p < .001, η2 = .31), a main effect of IQ group  = 13.20, p < .001, η2 = .13), and, most relevant to the threshold effect, an interaction of Cue by IQ group  = 9.51, p = .003, η2 = .10) indicating that the creativity cue yielded greater increases in semantic distance in the higher IQ group.To test whether an IQ threshold effect could be observed for augmentation of state creativity in our data , the dataset was split into groups of participants with higher and lower Verbal IQ. We used Verbal IQ ≥ 120 as the threshold for inclusion in the higher IQ group based on prior research , 42, 44.r = .36, p = .007). By contrast, the higher IQ group showed no correlation between change in semantic distance and Verbal IQ . Fisher’s r-z transformations suggested a difference between IQ groups for these correlation coefficients that approached significance (p = .053 one-tailed).In the lower IQ group, change in semantic distance (effect of cue) was significantly correlated with Verbal IQ , and formed a greater number of valid analogies. Critically, the increase in formation of creative analogies was not due to an increase in false alarm formation of invalid analogies, and invalid analogies were not more numerous after the creativity cue. This indicates that the augmentation of state creativity we elicited does not reflect an augmentation of divergence at the expense of reasonable constraint . In addition, the Analogy Finding Task was not easily susceptible to inappropriate use of outside materials; the correct answers could not be found in any external resource. Other confounds are more difficult to address, including potential interactions of varying testing environments with our creativity cue manipulation.Analysis of the relationship between a measure of Verbal IQ and augmentation of state creative performance indicated preliminary support for a threshold effect. We found an interaction of cue by IQ group on the semantic distance of analogies, and the correlation between IQ and cued augmentation of creative performance was substantially higher in the lower IQ group. This research is a first empirical exploration of the threshold hypothesis in the context of state creativity. Taken together, the findings provide a preliminary indication that the threshold hypothesis may extend into this novel domain.Some prior research has questioned the validity of the threshold hypothesis. Runco and Albert  concludeAugmentation of state creativity to improve creative reasoning is a promising research direction with potential to inform strategies for innovation in multiple contexts. Here, we extended prior evidence of successful conscious augmentation of creative state in response to an explicit creativity cue. The data provide new evidence that conscious state creativity augmentation can be extended to formation of analogies in an open-ended workspace, and that remote cueing of state creativity is effective in an online environment. A key element of the present findings was that increases in creative analogy finding appear to reflect “real” creativity rather than simply augmented divergence at the expense of sensible constraint. The present data also provide preliminary evidence that the threshold hypothesis, which has been influential in understanding their relationship between intelligence and trait creativity, may be extensible to the domain of state creativity. This work sets the stage for further work to test the boundary conditions of the efficacy of state creativity augmentation in reasoning, including exploration of this phenomenon in increasingly ecologically valid paradigms.S1 Appendix(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


For several decades, p53 has been detected in cancer biopsies by virtue of its high protein expression level which is considered indicative of mutation. Surprisingly, however, mouse genetic studies revealed that mutant p53 is inherently labile, similar to its wild type (wt) counterpart. Consistently, in response to stress conditions, both wt and mutant p53 accumulate in cells. While wt p53 returns to basal level following recovery from stress, mutant p53 remains stable. In part, this can be explained in mutant p53-expressing cells by the lack of an auto-regulatory loop with Mdm2 and other negative regulators, which are pivotal for wt p53 regulation. Further, additional protective mechanisms are acquired by mutant p53, largely mediated by the co-chaperones and their paralogs, the stress-induced heat shock proteins. Consequently, mutant p53 is accumulated in cancer cells in response to chronic stress and this accumulation is critical for its oncogenic gain of functions (GOF). Building on the extensive knowledge regarding wt p53, the regulation of mutant p53 is unraveling. In this review, we describe the current understanding on the major levels at which mutant p53 is regulated. These include the regulation of p53 protein levels by microRNA and by enzymes controlling p53 proteasomal degradation. Wild type (wt) p53 is a tumor suppressor, which plays a key role in the cellular stress response. Abrogating p53 function is a key event in human cancer, leading to deregulated cell cycle, genomic instability, resistance to stress signals, and ultimately leading to cancer development , 2. DysfMost p53 mutations are missense  and occur at its DNA-binding domain, which accounts for the improper DNA engagement and disruption of transcriptional activity. P53 mutants also gain new oncogenic functions including resistance to chemotherapies, enhanced cell growth, metabolism, and invasion . Dein vivo.p53 stability is tightly controlled by ubiquitin E3 ligases, which together with the enzymatic activities of E1 and E2, and in certain cases also E4 ligases coordinate the efficient degradation of proteins through the 26S proteasome machinery . The temin vivo , which cleave ubiquitin from proteins. Unlike E3 ligases, the role of DUBs in controlling mutant p53 stability is poorly explored. USP10 deubiquitinates and stabilizes both wt and mutant p53 . InhibitAlthough much of the focus in the field has been devoted to the 26S-mediated proteasomal degradation of p53 during post-stress recovery, the 20S proteasome has been identified as the destination of unmodified p53 that is inherently unstable, unless protected by the NADH quinone oxidoreductase 1 (NQO1). Specifically, inhibition of NQO1 (for example by dicoumarol) promotes p53 degradation through the 20S proteasome in an Mdm2-independent manner. Interestingly, mutant p53 interacts strongly with NQO1, rendering it resistant to NQO1 inhibitors [reviewed in Ref. ]. PertinFree ribosomal proteins are known to regulate the Mdm2/MdmX-p53 axis and activate wt p53, thereby inhibiting tumor proliferation [reviewed in Ref. ]. For exThe regulation of wt p53 degradation is modulated by PTMs. Wt p53 is extensively modified post-translationally in response to stress conditions, which lead to the stabilization and/or activation of p53 [reviewed in Ref. ]. CriticIn addition to mutant p53 itself, modifications of Mdm2/MdmX contribute to the protection of mutant p53 from these key inhibitors. In response to DNA damage, Mdm2 is phosphorylated by ATM and c-Abl, which compromises the ability of Mdm2 to degrade p53 , 84. ATMWhile wt and mutant p53 have distinct and opposing effects on cancer cells, many aspects of their regulation are shared. The majority of the positive and negative regulators of wt p53 that have been tested have a similar regulatory effect on mutant p53. Critically, however, the tightly controlled myriad of positive and negative auto-regulatory loops, which govern wt p53 levels, is uncoupled in the context of mutant p53. In addition, mutant p53 is recognized as a misfolded protein by the heat shock protein chaperons. Together, these contribute to the protection of mutant p53 from the well-coordinated recovery from stress conditions. This results in the chronic accumulation of active mutant p53, which exerts its gain of functions. It is therefore of prime importance to screen patients for p53 mutations prior to treatments, which are known to activate and stabilize p53. The identification of mechanisms that protect mutant p53, as shown by the chaperon HSP proteins, identifies novel approaches to expose mutant p53 to its negative regulators and drive its destruction. Future studies identifying the unique protectors of mutant p53 are a rational approach to define novel approaches to target mutant p53 in cancer cells.RV contributed to writing and editing the paper and prepared a figure. KT contributed to writing and prepared a figure. PJM contributed to writing. SH and YH contributed to writing and editing the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


However, there is some conflicting evidence.Juvenile-onset SLE (JSLE) is a severe auto-immune disease that can occur in children at any age. Variations regarding the extent of organ involvement, disease activity and damage are found in different age categories. Factors that may contribute to an earlier age of onset are gender, ethnicity and positive family history of SLE. It has been shown that JSLE has a more aggressive disease course compared to adult onset SLE. Correspondingly, it seems that disease severity in younger JSLE patients increases with decreasing age To determine the differences in gender, ethnicity and family history of SLE in JSLE patients with age of onset <10 years and >10 years respectively, and to characterize differences in disease characteristics  between these groups.Data on patient demographics, family history and disease activity (BILAG) and damage (SLICC) at diagnosis and last follow-up visit were collected from the UK JSLE Cohort Study database. Patients were divided into two age categories based on age of onset (≤10 or >10 years) and were analyzed. BILAG scores of a subset of patients (n = 24) who were followed for five years were analyzed, to evaluate influence of disease duration.A total of 313 patients with JSLE, diagnosed using the ACR-criteria, were included in the analysis. Their data is summarized in the following table: The percentage of female patients was 80% in the <10 group and 84% in the >10 group (p = 0.423). However, the proportion of black children in the <10 group was higher (p = 0.073) and the proportion of Caucasian children in the <10 group was significantly lower (p = 0.047). Family history for SLE was not significantly different between the age categories (p = 0.121).Disease activity at onset was higher in the older group but not significantly (p = 0.105) and no significant differences were found in organ systems involvement. This is in contrast with most literature. Referral time might be a factor causing this and would be an interesting factor to study in this population. Disease activity and damage at follow up  were low in both groups, irrespective of disease duration. Five years after disease onset, disease activity in the <10 group (n = 15) was 1 ± 3, in the >10 group (n = 9) it was 4 ± 5 (p = 0.290). This indicates that for most patients in this cohort, their disease is probably managed well.In contrast to other published cohorts, there were no striking differences in demographics, family history or disease characteristics in this cohort between children diagnosed before or after the age of 10 years old.None declared.