Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spontaneous tumors in the dog offer a unique opportunity as models to study human cancer etiology and therapy. p53, the most commonly mutated gene in human cancers, is found to be altered in dog cancers. However, little is known about the role of p53 in dog tumorigenesis. Here, we found that on exposure to DNA damage agents or MDM2 inhibitor nutlin-3, canine p53 is accumulated and capable of inducing its target genes, MDM2 and p21. We also found that on DNA damage, canine p53 is accumulated in the nucleus, followed by MDM2 nuclear translocation and increased 53BP1 foci formation. In addition, we found that canine p63 and p73 are up-regulated by DNA damage agents. Furthermore, colony formation assay showed that canine tumor cells are sensitive to DNA damage agents and nutlin-3 in a p53-dependent manner. Surprisingly, canine p21 is expressed as two isoforms. Thus, we generated multiple canine p21 mutants and found that amino acids 129 to 142 are required, whereas amino acid 139 is one of the key determinants, for the expression of two p21 isoforms. Finally, we showed that although the full-length human p21 cDNA expresses one polypeptide, amino acid 139 seems to play a similar role as that in canine p21 for various migration patterns. Taken together, our results indicate that canine p53 family proteins have biological activities similar to human counterparts. These similarities make the dog an excellent outbred spontaneous tumor model, and the dog can serve as a translation model from benchtop to cage side and then to bedside.
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PMID:Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor. 1914 38

Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we show that birth defect and cancer-associated FGFR2 mutants promote DNA-damage signaling and p53-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to be become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. Our data suggest that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. Our results also raise the possibility that cancers originating through a combination of constitutive FGFR activation and deregulated Myc expression may be particularly sensitive to small molecule inhibitors of FGF receptors.
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PMID:The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects. 1940 60

Inactivation of the tumor suppressor p53 is central to carcinogenesis and acquisition of resistance to drug-induced apoptosis. The majority of alterations are missense mutations and occur within the DNA-binding domain. However, little is known about the point mutations in the tetramerization domain (TD). Here we investigated the properties of a new p53 mutant (Lys 351 to Asn) in the TD identified in a cisplatin-resistant ovarian carcinoma cell line (A2780 CIS). We found that K351N substitution significantly reduces the thermodynamic stability of p53 tetramers without affecting the overall half-life of the protein. Moreover, p53 K351N has a reduced ability to bind DNA and to trans-activate its specific target gene promoters, such as bax. Data obtained from the analysis of p53 subcellular localization revealed that K351N mutation inhibits the nuclear export of p53 and accumulation in the cytoplasm induced by cisplatin treatment. These results identify p53 K351N as a new cancer associated mutant with reduced tumor suppressor activity and altered functions in response to apoptotic stimuli.
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PMID:Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. 1982 22

The aim of this study was to investigate the effects of mobile phone exposure on glial cells in brain. The study carried out on 31 Wistar Albino adult male rats. The rat heads in a carousel exposed to 900 MHz microwave. For the study group (n:14), rats exposed to the radiation 2 h per day (7 days in a week) for 10 months. For the sham group (n:7), rats were placed into the carousel and the same procedure was applied except that the generator was turned off. For the cage control (n:10), nothing applied to rats in this group. In this study, rats were euthanized after 10 months of exposure periods and brains were removed. Brain tissues were immunohistochemically stained for the active (cleaved) caspase-3, which is a well-known apoptosis marker, and p53. The expression of the proteins was evaluated by a semi-quantitative scoring system. However, total antioxidative capacity (TAC), catalase, total oxidant status (TOS), and oxidative stress index were measured in rat brain. Final score for apoptosis in the exposed group was significantly lower than the sham (p < 0.001) and the cage control groups (p < 0.01). p53 was not significantly changed by the exposure (p > 0.05). The total antioxidant capacity and catalase in the experimental group was found higher than that in the sham group (p < 0.001, p < 0.05). In terms of the TOS and oxidative stress index, there was no statistically significant difference between exposure and sham groups (p > 0.05). In conclusion, the final score for apoptosis, total antioxidant capacity and catalase in rat brain might be altered by 900 MHz radiation produced by a generator to represent exposure of global systems for mobile communication (GSM) cellular phones.
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PMID:Effect of mobile phone exposure on apoptotic glial cells and status of oxidative stress in rat brain. 2001 25

A 9-month-old p53-null female mouse was found dead in its cage. At necropsy, a large thymic mass encompassed the heart. Microscopically, the mass was composed of numerous varying-sized cysts lined with simple squamous epithelial cells to columnar ciliated cells. Also present within this mass was a large aggregate of loosely arranged fusiform-shaped cells. These cells also were found in smaller numbers in the connective tissue surrounding the cysts. The larger aggregate of fusiform cells was positive for desmin and S-100 and negative for smooth muscle actin. Electron microscopy revealed well-formed Z lines and I bands of skeletal muscle phenotype. A diagnosis of rhabdomyoma within a congenital multilocular thymic cyst was made. The thymus contains a small population of myoid cells, which should be taken in consideration when evaluating thymic tumors.
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PMID:A rhabdomyoma within a multilocular thymic cyst in a p53-null mouse. 2008 Apr 93

p53 is a master regulatory, sequence-specific transcription factor that directly controls expression of over 100 genes in response to various stress signals. Transactivation is generally considered to occur through p53 binding to a consensus response element (RE) composed of two 5'-RRRCWWGYYY-3' decamers. Recently, studying the human angiogenesis-related gene FLT1 we discovered that p53 can mediate limited transactivation at a noncanonical 1/2 site and could synergize with the estrogen receptor (ER) acting in cis at a nearby ER 1/2 site. To address the generality of concerted transactivation by p53 and ER, the 1/2 site in the FLT1 promoter was replaced with a variety of 1/2 sites, as well as canonical weak and strong p53 REs of human target genes. The p53 transactivation of all tested sequences was greatly enhanced by ligand-activated ER acting in cis. Furthermore, enhanced transactivation extends to several cancer-associated p53 mutants with altered function, suggesting ER-dependent mutant p53 activity for at least some REs. The enhanced transactivation was also found with p63 and p73. We propose a general synergistic relationship between p53 family and ER master regulators in transactivation of p53 target canonical and noncanonical REs, which might be poorly responsive to p53 on their own. This relationship greatly expands the transcriptional master network regulated by p53 in terms of genes affected and levels of expression and has implications for the appearance and possible treatments of cancer.
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PMID:Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. 2008 Jun 30

T-cadherin is believed to act against carcinogenesis in various tissues; however, its tumor-suppressor mechanism remains largely unclear. Using subtractive mRNA hybridization and immunoblotting, the present study identified several cancer-associated molecules whose expression was modified by T-cadherin in gallbladder cancer cells. Restoration of T-cadherin decreased the expression of Akt3 and phosphorylated Akt molecules. SET7/9, which stabilizes chromatin-bound p53, was downregulated by silencing of T-cadherin but was not regulated by the expression of T-cadherin. These finding suggest that T-cadherin might inhibit tumor progression through multiple pathways, including the Akt and SET7/9-p53 pathways.
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PMID:T-cadherin modulates tumor-associated molecules in gallbladder cancer cells. 2012 46

The RNA-binding protein tristetraprolin (TTP) regulates expression of many cancer-associated and proinflammatory factors through binding AU-rich elements (ARE) in the 3'-untranslated region (3'UTR) and facilitating rapid mRNA decay. Here we report on the ability of TTP to act in an anti-proliferative capacity in HPV18-positive HeLa cells by inducing senescence. HeLa cells maintain a dormant p53 pathway and elevated telomerase activity resulting from HPV-mediated transformation, whereas TTP expression counteracted this effect by stabilizing p53 protein and inhibiting hTERT expression. Presence of TTP did not alter E6 and E7 viral mRNA levels indicating that these are not TTP targets. It was found that TTP promoted rapid mRNA decay of the cellular ubiquitin ligase E6-associated protein (E6-AP). RNA-binding studies demonstrated TTP and E6-AP mRNA interaction and deletion of the E6-AP mRNA ARE-containing 3'UTR imparts resistance to TTP-mediated downregulation. Similar results were obtained with high-risk HPV16-positive cells that employ the E6-AP pathway to control p53 and hTERT levels. Furthermore, loss of TTP expression was consistently observed in cervical cancer tissue compared to normal tissue. These findings demonstrate the ability of TTP to act as a tumor suppressor by inhibiting the E6-AP pathway and indicate TTP loss to be a critical event during HPV-mediated carcinogenesis.
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PMID:The mRNA decay factor tristetraprolin (TTP) induces senescence in human papillomavirus-transformed cervical cancer cells by targeting E6-AP ubiquitin ligase. 2015 55

In its wild-type form, p53 is a major tumor suppressor whose function is critical for protection against cancer. Many human tumors carry missense mutations in the TP53 gene, encoding p53. Typically, the affected tumor cells accumulate excessive amounts of the mutant p53 protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wild-type p53, the common types of cancer-associated p53 mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mutant p53 gain-of-function. This article addresses the biological manifestations of mutant p53 gain-of-function, the underlying molecular mechanisms, and their possible clinical implications.
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PMID:Mutant p53 gain-of-function in cancer. 2018 18

Cyclooxygenases (COXs) have important functions in various physiological and pathological processes. COX-2 expression is highly induced by a variety of stimuli and is observed during certain periods of embryonic development. In this report, the direct effect of COX-2 expression on embryonic development is examined in a novel COX-2 transgenic mouse model that ubiquitously expresses human COX-2 from the early stages of embryonic development. COX-2 transgenic fetuses exhibit severe skeletal malformations and die shortly after birth. Skeletal malformations are localized along the entire vertebral column and rib cage and are linked to defective formation of cartilage anlagen. The cartilage anlagen of axial skeleton fail to properly develop in transgenic embryos because of impaired precartilaginous sclerotomal condensation, which results from the reduction of cell number in the sclerotome. Despite the ubiquitous expression of COX-2, the number of apoptotic cells is highly increased in the sclerotome of transgenic embryos but not in other tissues, suggesting that it is a tissue-specific response. Therefore, the loss of sclerotomal cells due to an increased apoptosis is probably responsible for axial skeletal malformations in transgenic fetuses. In addition, the sclerotomal accumulation of p53 protein is observed in transgenic embryos, suggesting that COX-2 may induce apoptosis via the up-regulation of p53. Our results demonstrate that the aberrant COX-2 signaling during embryonic development is teratogenic and suggest a possible association of COX-2 with fetal malformations of unknown etiology.
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PMID:Embryonic expression of cyclooxygenase-2 causes malformations in axial skeleton. 2023 42


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