UNIPROT:B6E4X6 - FACTA Search

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Query: UNIPROT:B6E4X6 (mutant p53)
3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of wild-type p53 tumor suppressor function is the primary mechanism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with germline p53 mutations. Tumors derived from LFS patients frequently retain the normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA tumor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS families, each of whom presented with multiple malignant neoplasms. Patient 1 developed an embryonal rhabdomyosarcoma (RMS) and a choroid plexus carcinoma (CPC), while patient 2 developed a CPC and subsequently presented with both an osteosarcoma (OS) and renal cell carcinoma (RCC). We utilized DNA sequence analysis and immunohistochemistry to determine p53 gene status in the germline and tumors, as well as evidence for SV40 T-antigen oncoprotein expression. Each patient harbored a heterozygous germline p53 mutation at codons 175 and 273, respectively. In patient 1, the normal p53 gene was lost while the mutant p53 allele was reduced to homozygosity in the RMS. Both normal and mutant genes were maintained in the CPC. In patient 2, normal and mutant p53 alleles were retained in both the CPC and RCC. Both specific PCR and immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addition to chromosomal alterations, epigenetic mechanisms may disrupt p53 function during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the normal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetically susceptible individuals.
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PMID:Tissue-specific expression of SV40 in tumors associated with the Li-Fraumeni syndrome. 1149 39

Loss of p53 function is known to compromise cell cycle regulation, inductionof apoptosis, and DNA damage repair and can facilitate neoplastic transformation of cells. Mutations in the p53 gene are identified frequently in breast carcinomas. Li-Fraumeni patients inheriting a mutant p53 allele have an increased risk for developing tumors including breast cancer. Although mouse lines carrying mutations in the p53 gene have been generated, they die primarily of lymphoma and thus to date provide a limited model for the study of this disease and the role of p53 in nonfamilial breast cancer. An increasing body of literature suggests that the incidence of various tumors is determined largely by the genetic background on which mutations are studied. In addition, population studies and studies in animals suggest that environmental factors, together with genetic factors, determine overall risk for development of specific types of tumors. We therefore examined the impact of genetic background together with exposure to ionizing radiation on the development of tumors, particularly mammary tumors, in p53-deficient animals. We report here that modifier alleles present in the BALB/c strain increase the incidence of hemangiosarcomas [15 of 53 (28.3%); P = 0.0007] in p53(-/-) mice above rates reported previously in p53(-/-) mice on a mixed background as compared to the incidence observed in DBA/p53(-/-) mice. However, no increase in the frequency of mammary tumors is seen in these mice or in p53(-/-) DBA/2 animals, nor was an increase in mammary tumors observed in the DBA/2 p53(+/-) mice, even after exposure to 5 Gy of whole-body ionizing radiation. In contrast, a significant increase in the incidence of mammary tumors was observed in similarly treated BALB/c p53(+/-) mice (37.3% versus 6.8%; P = 0.0007). This was accompanied by a comparable decrease in the incidence of lymphomas. These results show that environmental agents together with genetic factors can increase the frequency and decrease the latency of mammary tumors, leading to an incidence similar to that observed in Li-Fraumeni syndrome. Furthermore, it suggests that the risk of development of a particular type of tumor by individuals deficient in p53 after exposure to damaging agents can be influenced by modifier alleles.
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PMID:Impact of ionizing radiation and genetic background on mammary tumorigenesis in p53-deficient mice. 1152 57

Recent evidence identified a genetic and functional link between Chk2 kinase and p53 as a candidate genome integrity checkpoint and a tumour suppressor pathway. Here we report that in human cells, Chk2 and p53 form protein-protein complexes whose abundance increased upon DNA damage, and whose formation was abrogated through cancer associated mutations in the FHA domain of Chk2, or mutations in the tetramerization domain of p53. Whereas among Li-Fraumeni syndrome families mutations of Chk2 or p53 occur in a mutually exclusive manner, we document that the colon cancer cell line HCT-15 concomitantly lacks functions of both Chk2 and p53, the latter demonstrated by a non-invasive reporter assay monitoring p53-dependent transactivation in live cells. Despite the preserved ability of common cancer-derived mutant p53 proteins to bind and potentially 'titrate' activated Chk2, the integrity of the S phase checkpoint response to ionizing radiation remained largely intact and dependent on Chk2 in cells with wild-type, mutant, or no p53. These results provide new mechanistic insights into the Chk2-p53 interplay, suggest how mutations in Chk2 may abrogate its tumour suppressor function, and indicate that compared with individual defects in either Chk2 or p53, concomitant mutations in both of these cell cycle checkpoint regulators may provide some additional selective advantage to tumour cells.
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PMID:Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. 1157 48

The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer.
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PMID:Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer? 1205 52

Mutations and deletions in p53 are the most common genetic lesions in human cancer,and an extraordinarily high incidence of lung cancer occurs in smokers suffering from Li-Fraumeni syndrome, which is characterized by germ-line inactivation of one p53 allele. In contrast, p53 mutations are infrequent in lung tumors formed in A/J mice. Moreover, despite the dominant role of cigarette smoke in the epidemiology of human lung cancer, it is very difficult to reproduce the lung tumorigenicity of this complex mixture in animal models. We used a transgenic mouse with a dominant-negative p53 mutation to examine the effects of a mutant p53 on smoke-induced lung carcinogenesis in mice. p53 mutant (UL53-3 x A/J)F(1) mice of both genders and their wild-type (wt) littermate controls were exposed whole-body to environmental cigarette smoke (ECS) for up to 9.5 months. Untreated mutant mice of both genders underwent an early stimulus of bronchial cell proliferation, and an age-related formation of DNA adducts in lung and heart. In males, there was an age-related increase of micronucleated normochromatic erythrocytes in peripheral blood and an impairment of body weight gain. These findings underscore a physiological protective role of p53 in wt A/J mice. The response of wt and mutant mice to ECS was similar in terms of oxidative DNA damage in lung and heart, proliferation of the bronchial epithelium, and levels of p53 oncoprotein, as assessed after exposure for 28 days. In contrast, ECS-exposed mutant mice underwent a lower induction of apoptosis in bronchial epithelium, a greater formation of DNA adducts in lung and heart, and a more intense cytogenetic damage, shown by a higher frequency of micronuclei in pulmonary alveolar macrophages and in peripheral blood normochromatic erythrocytes. Interestingly, at the end of the experiment, DNA adducts were not repaired in either wt or mutant mice after discontinuing exposure to ECS for 1 week. A weak but significant increase of lung tumor incidence and multiplicity was induced in p53 mutant (UL53-3 x A/J)F(1) mice after exposure to ECS for either 5 months, followed by recovery in air for 4.5 months, or 9.5 continuative months. Conversely, no tumorigenic effect was observed in their wt littermate controls, carrying a 99.9% A/J background and 5% FVB genome. This contrasts with the weakly positive results obtained in previous studies using wt A/J mice. Thus, in agreement with the results of previous lung tumorigenicity studies performed with the smoke carcinogens benzo(a)pyrene and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, (UL53-3 x A/J)F(1) mice carrying a mutant p53 transgene appear to be more sensitive to ECS than the corresponding wt littermate controls. These findings provide evidence that p53 mutations play a role in smoke-related carcinogenesis not only in humans but also in A/J mice.
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PMID:Molecular alterations and lung tumors in p53 mutant mice exposed to cigarette smoke. 1259 28

Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were characterized with respect to telomere length and genomic instability. The remaining wild-type p53 allele is lost in the cell lines. Telomerase activity was undetectable in all immortal cell lines. Five subclones of each cell line and five re-subclones of each of the subclones also showed undetectable telomerase activity. All five immortal cell lines exhibited variability in the mean length of terminal restriction fragments (TRFs). Subclones of each cell line, and re-subclones of the subclones also showed TRF variability, indicating that the variability is owing to clonal heterogeneity. Chromosome aberrations were observed at high frequencies in these cell lines including the subclones and re-subclones, and the principal types of aberrations were breaks, double minute chromosomes and dicentric chromosomes. In addition, minisatellite instability detected by DNA fingerprints was observed in the immortal cell lines. However, all of the cell lines were negative for microsatellite instability. As minisatellite sequences are considered recombinogenic in mammalian cells, these results suggest that recombination rates can be increased in these cell lines. Tumor-derived human cell lines, HT1080 cells and HeLa cells that also lack p53 function, exhibited little genomic instability involving chromosomal and minisatellite instabilities, indicating that chromosomal and minisatellite instabilities observed in the immortal cell lines lacking telomerase activity could not result from loss of p53 function.
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PMID:Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities. 1277 Oct 41

p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca(2+) from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress.
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PMID:p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. 1505 85

The p53 tumor suppressor gene is commonly altered in human tumors, predominantly through missense mutations that result in accumulation of mutant p53 protein. These mutations may confer dominant-negative or gain-of-function properties to p53. To ascertain the physiological effects of p53 point mutation, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/- mice. In addition, p53R270H/- and p53R172H/- mice developed novel tumors compared to p53-/- mice, including a variety of carcinomas and more frequent endothelial tumors. Dominant effects that varied by allele and function were observed in primary cells derived from p53R270H/+ and p53R172H/+ mice. These results demonstrate that point mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss of p53 function.
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PMID:Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. 1560 80

The p53 alterations frequently found in human tumors are missense mutations in the DNA binding domain. These p53 mutations have been shown to have gain-of-function or dominant-negative properties in multiple experiments. The consequences of these p53 mutations at physiological levels on the development of a tumor were unclear. Using mouse models, three recent papers have shed light on the mechanisms of mutant p53 and its family members, p63 and p73, in tumorigenesis. Interestingly, the p53 point mutant mice had a similar phenotype to p53 family compound mutant mice suggesting that there is an interplay between the p53 family members in tumorigenesis and Li-Fraumeni syndrome.
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PMID:Li-Fraumeni syndrome: a p53 family affair. 1591 54

The tumor suppressor p53 is the most frequently mutated gene in human cancer. In vivo models have been generated using knock-in alleles in which missense mutations are introduced that mimic the kinds of mutations found in human cancers, or that abolish specific p53 functions. Critically, these studies examine the in vivo and physiological functions of p53. Studies indicate that p53 missense mutations in the DNA-binding domain identical with those inherited in the Li-Fraumeni syndrome, have distinct properties. Studies in mice with mutants that separate cell-cycle arrest and apoptosis functions of p53 show delayed onset of tumor development, suggesting that both p53 functions are crucial for suppressing tumors. Mice with mutations at post-translational modification sites exhibit subtle effects on p53 activity and tumor development, indicating a fine-tuning mechanism of p53 activity in vivo. Importantly, each mutant mouse has a distinct phenotype, suggesting diverse and exquisite mechanisms of p53 regulation in different environments, different tissues and different genetic backgrounds. The generation of these mutant p53 knock-in mice has laid the groundwork for future studies to elucidate the in vivo physiological function of mutant p53 and to examine cooperating effects in combination with other alterations.
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PMID:Crippling p53 activities via knock-in mutations in mouse models. 1740 26

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