共查询到20条相似文献,搜索用时 93 毫秒
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G. J. S. Jenkins C. Morgan J. N. Baxter E. M. Parry J. M. Parry 《Mutation Research - Genetic Toxicology and Environmental Mutagenesis》2001,498(1-2)
We have analysed five mutation hotspots within the p53 gene (codons 175, 213, 248, 249, and 282) for mutations induced by hydrogen peroxide (H2O2), employing the restriction site mutation (RSM) assay. In addition, four other restriction sites covering non-hotspot codons of exons 5–9 of the p53 gene (codons 126, 153/54, 189 and the 3′ splice site of exon 9) were analysed by the RSM assay for H2O2-induced mutations. Two cell types were concurrently analysed in this study, i.e. primary fibroblast cells and a gastric cancer cell line. Using the RSM assay, H2O2-induced mutations were only detected in exon 7 of the p53 gene. This was true for both cell types. These mutations were mainly induced in the Msp I restriction site (codon 247/248) and were predominantly GC to AT transitions (71%). Hence these GC to AT mutations were presumably due to H2O2 exposure, possibly implicating the 5OHdC adduct, which is known to induce C to T mutations upon misreplication. Importantly, this study demonstrates that the RSM methodology is capable of detecting rare oxidative mutations within the hotspot codons of the p53 tumour suppressor gene. Hence, this methodology may allow the detection of early p53 mutations in pre-malignant tissues. 相似文献
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Wu CC Krahe R Lozano G Zhang B Wilson CD Jo EJ Amos CI Shete S Strong LC 《Human genetics》2011,129(6):663-673
Li–Fraumeni syndrome (LFS) is a rare familial cancer syndrome characterized by early cancer onset, diverse tumor types, and multiple
primary tumors. Germ-line TP53 mutations have been identified in most LFS families. A high-frequency single-nucleotide polymorphism, SNP309 (rs2279744),
in MDM2 was recently confirmed to be a modifier of cancer risk in several case-series studies: substantially earlier cancer onset
was observed in SNP309 G-allele carriers than in wild-type individuals by 7–16 years. However, cancer risk analyses that jointly
account for measured hereditary TP53 mutations and MDM2 SNP309 have not been systematically investigated in familial cases. Here, we determined the combined effects of measured
TP53 mutations, MDM2 SNP309, and gender and their interactions simultaneously in LFS families. We used the method that is designed for extended
pedigrees and structured for age-specific risk models based on Cox proportional hazards regression. We analyzed the cancer
incidence in 19 extended pedigrees with germ-line TP53 mutations ascertained through the clinical LFS phenotype. The dataset consisted of 463 individuals with 129 TP53 mutation carriers. Our analyses showed that the TP53 germ-line mutation and its interaction with gender were strongly associated with familial cancer incidence and that the association
between MDM2 SNP309 and increased cancer risk was modest. In contrast with several case-series studies, the interaction between MDM2 SNP309 and TP53 mutation was not statistically significant in our LFS family cohort. Our results showed that SNP309 G-alleles were associated
with accelerated tumor formation in both carriers and non-carriers of germ-line TP53 mutations. 相似文献
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Richard B Richardson 《Cell cycle (Georgetown, Tex.)》2013,12(15):2468-2478
TP53’s role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer’s TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies other than TP53 that reduce p53 activity. 相似文献
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Mutability in Pseudomonas viridiflava as a programmed balance between antibiotic resistance and pathogenicity
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Claudia Bartoli Jay Ram Lamichhane Odile Berge Leonardo Varvaro Cindy E. Morris 《Molecular Plant Pathology》2015,16(8):860-869
Mutable bacterial cells are defective in their DNA repair system and often have a phenotype different from that of their wild‐type counterparts. In human bacterial pathogens, the mutable and hypermutable phenotypes are often associated with general antibiotic resistance. Here, we quantified the occurrence of mutable cells in Pseudomonas viridiflava, a phytopathogenic bacterium in the P. syringae complex with a broad host range and capacity to live as a saprophyte. Two phenotypic variants (transparent and mucoid) were produced by this bacterium. The transparent variant had a mutator phenotype, showed general antibiotic resistance and could not induce disease on the plant species tested (bean). In contrast, the mucoid variant did not display mutability or resistance to antibiotics and was capable of inducing disease on bean. Both the transparent and mucoid variants were less fit when grown in vitro, whereas, in planta, both of the variants and wild‐types attained similar population densities. Given the importance of the methyl‐directed mismatch repair system (MMR) in the occurrence of mutable and hypermutable cells in human bacterial pathogens, we investigated whether mutations in mut genes were associated with mutator transparent cells in P. viridiflava. Our results showed no mutations in MMR genes in any of the P. viridiflava cells tested. Here, we report that a high mutation rate and antibiotic resistance are inversely correlated with pathogenicity in P. viridiflava, but are not associated with mutations in MMR. In addition, P. viridiflava variants differ from variants produced by other phytopathogenic bacteria in the absence of reversion to the wild‐type phenotype. 相似文献
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Complete sequence of p53 gene in 20 patients with lung cancer: comparison with chemosensitivity and immunohistochemistry 总被引:2,自引:0,他引:2
Daniel Brattstr?m Michael Bergqvist Kristina Lamberg Wolfgang Kraaz Lena Scheibenflug Gunnar Gustafsson Mats Inganas Gunnar Wagenius Ola Brodin 《Cancer immunology, immunotherapy : CII》1998,15(4):255-261
In this study the entirep53 complementary DNA has been sequenced in 20 non-small cell lung carcinomas (NSCLC) and the results correlated with chemosensitivity,
immunohistochemistry and clinical data. Ten patients had mutations inp53, 8 missense mutations and 2 nonsense mutations. The method discovered two mutations never described previously and two other
mutations that have never been described before in connection with NSCLC tumours. Chemosensitivity data, according to a short-term
assay (FMCA), indicated that tumours with p53 mutation were more resistant to cisplatin and cyclophosphamide. Immunohistochemical
studied demonstrated a 70% concordance between over-expression of p53 protein and mutation inp53. No conclusions or trends could be drawn from the immunohistochemical studies ofBcl-2 andBax. 相似文献
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Monica Driscoll 《Developmental neurobiology》1992,23(9):1327-1351
In C. elegans, cell death can be readily studied at the cellular, genetic, and molecular levels. Two types of death have been characterized in this nematode: (1) programmed cell death, which occurs as a normal component in development; and (2) pathological cell death which occurs aberrantly as a consequence of mutation. Analysis of mutations that disrupt programmed cell death in various ways has defined a genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells. Molecular analysis is providing insightinto the nature of the molecules that function in these aspects of programmed cell death. Characterization of some genes that mutate to induce abnormal cell death has defined a novel gene family called degenerins that encode putative membrane proteins. Dominant alleles of at least two degenerin genes, mec-4 and deg-1, can cause cellular swelling and late onset neurodegeneration of specific groups of cells. © 1992 John Wiley & Sons, Inc. 相似文献
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To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer. 相似文献
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Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner
Sue Haupt Catherine Mitchell Vincent Corneille Jake Shortt Stephen Fox Pier Paolo Pandolfi Mireia Castillo-Martin Dennis M. Bonal Carlos Cordon-Cardo Guillermina Lozano Ygal Haupt 《Cell cycle (Georgetown, Tex.)》2013,12(11):1722-1731
p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers. In healthy cells these two key tumor suppressors exist in a positive regulatory loop, promoting cell death and cellular senescence. However, the influence of their interplay on tumorigenesis has not been explored directly in vivo. The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53wild-type/R172H) that recapitulates a frequent p53 mutation (p53R175H) in human sporadic and Li-Fraumeni cancers. These mice with PML displayed perturbation of the hematopoietic compartment, manifested either as lymphoma or extramedullary hematopoiesis (EMH). EMH was associated with peripheral blood leucocytosis and macrocytic anemia, suggestive of myeloproliferative- myelodysplastic overlap. In contrast, a complete loss of PML from these mice resulted in a marked alteration in tumor profile. While the incidence of lymphomas was unaltered, EMH was not detected and the majority of mice succumbed to sarcomas. Further, males lacking PML exhibited a high incidence of soft tissue sarcomas and reduced survival, while females largely developed osteosarcomas, without impact on survival. Together, these findings demonstrate that PML is an important tumor suppressor dictating disease development in a pertinent mouse model of human cancer. Key Points: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative / myelodysplastic overlap. (2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC). 相似文献
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Sarah G. Bailey Tilman Sanchez-Elsner Anastasis Stephanou Mark S. Cragg Paul A. Townsend 《Apoptosis : an international journal on programmed cell death》2010,15(5):541-552
The p53 gene super family consists of three members; TP53, TP63 and TP73, encoding proteins p53, p63 and p73. Whilst p63 appears to have an essential role in embryonic development with a less clear role in carcinogenesis, irregularities
in p53 and p73 signalling are implicated in tumour formation. As such, p53 is a tumour suppressor which is mutated in over
50% cancers and p73 was recently formally classified as a tumour suppressor based on data showing p73 deficient mice generate
spontaneous tumours similar to those observed in p53 null mice. Dysregulation of both p53 and p73 has been correlated with
cancer progression in many cell types and although mutation of these genes is often observed, some form of p53/p73 deregulation
likely occurs in all tumour cells. The discovery that complementary micro RNAs (miRNAs) are able to target both of these genes
provides a potential new means of perturbing p53/p73 signalling networks in cancer cells. Here we summarise the current literature
regarding the involvement of miRNAs in the modulation of p53 family proteins and cancer development and detail the use of
in silico methods to reveal key miRNA targets. 相似文献
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Yuji?Yamanishi David?L?Boyle Douglas?R?Green Edward?C?Keystone Alison?Connor Susan?Zollman Gary?S?Firestein
Abnormalities in the p53 tumor suppressor gene have been detected in rheumatoid arthritis (RA) and could contribute to the pathogenesis of chronic
disease. To determine whether synoviocytes from invasive synovium in RA have an increased number of mutations compared with
non-erosion synoviocytes, p53 cDNA subclones from fibroblast-like synoviocytes (FLS) derived from erosion and non-erosion sites of the same synovium were
examined in patients requiring total joint replacement. Ten erosion FLS lines and nine non-erosion FLS lines were established
from nine patients with RA. Exons 5–10 from 209 p53 subclones were sequenced (114 from erosion FLS, 95 from non-erosion FLS). Sixty percent of RA FLS cell lines and 8.6% of
the p53 subclones isolated from FLS contained p53 mutations. No significant differences were observed between the erosion and non-erosion FLS with regard to the frequency
or type of p53 mutation. The majority of the mutations were missense transition mutations, which are characteristic of oxidative damage.
In addition, paired intact RA synovium and cultured FLS from the same joints were evaluated for p53 mutations. Matched synovium and cultured synoviocytes contained p53 mutations, although there was no overlap in the specific mutations identified in the paired samples. Clusters of p53 mutations in subclones were detected in some FLS, including one in codon 249, which is a well-recognized 'hot spot' associated
with cancer. Our data are consistent with the hypothesis that p53 mutations are randomly induced by genotoxic exposure in small numbers of RA synoviocytes localized to erosion and non-erosion
regions of RA synovium. The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence
of a p53 mutation. 相似文献
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Yong Chen Jian-Xin Shi Xu-Feng Pan Jian Feng Heng Zhao 《Genetics and molecular biology》2013,36(3):455-464
Over the past three decades, mortality from lung cancer has sharply and continuously increased in China, ascending to the first cause of death among all types of cancer. The ability to identify the actual sequence of gene mutations may help doctors determine which mutations lead to precancerous lesions and which produce invasive carcinomas, especially using next-generation sequencing (NGS) technology. In this study, we analyzed the latest lung cancer data in the COSMIC database, in order to find genomic “hotspots” that are frequently mutated in human lung cancer genomes. The results revealed that the most frequently mutated lung cancer genes are EGFR, KRAS and TP53. In recent years, EGFR and KRAS lung cancer test kits have been utilized for detecting lung cancer patients, but they presented many disadvantages, as they proved to be of low sensitivity, labor-intensive and time-consuming. In this study, we constructed a more complete catalogue of lung cancer mutation events including 145 mutated genes. With the genes of this list it may be feasible to develop a NGS kit for lung cancer mutation detection. 相似文献
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