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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent developments in the field of oncogenes and growth stimulatory factors have provided limited but essential models in neuro-oncology. The observation in gliomas of platelet growth factor (PDGF)-like immunoreactivity fits with the autocrine secretion model, rising the possibility for the growth factor independence of the cancer cells. The discovery of the tumor suppressor genes, for which loss of function mutations are oncogenic as in the RB gene of the retinoblastoma and p53 gene, has introduced a new concept of oncogenesis which could be useful even in the cure of the neoplasms. Several oncogenes are amplified and/or expressed in brain tumors, some associated with polymorphism leading to abnormal protein products. Therefore, corresponding functions, such as production of deficient epidermal growth factor receptor (EGFR) encoded by erb-B, are impaired. Abnormal chromosomal patterns have been recognized in brain tumors and found mainly in chromosomes 7 and 22 on which oncogenes erb-B and sis are located, respectively. Location of proto-oncogenes, which are normally expressed in the brain, indicate that they share common distribution patterns mainly involving the cerebellum, hippocampus and olfactory bulbs. These proto-oncogenes may be regulated by physiological and pathological events. The concept of oncogene involvement in brain tumors must be extended to include the other factors such as G-proteins, growth factor receptors, membrane-associated and cytoplasmic protein kinases, which are all responsible for the control of the cell growth and their response to external signals including chemotherapeutic drigs.
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PMID:Oncogenes: cause or consequence in the development of glial tumors. 133 37

The tumor suppressor p53 is a potent transcriptional activator that has been shown to regulate its own expression. In earlier studies, deletion analysis and site-specific mutagenesis identified the p53-responsive element that fits the p53 consensus sequence. In addition, the p53-responsive element was predicted to be a binding site for NF-kappa B. In this study, we showed that NF-kappa B present in HeLa nuclear extracts could bind the same DNA element in a sequence-specific manner. Co-transfection experiments showed that the p65 subunit of NF-kappa B, but not the p50 subunit, could activate the p53 promoter. In HeLa cells, tumor necrosis factor alpha (TNF-alpha) induced NF-kappa B activity. The p53 promoter was also induced by TNF-alpha under the same conditions. Both p65 transactivation and TNF-alpha induction of the p53 promoter depended on an intact NF-kappa B site. Detailed mutational analysis of the p53 and NF-kappa B responsive elements allowed differentiation of these two responses. Thus, we show that NF-kappa B activates p53 and that this activation is inducible by TNF-alpha. Since NF-kappa B induction occurs as a response to stress and p53 arrests cells in G1/S, where repair may be initiated, activation of p53 by NF-kappa B could be a mechanism by which cells can recover from stress.
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PMID:NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. 805 Oct 93

Genetic and molecular abnormalities, in association with malignant phenotypes, have been previously demonstrated in a variety of human tumors. Although the multistep theory fits well for some cancers such as retinoblastoma and colon carcinoma, for many others it still remains to be proven. Neuroblastoma, a tumor found in pediatric patients, seems to fall into the multistep model. Nonrandom chromosome abnormalities have been found with 1p deletion, loss of heterozygosity for short arm of chromosome 1 and for chromosome 11q and 14q. Amplification of N-myc oncogene and an increased level of Ras protein have also been demonstrated. Therefore, even if it is not possible to show that these mutations happen as discrete events in their order of appearance, the multistep model seems involved in neuroblastoma development. Neuroblastoma has a peculiar aspect, however, that makes this tumor a natural model of defect of cell differentiation. In fact, there is a particular subset of metastatic tumors that show spontaneous regression. In vitro, neuroblastoma cell lines can be induced to differentiate along the neural pathway using retinoic acid. Other natural and chemical substances are also able to induce cell differentiation. During retinoic acid treatment, N-myc oncogene expression decreases and other genes are deregulated. p53 and MDR1 gene expression increases. These two different aspects, failure of cell differentiation pathway and genetic mutations, make the neuroblastoma one of the most difficult problems of modern molecular biology.
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PMID:Neuroblastoma: the result of multistep transformation? 840 Dec 51

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.
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PMID:Genetic heterogeneity and unmapped genes for colorectal cancer. 864 Aug 29

Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish 'gatekeeper' and 'caretaker' genes in other tumorigenic pathays.
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PMID:Stochastic modelling of tumorigenesis in p53 deficient mice. 946 Sep 95

We describe a patient in whom synchronous breast cancer and small-cell lung cancer, and metachronous renal cell carcinoma were diagnosed within an 11 months period. All three tumors were treated surgically, followed by administration of tamoxifen, adjuvant chemotherapy with etoposide (2.8 g/m2 total) and vindesine, and administration of interferon alpha and flutamide. The patient developed acute myelomonocytic leukemia 26 months after discontinuation of etoposide-containing chemotherapy. This pattern of multiple neoplasms fits the wider disease spectrum associated with germline mutations of the p53 gene; however, analysis of p53 exons 5-8 did not disclose any sequence abnormalities in this patient. In conclusion, clustering of four (synchronous and metachronous) malignancies may on rare occasions occur in an individual patient and in the absence of a family history of cancer; the sequence during which treatment of primary malignancies may result in treatment-related acute myelocytic leukemia is discussed.
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PMID:Acute myelomonocytic leukemia secondary to synchronous carcinomas of the breast and lung, and to metachronous renal cell carcinoma. 962 Feb 29

Germline mutations of the p53 gene are associated to the Li-Fraumeni, a rare autosomal dominant syndrome characterized by a wide spectrum of tumours including sarcomas, breast carcinomas, brain tumors and adrenocortical carcinomas. In most of the cases, tumours will develop in children and young adults. Germline p53 mutations have been identified in approximately 50% of the families with the Li-Fraumeni syndrome, and in families which only partially fulfilled the definition of the syndrome. Germline p53 mutations are mostly missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53 and these mutations inactivate the transcriptional activity of the protein. In tumours, the wild-type allele is usually lost, which indicates, that p53 inactivation fits the Knudson model. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis and screening for germline p53 mutations may be performed in 1) families including two first degree relatives with cancers belonging to the Li-Fraumeni spectrum, one relative being affected before age 45, 2) children or young adults with a rare tumour of in the general population, belonging to the Li-Fraumeni spectrum, such as adrenocortical carcinoma, and 3) children or young adults under age 45 with multiple primary tumours of the Li-Fraumeni spectrum. In contrast, the clinical benefit of identifying germline p53 mutations carriers in affected families, considering the wide spectrum of tumours associated to this syndrome, remains to be established.
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PMID:[Germline mutations of the p53 gene]. 976 48

In 1998, Storey and co-workers suggested that individuals homozygous for arginine (Arg) at codon 72 of the p53 gene are about seven times more susceptible to human papillomavirus (HPV)-related carcinogenesis than heterozygotes. Since then, several studies from Northern Europe, Japan and the USA have failed to demonstrate a similar correlation. By contrast, a study in Brazil as well as one recent study in Italian and Swedish populations showed strong positive associations. We examined the frequency of p53 codon 72 polymorphism in samples from both invasive and intra-epithelial cervical neoplasias (CIN), and compared them with samples from healthy controls. All 88 samples came from women with a Greek ethnic background. Tissue specimens were collected from archival material with histologically diagnosed low-grade CIN (LGCIN), high-grade CIN (HGCIN) or cervical cancer (CxCa). As a control, we used cellular material newly collected by cytobrush from the cervices of 30 healthy women with normal cytological and colposcopical examinations. p53 Arg homozygosity (Arg/Arg) alone was associated with four-, six- or eight-fold increased risks for LGCIN, HGCIN or invasive cancer, respectively. The frequency of the p53Arg/Arg genotype and of the proline (Pro) allele showed significant linear trends according to the degree of severity of the lesion (P = 0.0007 and P = 0.0009, respectively). Exclusion of the ten HPV16/18-negative cases did not substantially alter the Arg/Arg frequency among the groups nor the significant linear trend. Our results confirm the initial findings of Storey and co-workers, as well as the data of the Brazilian and the recent European study, but do not accord with those of the other aforementioned studies. Variations in ethnic background, laboratory performance, verification of the HPV status, definition of controls, and sample size are the most plausible explanations for this controversy. In all our samples, the distribution of the p53 alleles fits the Hardy-Weinberg equilibrium and the 0.48 frequency of the Pro allele in our controls accords well with the percentages previously reported for different ethnic groups as characteristic of the assumed north-south cline. Some authors assert that the discrepancy in the results could not be attributed to differences in the methods; however, the Brazilian study emphasized the effect of inter-laboratory variation in detecting the association between p53 polymorphism and cervical cancer. Regarding the control group, our samples were only from women with a cytologically and colposcopically benign cervical epithelium. We think that simply choosing 'normal volunteers' for collecting control DNA blood samples without knowing the status of their cervical epithelium is indeed a possible source of bias. Finally, it is very unlikely that loss of heterozygosity at the p53 locus could be a factor interfering with the allelotype distribution. Our present small study results, which suggest a biologically relevant association, provide strong evidence that homozygous arginine at codon 72 of p53 may confer a higher susceptibility to HPV-associated intra-epithelial and invasive cervical neoplasia.
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PMID:p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women. 1083 May 78

To characterize the nature of multiple mutations in the tissues of an intact animal, the Big Blue transgenic mouse mutation detection system was used to examine 1459 mutants from eight normal tissues and 507 mutants from 11 tumors. Multiple mutations occurred and predominantly doublet mutants were identified (i.e. two mutations within one mutant lacI gene), but multiplets of up to five mutations were observed. The frequency of doublets in normal tissues and spontaneous tumors from p53-deficient mice was enhanced to the same degree (660 and 667 fold, respectively) over that expected for two independent mutational events. Doublets, multiplets and singlets have similar patterns of mutation. The distance between mutations in doublets fits an exponential distribution, not that expected for randomly spaced events, suggesting that many doublets occur in rapid succession within the same cell cycle.
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PMID:Evidence that proximal multiple mutations in Big Blue transgenic mice are dependent events. 1102 81

HER2 amplification/overexpression is a marker of poor prognosis in breast cancer. The prognostic impact of HER2 positivity is lower in node-negative compared with node-positive women. The only significant, independent prognostic factors in breast cancer are node status, HER2 status and menopausal status. HER2-positive tumors also contain p53 abnormalities, tend to be hormone receptor and bcl-2 negative, have lymphoid infiltration (LI) and a high mitotic index. Patients with LI who are HER2 positive have a better prognosis than those who are HER2 negative, whereas HER2-positive patients without LI have a significantly worse prognosis than HER2-negative patients. Morphological and biological alterations appear to identify two categories of breast tumor. Two hypotheses may explain the progression to two tumor types: (1) atypical ductal hyperplasia (ADH) is a precursor of ductal carcinoma in situ (DCIS), which is a precursor of invasive ductal carcinoma (IDC); or (2) ADH is a precursor of HER2-negative IDC whereas DCIS is a precursor of HER2-positive IDC. The second theory fits well with two breast cancer subsets and the characteristics of ADH and DCIS. The first type of IDC occurs in older patients, progresses slowly due to estrogen dependency but is aggressive long term. The other type progresses rapidly, is HER2 positive and is more likely to occur in young patients.
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PMID:HER2 as a prognostic factor in breast cancer. 1169 90


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