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

Cancer is generally understood to be a genetic disease in the sense that somatic mutations are the cause of tumour initiation and development. Our knowledge of cancer-associated genes and gene products has evolved mainly over the past 20 years. The identification and characterization of tumour suppressor genes (TSGs) as normal growth-inhibiting or apoptosis-inducing genes have helped us to understand how mutations are tumorigenic. Various TSG encoding membrane-, cytosol-, or nuclear proteins have been identified. Tumor suppressor genes are often functionally inactive in cancer cells because of mutations of both parental gene copies. Many TSGs are associated with hereditary cancer diseases or syndromes caused by the existence of one mutant allele in the germ-line. Individuals who carry only one functional gene copy, are therefore at great risk of developing cancer. Several TSGs, such as TP53, RB1 and CDKN2A, encode proteins that are significant to the cell cycle. TP53 is the most frequently mutated gene in human cancer, showing changes in more than 50% of all solid tumours. Both DNA repair and apoptosis are stimulated by p53-induced transcription of genes involved in the two processes. The characterization of TSGs and their gene products has led to the identification of a number of new diagnostic and prognostic molecular genetic parameters in oncology. Furthermore, some TSGs are potentially among the most promising and important targets for gene therapy in cancer and other hyperproliferative diseases.
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PMID:[Tumor suppressors--genes and proteins]. 963 59

We investigated the dynamics of the genetic changes that are associated with two types of glioma recurrence, that is, progression from a lower-grade to a high-grade tumor (7 cases) and development of a same high-grade recurrence (15 cases). Each pair of tumors was analyzed for TP53 mutation, EGFR amplification, and loss of heterozygosity for tumor suppressor genes (TP53, RB1, CDKN2A, PTEN, DMBT1) and tumor suppressor gene regions (1p36, 19q13, 11p15, 10p15) known to be frequently implicated in glioma tumorigenesis. By comparing the genetic changes in the primary and corresponding secondary tumors, we found that additional loss of CDKN2A and/or RB1, encoding important components of the cell cycle regulatory pathway, was the most frequent genetic change in both types of recurrence development (10 of 22 cases, 45%). Additional loss of heterozygosity for the 10p15 region, for PTEN, and/or for DMBT1 in the recurrent tumor was noted in 7 of 22 cases (32%), suggesting that additional inactivation of tumor suppressor genes on chromosome 10 is another important feature of glioma relapse. Less frequent additional losses were detected for chromosome regions 11p15 and 19q13 (3 of 22 cases, 14%, each). We conclude that glioma recurrences are characterized by an increased involvement of tumor suppressor genes, even in those cases in which the primary and secondary tumor are of the same high malignancy grade.
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PMID:Dynamics of genetic alterations associated with glioma recurrence. 973 18

We have used FISH to determine the level of synchronisation in replication timing of four pairs of alleles, unrelated to chromosome 21 (p53, HER2, RB1, and c-myc), in foetal (amniotic fluid) cell samples of Down syndrome and in normal foetuses. All samples derived from the Down syndrome subjects showed large temporal differences in replication timing, in contrast to the high level of synchrony shown in all samples of normal individuals. Thus, as judged by four independent loci which are not associated with chromosome 21, the additional chromosome in the Down syndrome genome induces changes in the replication pattern of an allelic pair: from a synchronous pattern characteristic to concomitantly expressed alleles to an unsynchronised one shown by alleles displaying an allele-specific mode of expression.
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PMID:Asynchronous replication of allelic loci in Down syndrome. 978 Oct 44

The p16-pRb and p53-MDM2 pathways represent vital cell cycle checkpoints. Recent studies provide evidence that these pathways are directly linked via MDM2-pRb interaction and p53 suppression of the RB1 gene. In the present study we investigated the alterations of this G1 phase protein network using immunohistochemical and molecular methods in a series of 68 non-small-cell lung carcinomas (NSCLCs) and correlated the findings with clinicopathological features and prognosis of the patients. Aberrant expression (Ab) of p16 and pRb was observed in 33 (49%) and 27 (40%) of the carcinomas, respectively. Analysis of the region that encodes for p16 by deletion mapping, a polymerase chain reaction (PCR)-based methylation assay and PCR single-strand conformation polymorphism (SSCP) analysis revealed that deletions and transcriptional silencing by methylation might represent the main mechanisms of CDKN2/p16ink4a inactivation in NSCLCs. The results of deletion mapping also suggest that other tumor suppressor genes may reside at the 9p21-22 region, which encodes for CDKN2/MTS1/p16ink4a, p14ARF, and MTS2/p15ink4b. In addition, microsatellite instability was observed with a frequency of 16% in the 9p21-22 chromosome area. Overexpression (P) of p53 and MDM2 proteins was found in 39 (58%) and 47 (70%) of the cases, respectively. A highly significant association was observed between p53 overexpression and p53 mutations (P = 0.006). Statistical analysis of the expression patterns of the biologically relevant molecules (p16/pRb, p53/MDM2, MDM2/pRb, and p53/pRb) showed coincident overexpression of p53 and MDM2 (P = 0.04) and that abnormal pRb was correlated with elevated levels of MDM2 (P = 0.013) and p53 (P = 0.01), respectively. We suggest that deregulated expression of these molecules may act synergistically. An important finding of the study was that multiple impairments (three and four molecules affected) of the p16/pRb/p53/MDM2 network occurred in a large proportion (43%) of the carcinomas. This finding in addition to the absence of correlation with clinical stage of the tumors suggests that multiple hits of this network may be a relatively early event in the development of a subset of NSCLCs. The relationship between the factors examined in the present study, clinicopathological features, and survival of the patients did not reveal any significant correlations with the exception of smoking, which was associated with microsatellite alterations (loss of heterozygosity and microsatellite instability) at the 9p21-22 locus (P = 0.04) and the immunophenotypes p53(P)/MDM2(P) (P = 0.04) and p16(Ab)/pRb(Ab)/p53(P)/MDM2(P) (P = 0.03), respectively. We suggest that in a subset of NSCLCs, simultaneous deregulation of the members of this network may represent one way of initiating the oncogenic procedure whereas in other NSCLC subgroups alternative pathways may play this role.
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PMID:Alterations of the p16-pRb pathway and the chromosome locus 9p21-22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. 984 66

Transformation and immortalization require the inactivation of key cell cycle regulatory genes. We examined 19 bladder cancer cell lines derived from 17 patients for alterations in TP53, RB1, CDKN2A, and ARF. Twelve cell lines had a mutation in exons 5-11 of TP53 and, with only one exception, a concomitant loss of RB1 protein expression. Another group of seven cell lines had a wild-type TP53 gene or a mutation in exons 1-4 of TP53 and concomitant alterations in both CDKN2A and ARF in every case. This demonstrates the requirement, in all but one line, for inactivation of both the CDKN2A/RB1 and ARF/TP53 pathways in bladder cancer cell lines and provides the first evidence for potential differences in the penetrance of mutations in the transactivation and DNA-binding domains of TP53.
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PMID:Presence and location of TP53 mutation determines pattern of CDKN2A/ARF pathway inactivation in bladder cancer. 985 64

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.
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PMID:Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. 1008 36

Advanced-stage epithelial ovarian cancers (EOC) from 114 patients were assessed for loss of heterozygosity (LOH or allelic imbalance) at several tumor suppressor gene loci as an initial step in identifying gene alterations important to the development of these tumors. The highest frequency of loss, 84% (86 of 102 cases), was observed for markers mapping near or within BRCA1; other significant frequencies of LOH were observed for loci mapping near or within CDKN2A/CDKN2B (56%), BRCA2 (61%), RB1 (67%), or TP53 (73%). No instance of TP53 LOH was observed without simultaneous allelic imbalance at the BRCA1 region (P = 0.0005). LOH of CDKN2 without loss near the BRCA1 region was seen in only 2 of 75 cases (P < 0.0001), and RB1 LOH without BRCA1 loss occurred in only 1 of 35 tumors (P = 0.0703). These data suggest that LOH of BRCA1, or a closely linked locus, precedes the loss of CDKN2, TP53, and RB1, and imply that inactivation of a tumor suppressor gene in this region is an important early step in the development of these tumors.
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PMID:Loss of markers linked to BRCA1 precedes loss at important cell cycle regulatory genes in epithelial ovarian cancer. 1022 42

Using a series of tumorigenic and non-tumorigenic somatic cell hybrids that resulted from the fusion of the human osteosarcoma cell line OHS50-P16T (P16T) with the HeLa cell line D98OR, we investigated the role that genetic mutations, including alterations of oncogenes, tumor suppressor genes, and chromosomes, play in P16T tumorigenicity. Analysis of a previously identified oncogene mutation, c-myc amplification, in the P16T cell line demonstrated that both the tumorigenic and non-tumorigenic hybrids contained the amplified c-myc gene. Analysis of previously identified P16T tumor suppressor gene alterations, p53 mutation, and loss of RB1 expression demonstrated that the mutated p53 gene was selectively maintained in both the non-tumorigenic and tumorigenic hybrids, whereas loss of RB1 expression was not maintained in either the non-tumorigenic or tumorigenic hybrids. Chromosomes 11, 13, 17, and 22 were analyzed for loss of heterozygosity (LOH) to characterize the status of these previously described chromosomal alterations in the tumorigenic and non-tumorigenic hybrids. Loss of HeLa D98OR chromosome 22, with maintenance of P16T chromosome 22, was observed in the tumorigenic hybrids, a result confirmed by LOH analysis, which demonstrated the specific loss of HeLa chromosome 22 genetic material in the tumorigenic segregants. Together, these results demonstrated that amplified c-myc, mutant p53, and RB1 genes seem to be important in osteosarcoma tumorigenicity and that an additional altered gene or genes on chromosome 22 may play a key role in osteosarcoma tumorigenicity.
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PMID:Analysis of oncogene, tumor suppressor gene, and chromosomal alterations in HeLa x osteosarcoma somatic cell hybrids. 1033 42

Gliomas are thought to arise from the glial cells of brain tissue. The spectrum of tumours varies with age, implying that cells in a particular state of development are a prerequisite for the occurrence of some tumour types. Premalignant states are not recognized, so we know little about the earliest events in oncogenesis. However, progression of gliomas has been examined by studying large series of tumours of different malignancy grades and by following cases where the tumour is of low malignancy grade at first diagnosis and recurs later as a tumour of higher malignancy grade. When considering premalignant states we can only extrapolate from our knowledge of progression from the least to the most malignant tumour forms. The best studied variants are the astrocytic tumours. There are no consistent genetic aberrations known to characterize the most benign variant of astrocytoma, the pilocytic astrocytoma (malignancy grade I), which occurs mainly in children. Astrocytomas (malignancy grade II) show loss of alleles at 13q, 17p and 22q and occur mainly in early middle age. Loss of one TP53 allele (17p) is associated with mutation of the remaining allele. Loss of one RB1 allele is not. Anaplastic astrocytomas (malignancy grade III) have in approximately 50% of cases aberrations of genes coding for proteins involved in the control of entry into the S phase of the cell cycle, as well as other genetic defects affecting unknown genes. The greatest number of genetic abnormalities is seen in glioblastomas (malignancy grade IV), which have a peak incidence in late middle age. Around 80% of glioblastomas can be shown to have genetic alterations resulting in aberrant control of progression from G1 to the S phase of the cell cycle, and many show amplification of growth factor receptor genes as well as other abnormalities. The bewildering number of genetic anomalies becomes intelligible as we discover that different components of the same cellular control mechanisms are being targeted in individual tumours resulting in a similar phenotype.
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PMID:Gliomas. 1048 22

The human genome is thought to contain about 80,000 genes and presently only 3,000 are known to be implicated in genetic diseases. In the near future, the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers, which is growing in frequency in industrial states. The collection of these mutations will be critical for researchers and clinicians to establish genotype/phenotype correlations. Other fields such as molecular epidemiology will also be developed using these new data. Consequently, the future lies not in simple repositories of locus-specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on-line. To meet this goal, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data. Thanks to the flexible structure of the UMD software, it has been successfully adapted to nine genes either involved in cancer (APC, P53, RB1, MEN1, SUR1, VHL, and WT1) or in genetic diseases (FBN1 and LDLR). Four new LSDBs are under construction (VLCAD, MCAD, KIR6, and COL4A5). Finally, the data can be transferred to core databases.
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PMID:UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. 1061 27


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