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

The gene p53 encodes a transcriptional activator of genes involved in growth arrest, DNA repair and apoptosis. Loss of p53 function contributes to tumour development in vivo. The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product. Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumour development. To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 and p53 and obtained progeny homozygous for both p53 and mdm2 null alleles. Rescue of the mdm2-/- lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.
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PMID:Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. 747 26

The growth suppressor p53 plays an important role in the regulation of cell proliferation, DNA repair and apoptosis. In wild-type p53 expressing cells, gamma-irradiation induces an increase in the level of p53 protein and these cells exhibit a G1 growth arrest. The p53-induced G1 growth arrest is abrogated in cells expressing mutant p53, or in cells where p53 is inactivated by complex formation with cellular or viral proteins such as mdm2 or the E6 proteins of human papillomavirus (HPV) 16 or HPV18. Wild-type p53 expressing cells are radiosensitive whereas mutant p53 expressing cells are radioresistant. In some cell types, p53 mutations are observed after gamma-irradiation of cells although this observation is not consistent for all cell types. Furthermore, it is not clear whether these mutations are the direct result of irradiation or secondary effects.
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PMID:Marker genes for cytotoxic exposure: p53. 748 39

Inhalation of diesel exhaust (DE), which contains soot particles with adsorbed mutagenic organic compounds, and its virtually mutagen-free soot particle analog, carbon black (CB), produce similar types and prevalences of pulmonary neoplasms in chronically exposed F344 rats. This result suggests that DE-induced neoplasia develops from the effects of a high lung burden of carbonaceous particles rather than from the genotoxicity of organic constituents. In this investigation, pulmonary carcinomas from rats exposed to DE or CB were analyzed for alterations in K-ras and p53 to determine if mutations caused by these agents are also similar. K-ras and p53 were chosen for this study because mutation patterns of these genes in lung neoplasms have been associated with specific exposures. A low frequency (3/50) and variable pattern of activating mutations were identified in codons 12 and 61 of the K-ras gene. Immunoreactive levels of p53 protein, suggesting gene dysfunction, were present in 7/13 squamous cell or adenosquamous carcinomas, regardless of the associated exposure. However, single-strand conformational polymorphism analysis and direct sequencing of p53 did not detect any mutations in these neoplasms. No immunoreactivity or mutations in p53 were observed in adenocarcinomas. The increased level of p53 protein in the squamous carcinomas is not explained by stabilization by the mdm2 gene product, because this protein was not overexpressed based on immunohistochemical analysis. No pattern of mutation was detected that would suggest a differential mechanism of carcinogenicity between DE and CB; however, inactivation of the p53 pathway may have a role in the development of rat lung neoplasms with a squamous cell carcinoma component.
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PMID:Low frequency of alterations in p53, K-ras, and mdm2 in rat lung neoplasms induced by diesel exhaust or carbon black. 753 40

Fifty-three non-small cell lung carcinomas (NSCLC), previously investigated for p53 abnormalities, were studied to evaluate the status of the mdm2 gene by Southern and Northern blot analysis and expression of the mdm2 protein by immunohistochemistry with specific monoclonal antibodies. Amplification and overexpression of the mdm2 gene and nuclear accumulation of its protein product were observed in three (6%) of the NSCLC examined. All of the tumors having mdm2 abnormalities belonged to a subset of NSCLC characterized by a strong accumulation of the p53 protein in the absence of p53 gene mutations. Since mdm2 is capable of forming tight complexes with p53, possibly stabilizing it, our results suggest that this event may take place in a low percentage of NSCLC. Moreover, all of the mdm2-positive tumors were histologically classified as lung adenocarcinomas. This may indicate that the mdm2 gene is preferentially altered in this particular subtype of lung tumors.
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PMID:mdm2 gene amplification and overexpression in non-small cell lung carcinomas with accumulation of the p53 protein in the absence of p53 gene mutations. 755 Dec 99

We performed a serologic analysis for anti-murine double minute-2 (anti-mdm2) antibodies in sera of patients with different gynaecological diseases using immunoblotting technique with recombinant mdm2 as antigen. In addition, for large scale screening we established an anti-mdm2 enzyme-linked immunosorbent assay (ELISA). Serum samples from patients with breast cancer, ovarian carcinoma, cervix carcinoma and benign gynaecological tissue alterations were tested. We detected antibodies specific for mdm2 in sera derived from cancer patients, as well as from patients with non-malignant diseases. Some of the sera with antibodies against mdm2 also contained antibodies against the growth suppressor gene product p53.
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PMID:Antibodies against murine double minute-2 (mdm2) in sera of patients with various gynaecological diseases. 755 98

The cellular protein MDM2 can bind to the tumor suppressor gene product p53 and abrogate its transcriptional activity. In addition, p53 can regulate expression of the mdm2 gene. We and others have previously shown that p53 is present at high levels in adenovirus-transformed cells which express the larger E1B protein. In view of these observations the expression of MDM2 in a panel of adenovirus transformed human cell lines has been examined. Two major species (98K and 80K) were detected, together with a number of minor species of higher and lower molecular weight. While there was little variation in levels of 98K protein between cell lines, appreciable differences in the expression of the 80K component were apparent. There was no correlation between MDM2 and p53 expression in any of the adenovirus transformants, nor with the viral proteins expressed. The pattern and level of MDM2 detected was similar to that seen in human tumor cell lines and in human fetal tissue. Northern blot analysis suggested that MDM2 expression was regulated at the transcriptional level. Stable interactions were observed between p53 and MDM2 in the adenovirus-transformed cell lines and in Ad5 E1 HEK 293 cells a ternary complex of p53, MDM2, and the Ad5 E1B 58K protein was demonstrated. In view of the lack of correlation between the level of p53 and MDM2 in adenovirus E1-transformed cells, the capacity of p53 to cause transcriptional activation was assessed using transfected CAT constructs linked to p53 responsive elements. p53 transcriptional activity was similar in all of the cell lines examined and did not correlate with protein expression. It is concluded, on the basis of all of these data, that the high concentrations of p53 found in adenovirus transformants are not transcriptionally active and have no influence on MDM2 expression. However, when expression of p53 was increased following infection with mutant adenoviruses, which do not express the larger E1B proteins, there was an appreciable increase in p53 transcriptional activity and in the levels of all of the MDM2 components.
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PMID:The high levels of p53 present in adenovirus early region 1-transformed human cells do not cause up-regulation of MDM2 expression. 761 70

The replacement of functional genes into cells that lack genes or have mutant genes is the basis of gene therapy. In cancer, where cells often have multiple genetic defects, the replacement of critical genes may suffice to suppress cell growth or induce cell death. The high frequency of mutations of the p53 tumor-suppressor gene in human cancers, including primary brain tumors, suggests that p53 plays a critical role in carcinogenesis and tumor progression. We report the successful transfer of the wild-type p53 gene using a defective herpes simplex viral vector into a human medulloblastoma cell line containing a mutant copy of p53. Upon gene transfer, we detected novel expression of wild-type p53 protein in the cells. In addition, the p53 protein was functionally active, since gene transfer resulted in increased levels of mdm2 proteins and induced cell cycle arrest of the majority of transduced cells. To our knowledge, this is the first report of the use of this vector system to carry wild-type p53. We conclude that defective herpes simplex viral vectors can transfer and express p53 in human primary brain tumor cells in vitro, restoring wild-type p53 tumor-suppressor functions.
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PMID:Gene transfer of wild-type p53 results in restoration of tumor-suppressor function in a medulloblastoma cell line. 764 54

The temperature-sensitive mutant p53 tsp53val135 (tsp53) displays a mutant phenotype at 38 degrees C, but assumes properties of a wild-type (wt) p53 at 32 degrees C. We analysed the cellular responses of two cell lines which ectopically overexpress tsp53, and dramatically differ in their responses to tsp53 expressed at 32 degrees C. Clone 6 (cl6) cells [precrisis rat embryo fibroblasts transformed by tsp53val135 and an activated ras oncogene at 38 degrees C (Michalovitz et al., 1990. Cell 62, 671-680) stop to grow and arrest mainly in the G1 phase of the cell cycle, whereas MethAp53ts cells [BALB/c mouse MethA tumor cells, transfected with the same tsp53 encoding vector as cl6 cells (Otto and Deppert, 1993. Oncogene 8, 2591-2603)] do not growth arrest at 32 degrees C. Both cell lines expressed similar amounts of tsp53, which was mainly cytoplasmic at 38 degrees C and mainly nuclear at 32 degrees C. At 32 degrees C, both cell lines contained similar amounts of waf1/cip1 mRNA. However, the amount of mdm2 mRNA in MethAp53ts cells was considerably higher compared to that in cl6 cells. The different transcriptional regulation of the mdm2-gene in cl6 and MethAp53ts cells at 32 degrees C indicated that the tsp53 proteins in these cells were functionally different. This assumption was supported by our finding that at 32 degrees C phosphorylation of the tsp53 in these cells was markedly different. We conclude that the cellular environment is an important determinant of p53 function.
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PMID:Cell-specific transcriptional activation of the mdm2-gene by ectopically expressed wild-type form of a temperature-sensitive mutant p53. 765 32

The mdm2 gene is a target for transcriptional activation by the p53 tumor suppressor gene product. Previous work has revealed that the mouse mdm2 gene contains two promoters: one is located upstream to the gene and is active in the absence of p53, the other resides within the first intron and requires p53 for transcriptional activity. To determine whether this unique promoter activation pattern is biologically important, we investigated the structure and function of the corresponding region of the human mdm2 (hmdm2) gene. We report here that the hmdm2 gene also contains an intronic, p53-dependent promoter. The structural features of this promoter are highly conserved between mouse and man, as opposed to the lack of conservation of the first exon. This promoter is triggered in vivo in the presence of activated wild type p53, leading to the production of novel mRNA species. The intronic hmdm2 promoter contains two tandem p53 binding elements. Deletion analysis suggests that optimal promoter activity requires the simultaneous binding of p53 to both elements; this may serve to prevent premature triggering of the promoter by p53.
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PMID:A functional p53-responsive intronic promoter is contained within the human mdm2 gene. 765 18

Hyperplastic lesions of the oropharyngeal mucosa such as leukoplakia and oral lichen planus can eventually develop into squamous cell carcinomas (SCC) and provide an excellent model for multistage carcinogenesis. The development of carcinomas is assumed to be the result of the interaction of genetic factors, locally applied carcinogens and immunological unresponsiveness. Recently a novel gene termed mdm2 has been isolated that is found to be involved in transcriptional regulation and can inhibit p53 function by forming a complex with p53. In this study the immunohistochemical detection of the MDM2 protein in 186 paraffin embedded tissue sections of normal mucosa, premalignant, malignant and metastatic lesions of the oropharyngeal mucosa is reported for the first time. p53 protein expression was also investigated in the same tissue samples. The increase in the number of p53 and MDM2 positive biopsies was correlated with the dysplasia grade and the loss of differentiation in the premalignant and malignant lesions. In late stages of the disease the number of biopsies that expressed both p53 and MDM2 increased. Inactivation of p53 function in head and neck carcinogenesis may also be due to MDM2 binding. Detection of MDM2 protein expression by immunohistochemistry may be an important diagnostic tool in the future.
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PMID:Detection of p53 and MDM2 protein expression in head and neck carcinogenesis. 765 34


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