Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MDM2 (murine double minute 2) gene has recently been shown to code for a cellular protein that can complex the p53 tumor suppressor gene product and inhibit its function. We studied a series of 157 primary brain tumors and report here that the MDM2 gene is amplified and overexpressed in 8-10% of glioblastomas and anaplastic astrocytomas. Thus, MDM2 represents the second most frequently amplified gene after the epidermal growth factor receptor gene in these tumor types. Sequencing of the p53 transcripts in the cases with MDM2 amplification revealed no mutations and restriction fragment length polymorphism analysis showed, with one exception, no losses of alleles on chromosome 17. Our results indicate that amplification and overexpression of MDM2 may be an alternative molecular mechanism by which a subset of human malignant gliomas escapes from p53-regulated growth control.
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PMID:Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. 850 13

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of the TP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), or MDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p = 0.045 by the logrank test). TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, or MDM2 genes. These results demonstrate that, while only rare medulloblastomas contain TP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.
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PMID:Prognostic implications of chromosome 17p deletions in human medulloblastomas. 852 74

The proliferative capacity of breast carcinomas has prognostic significance as measured by S-phase fraction (SPF), yet the molecular parameters that influence the proliferative capacity of breast carcinomas have not been fully elucidated. Ninety-three cases of invasive ductal breast carcinomas, not otherwise specified, were studied by immunohistochemistry and flow cytometry to determine what correlations exist between nuclear grade (NG), SPF, proliferating cell nuclear antigen and the overexpression of p53, epidermal growth factor receptor (EGFR), and c-erb-B-2 in formalin-fixed tissues by the immunoperoxidase method. NG predicted elevated SPF in 78% of cases and was associated with high proliferating cell nuclear antigen score. The presence of p53 was detectable in 13% of cases, and, in each case, the NG was high (Grade 3), with nine aneuploid tumors and three diploid tumors. The SPFs for all p53-positive cases were markedly elevated, with 77.8% of the cases with SPF > 15%. EGFR was present in 20.4% of all tumors, including 77.8% of tumors positive for p53 and 14% of tumors negative for p53 (P < .001). The mean SPF for p53-positive EGFR-positive tumors was 17.5% versus 21.1% for p53-positive EGFR-negative tumors. The mean SPF for p53-negative tumors was significantly less, regardless of the presence of EGFR. The gene c-erb-B-2 was found in 28% of tumors, all of which were p53 negative. These data clearly show a close relationship between high NG and elevated SPF. As determined by flow cytometry, SPF is more consistent and more reliably related to NG than proliferating cell nuclear antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlations of morphology, proliferation indices, and oncogene activation in ductal breast carcinoma: nuclear grade, S-phase, proliferating cell nuclear antigen, p53, epidermal growth factor receptor, and c-erb-B-2. 853 97

We examined the reactivity of four p53-specific monoclonal antibodies--PAb 1801, p53-BP-12, D07 and CM1--on sections of formalin-fixed tissue collected from 245 breast carcinomas. Immunodetection of p53 varied between 37.6% and 46.6%. The greatest variation was observed among lobular carcinomas and low-grade tumors in which immunodetection varied between 8.3% and 27.3%. In contrast, immunodetection of p53 in invasive ductal carcinomas was subject to a lower degree of variability with between 40.6% and 49.7% of these tumours proving to be positive. In general, we found antibodies PAb 1801 and DO7 to be the most effective in immunolocalising p53. Immunodetection of p53 with each of the four antibodies was found to correlate strongly with tumour grade. In survival analysis, the results gained using antibody PAb 1801 proved to be of greatest statistical significance and to provide the strongest index of prognosis. A significant relationship was observed between immunodetection of p53 with each of the four antibodies and poor responsiveness to endocrine therapy. In addition, relationships were also observed between p53 immunostaining and tumour oestrogen receptor (ER) status as well as c-jun expression. We observed no correlation between abnormalities of the p53 and the Rb gene products or between elevated c-erbB-2 or epidermal growth factor receptor (EGFR) expression and immunodetection of p53.
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PMID:p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry. 855 79

We have sequenced p53 in three colon cancer cell lines capable of autonomous proliferation. SNU-C1 and SNU-C4 cells, whose autonomous growth is dependent upon autocrine stimulation of epidermal growth factor receptor (EGFR), had wildtype p53 sequence of exons 4-9. In contrast, an EGFR ligand-independent cell line, SNU-C5, had heterozygous missense mutations affecting codons 218 (valine to leucine) and 248 (arginine to tryptophan) of p53. Bacterial cloning of p53 from SNU-C5 cells showed that the 248trp and 218leu mutants were both expressed and on separate alleles. 248trp is a common 'hot spot' mutant of p53 with variable dominant negative activity depending on the celullar context. Valine 218, in contrast, is rarely affected by mutation in cancers and is located in a region of the hydrophobic core domain away from 'hot spot' DNA contact sights. However, valine 218 is completely conserved across species, prompting us to investigate the function of 218leu in SNU-C5 cells. SNU-C5 cells exhibited complete loss of normal p53 function as evidenced by over-expression of p53 protein and by failure to show induction of p53, waf-1, mdm-2 or G1/S arrest in response to the DNA damaging agent, bleomycin. In a yeast p53 functional assay (FASAY), 50% of the clones were unable to transactivate a p53-specific promoter required for yeast colony expansion at 25, 30 or 37 degrees C. Sequencing of the p53 insert from several randomly selected wild-type and mutant yeast clones revealed that 218leu-bearing clones retained their ability to transactivate the p53-specific promoter. As expected, the 248trp-bearing clones lost this function. These data indicate that although 218leu retains normal transactivation activity on a p53 promoter in yeast at physiological temperatures, it is not capable of normal p53 function in the presence of a 248trp allele in SNU-C5 cells. It remains unclear whether the strong dominant negative activity of 248trp in SNU-C5 cells is related to the cellular context or to an unresolved abnormality of 218leu function.
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PMID:p53 functional loss in a colon cancer cell line with two missense mutations (218leu and 248trp) on separate alleles. 855 7

Uterine malignant mixed mesodermal tumors (MMMT) are highly malignant tumors containing both malignant glands and stroma, while adenosarcomas (AS) are less aggressive tumors composed of malignant stroma and benign glands. Immunohistochemistry was used to grade overexpression of p53 protein, HER-2/neu protein, epidermal growth factor receptor (EGFR), and Ki-67 antigen in both the glands and stroma of tissue from 20 women with MMMT and 6 women with AS. EGFR was overexpressed in 2 AS and 9 MMMT, and was more commonly found in the sarcomatous component than the carcinomatous component in MMMT (P = 0.03). p53 was not found in any AS samples and was strongly present in 6 MMMT samples with a random distribution between the malignant components. HER-2/neu protein was not overexpressed in any AS or primary MMMT. Ki-67 antigen, a marker of cell proliferation, was found at higher levels in MMMT than AS samples (P = 0.03) and high Ki-67 antigen expression correlated with a decreased survival in patients with MMMT (P = 0.004). Independent characterization of oncogene proteins in the malignant components of these heterogeneous tumors may provide insight into the histogenesis and behavior of these malignancies.
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PMID:The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma. 855 33

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
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PMID:Multiple genetic alterations in malignant metastatic insulinomas. 856 94

p53 mutations are the most frequently detected genetic alterations of gliomas, appearing in a similar proportion of low and high grade astrocytomas, while the amplification of epidermal growth factor receptor (EGFR) gene appears mainly in glioblastomas. Thus, these changes seem to delineate two subgroups of high grade astrocytomas: those originating from preexistent low grade astrocytomas and those originating de novo. Paraffin-embedded surgical specimens from 56 human astrocytomas (8 pilocytic (I.) astrocytomas, 9 low grade (II.) fibrillary astrocytomas, 9 high grade (III.) anaplastic astrocytomas and 30 glioblastomas) were analyzed immunohistochemically for the presence of p53 protein and EGFR. Approximately 41% of all cases were p53-protein-positive while 23% were EGFR-positive. Five cases (8.9%) were double-positive for p53 protein and EGFR. The p53-immunopositive nuclei were revealed in 16 cases (53.3%) of glioblastomas, 3 cases (33.3%) of high grade and 4 cases (44.4%) of low grade astrocytomas. None of pilocytic tumors was p53-positive. EGFR immunopositivity increased with the grade of malignancy (11.1%, 22.2% and 33.3%). Double EGFR-p53-positive cases occuried in similar proportions in all grades (approximately 10%) and did not show different survival rate. There were no differences between average age of patients with only-p53-positive, p53-negative (pilocytic tumors excluded) and only-EGFR-positive tumors.
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PMID:p53 protein and epidermal growth factor receptor expression in human astrocytomas. 858 40

Basaloid-squamous carcinoma (BSC) of the esophagus is a rare but interesting neoplasm that occurs primarily in the upper aerodigestive tract. In this study, we reviewed 371 cases of esophageal malignancies and detected seven cases (1.9%) of BSC. The clinicopathologic features, light and electron microscopic findings, and immunohistochemical localization of various differentiation-related antigens, including cytokeratin (CK) subtypes, p53, and epidermal growth factor receptor (EGFR), were examined. DNA ploidy was also determined in an effort to characterize the biologic features of these tumors. The tumors were classified as stage I (n = 1), IIB (n = 3), III (n = 2) or IV (n = 1). Six patients had lymph node metastasis, in four the metastatic carcinoma exhibited basaloid components. Histologically, all the tumors displayed a biphasic pattern of basaloid and squamous components. The former predominated in three cases, the latter in four cases. All the tumors contained solid growth of basaloid cells with microcystic patterns and stromal hyalinosis as well as palisading of cells. Ultrastructurally, markedly replicated basement membrane was observed. Immunohistochemistry revealed staining with only CK 14 and CK 19 antibodies in the periphery of the basaloid tumor nests. These antibodies were also positive in the basal layer of normal esophagus. Diffuse immunoreactivity for EGFR was demonstrated in all the tumors. Five tumors displayed p53 nuclear immunoreactivity. All of the basaloid components demonstrated aneuploidy by DNA image cytometry. We conclude that BSC is a distinct type of esophageal carcinoma that should be differentiated from the usual types of esophageal carcinoma and may be associated with aggressive biologic behavior.
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PMID:Basaloid-squamous carcinoma of the esophagus. A clinicopathologic, DNA ploidy, and immunohistochemical study of seven cases. 860 12

Recent studies suggest that aberrations of c-erbB-2 may be involved in astrocytic brain tumours. We screened immunohistochemically c-erbB2 protein (p185) expression in 94 astrocytic grade 1-4 neoplasms of the brain. The amplification of the c-erbB-2 oncogene was investigated in protein overexpression cases by dual colour fluorescence in situ hybridisation (FISH). p185 overexpression was correlated with p53 and epidermal growth factor receptor (EGFR) expression, as well as with clinicopathological features. Only two anaplastic (grade 3) astrocytomas and one glioblastoma (grade 4) showed overexpression of p185 protein by immunohistochemistry (monoclonal MAb1 antibody TA250), whereas none of the grade 1-2 astrocytomas was positive. Interestingly, the expression of p185 was confined solely to the cytoplasm of neoplastic astrocytic cells and not to the cell membranes as found in malignancies with amplification of the c-erbB-2 oncogene. Two of the three overexpression cases were also positive by EGFR. No amplification of the c-erbB-2 gene was observed by FISH in the three tumours with immunohistochemical p185 overexpression or seven weakly positive/negative tumours. In conclusion, our results suggest that p185 overexpression is infrequent in astrocytomas, that it is of no important diagnostic or prognostic value and that c-erbB-2 oncogene amplification is not seen in the few cases in which there is overexpression.
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PMID:c-erbB-2 in astrocytomas: infrequent overexpression by immunohistochemistry and absence of gene amplification by fluorescence in situ hybridization. 860 96


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