UNIPROT:P04637 - FACTA Search

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

Expression of the p53 oncoprotein was examined in a wide range of primary human testicular germ-cell tumours using a new mouse monoclonal antibody (MAb) BP53-11 raised and characterized in this study, in parallel with a polyclonal rabbit antiserum CM-1. Immunohistochemistry on paraffin sections showed positive nuclear reaction in at least a fraction of malignant cells in 90 (84%) out of 107 cases studied. Aberrant accumulation of the p53 protein was found among testicular tumours of all major histological types, although generally a higher percentage of positive cases and a higher proportion of p53 over-expressing nuclei within individual lesions was observed in embryonal carcinomas when compared with seminomas. The typical heterogeneous staining pattern characteristic of histological specimens was also found in a cultured cell line derived from a human embryonal carcinoma. In contrast to immunohistochemically undetectable levels in normal testes and morphologically normal tissue areas in the tumour-bearing testes, the accumulation of the p53 protein was clearly identified in a high proportion (59% of cases) of the pre-invasive lesions with positive atypical intratubular germ cells often found in the tissue adjacent to invasive tumours. Altered expression of the p53 protein is therefore a unifying feature of the majority of invasive male germ-cell tumours and the change resulting in high levels of p53 appears to be a relatively early step in the human testicular cancer pathogenesis.
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PMID:p53 protein alterations in human testicular cancer including pre-invasive intratubular germ-cell neoplasia. 165 67

Alterations in the p53 tumor suppressor gene appear to be important in the development of many human tumors. The wild-type p53 gene has a polymorphism at codon 72 that presents the arginine (CGC) or proline (CCC) genotype, which recently has been reported to be associated with genetically determined susceptibility to smoking-related lung cancers. To determine whether this p53 genotype influences individual risk of urologic cancer and/or its progression, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis to assay the allelic frequencies of this polymorphism in 85 renal cell carcinoma patients, 151 urothelial cancer patients, 33 testicular cancer patients, 28 prostatic cancer patients and 56 patients without neoplastic disease. The allelic distributions of the three genotypes (Arg/Arg, Arg/Pro, Pro/Pro) in patients with renal cell carcinoma (29.4%, 55.3%, 15.3%), urothelial cancers (45.7%, 39.7%, 14.6%), testicular cancer (45.4%, 48.5%, 6.1%) or prostate cancer (42.9%, 50.0%, 7.1%) did not differ significantly from those in the normal controls. However, Pro/Pro genotype in renal cell carcinoma and urothelial cancer (smoking-related cancers) was more frequent than that in prostate cancer and testicular cancer (smoking-unrelated cancers) with borderline significance (P = 0.0881). There was no particular correlation between frequency of the three genotypes and grade or stage of each type of tumor. The association of genetic predisposition to urologic cancers with p53 gene codon 72 polymorphism is not so clear as the previous study of Japanese lung cancer patients, but this polymorphism may play some role in urothelial cancers and renal cell carcinoma, in which smoking is an epidemiological risk factor.
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PMID:Allelic frequency of p53 gene codon 72 polymorphism in urologic cancers. 755 95

Little is known of the molecular changes that occur in germ cell tumors (GCT) of the testis. We studied three GCT cell lines and 44 tumors for loss of heterozygosity (LOH) of the tumor suppressor genes APC, MCC, DCC, RB, TP53, and WT-1. We observed that LOH occurred in 55% (21 of 38) of informative cases at DCC, in 28% (10 of 36) of informative cases at APC, in 23% (6 of 26) at MCC, in 30% (13 of 43) at RB, and in 27% (6 of 22) at WT-1. The LOH level in these tumors using anonymous primers mapping to the short and long arms of chromosome 19, which is cytogenetically normal in GCT, revealed LOH of 11 and 5%, respectively. We also observed a LOH of 22% in the TP53 gene, despite the fact that mutations in TP53 do not occur in testis cancer. Since a high frequency of LOH at DCC (18q21.3) occurs equally at all histological subsets in GCT, we conclude that the loss of the function of this gene is an early event in testicular GCTs. However, the observed LOH levels at APC/MCC (5q21), RB (13q14), and WT-1 (11p13) could represent a functional loss of the corresponding tumor suppressor gene in some GCTs or reflect the loss of sequences in the same general chromosome region but involving a different tumor suppressor locus. Therefore, detailed mapping of these chromosomes is required to define the precise locations of maximal LOH in testis cancer.
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PMID:Loss of heterozygosity of tumor suppressor genes in testis cancer. 779 15

The tumor suppressor gene p53 is the most frequently mutated gene in human cancer. We have used polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing to examine the status of the p53 gene in human testicular cancers of various histologies. We were unable to find in 40 samples and four cell lines any mutations in the regions of this gene (exons 5 through 8) that are usually mutated in other cancers. Northern blot analysis showed expression of this gene in most of the samples analyzed, as well as in four human testicular tumor cell lines. The MDM-2 gene is amplified and overexpressed in sarcomas; it binds and functionally inactivates p53. The 44 testicular tumor samples and cell lines were examined for amplification of MDM-2 by dot-blot analysis; none was found. The proto-oncogene c-kit probably plays an important role in normal testicular development. Mutation of the tyrosine phosphorylation site of a closely related member of this family of tyrosine kinase receptors (c-fms) is associated with cellular transformation and cancer. Codon 936 is the analogous tyrosine of c-kit; using polymerase chain reaction-single-strand conformation polymorphism analyses, we were unable to detect mutations at this site in our 44 testicular cancer samples. We conclude from our studies that mutations in the most conserved region of the p53 gene, as well as at codon 936 of the c-kit gene and amplification of MDM-2, are extremely rare in human testicular cancers.
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PMID:Mutations of the p53 gene are not detectable in human testicular tumors. 806 72

To characterize the role of p53 in the development of testis cancer, we looked for mutations in the coding sequences of the p53 gene. DNA was obtained both from familial and sporadic testis cancer specimens, as well as from peripheral blood from members of a testis cancer kindred. Mutations in the p53 gene were screened using a combination of constant denaturant gel electrophoresis and single-strand conformational polymorphism analysis, 2 screening methods that can detect single base changes. Abnormalities detected by these methods were confirmed by sequencing of the corresponding cloned polymerase chain reaction products. All conserved regions of the p53 coding sequences were examined, encompassing all previously reported sites of mutations. No mutations were found in any of 22 germ cell cancers of the testis or in the germline DNA of 17 members of the testis cancer family. This is in striking contrast to most other human cancers, in which mutations of p53 are the most commonly described molecular event associated with tumorigenesis. We conclude that dysfunction of tumor suppressor gene or genes other than p53 may prove to play an important role in the development of germ cell cancers of the testis.
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PMID:Mutations of the p53 gene do not occur in testis cancer. 833 63

The rising rate of germ cell cancer of the testis over the past decade has been demonstrated to be occurring predominantly in the younger age group (15 to 19 years) in association with earlier onset of puberty and earlier onset of regular sexual activity. Chemicals and viruses, with their atrophogenic effect, remain the main candidates for inducing the final common pathway of tumor development and clonal evolution, ie, gonadotropin-driven mitosis in spermatogonia. The possibility of different genetic mechanisms regulating susceptibility and resistance to these two extreme causes of gonadal atrophy in families is raised by the failure of a genome screen in a series of sibling pairs with testicular cancer to identify a single significant linkage group. Studies demonstrating high levels of non-mutated p53 protein and rapid induction of apoptosis by chemotherapy provide a new insight into the cause of the exquisite chemosensitivity of these tumors. Durable responses to paclitaxel and in vitro activity in response to temezolamide provide further evidence of the plethora of agents that work against these tumors, although no new first-line therapeutic approaches have been reported recently. The most important clinical trial studied good-risk patients and demonstrated that to gain the benefit of reducing treatment time from 12 to 9 weeks it is essential to retain bleomycin in the BEP (bleomycin, etoposide, and cisplatin) regimen. The final new idea to emerge recently comes from a series of papers on management of primary tumors in patients with a solitary testis and the possible use of organ-conserving surgery plus postoperative radiation. Another study did suggest it might be possible to use preoperative chemotherapy in those wishing to retain spermatogenesis.
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PMID:Testicular cancer. 880 10

Three different treatment strategies for patients with stage I non-seminomatous testicular cancer are available that will all result in long-term survival in more than 98% of the patients: a "wait and see" strategy with follow-up and chemotherapy in cases of tumour progression, retroperitoneal lymphadenectomy, with or without application of systemic chemotherapy, in cases of retroperitoneal metastases (pathological stage II disease) or primary adjuvant chemotherapy following inguinal orchiectomy. Each treatment strategy is associated with specific side-effects. In several studies histological characteristics of the primary tumour, particularly the presence of vascular invasion and of embryonal carcinoma cells, have been demonstrated to be significant prognostic factors for the risk of occult retroperitoneal metastases in patients with stage I disease. In addition, new biological prognostic factors determined by flow cytometry, cytogenetic analysis or molecular-biological DNA or RNA analysis have been investigated, among which alterations of the p53 tumour-suppressor gene may represent a promising new prognostic factor. Although alterations of p53 gene expression seem to be associated with advanced tumour stage and may predict retroperitoneal metastatic disease, the independent role of these molecular genetic alterations needs to be prospectively studied. Currently a risk-adapted treatment strategy based on the histological criteria of vascular invasion and the presence of embryonal carcinoma can be used to stratify patients into a "high-" and "low-risk" group with respect to tumour progression. While primary-nerve-sparing retroperitoneal lymphadenectomy or adjuvant chemotherapy with two cycles of platinum, etoposide and bleomycin may be appropriate for patients with a high risk (above 40%) for tumour progression, a "wait-and-see" strategy can be used for "low-risk" (less than 15% risk of progression) patients. Molecular investigations of prognostic factors may be able to improve further the stratification of patients into these different risk categories.
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PMID:Treatment of clinical stage I testicular cancer and a possible role for new biological prognostic parameters. 887 54

Although the concept that transplacentally acting estrogen-mimicking chemicals damage fetal germ cells is still the most favored hypothesis to explain the link between declining sperm counts and rising testis cancer, there has been increasing recognition that other mechanisms may be contributing. With reports confirming the association between a sedentary lifestyle and rising incidence of testis cancer and a fourfold increased relative risk of delay in conception of more than 3 months found for those driving a vehicle for more than 3 hours a day, there is increasing recognition that heat may be one of the most important cofactors. The role of p53 in heat-mediated damage and deficiency of heat shock protein response of germ cells and germ cell cancer are providing increasing interest in the search for molecular mechanisms to explain the unique chemosensitivity of this group of tumors. Perhaps the most controversial report was the finding of mutations insufficient to block apoptosis in 67% of tumor p53 genes using a RNA-SSCP analysis, when only a quarter of them had mutations identified by conventional DNA sequencing. The acceptance that immunosuppression, whether HIV- or chemically induced, increases risk of germ cell cancer by 20 to 50 times that in the general population is perhaps the most important final confirmation of the immune-surveillance hypothesis, although there is no evidence as yet that it seriously worsens the chance of long-term cure in these patients. Further progress is being reported on the use of high-dose chemotherapy and stem-cell transplants, although the risks of treatment-related mortality still restrict its use to second line treatment. The problem of patient consent to the increasing range of options for early-stage disease is something highlighted from reports over the past year that will undoubtedly be an important issue in the future.
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PMID:Testis cancer. 922 52

The role of p53 in testicular germ cell tumours is still contradictory based on the finding of immunohistochemical overexpression at the protein level, but lack of mutations at the DNA level. In addition, p53 wild-type activity has been demonstrated in cell culture experiments. Overexpression of the proto-oncogene bcl-2 might block p53-induced apoptosis and might inhibit p53 functional activity. To clarify the apparent paradox with respect to p53 overexpression and lack of mutations, an immunohistochemical and mutational analysis of p53 and bcl-2 in TGCT was performed. Ten normal testes, 52 CIS and 151 clinical stage I nonseminomatous GCTs were included in our study. A commercially available anti-p53 polyclonal rabbit antibody and an anti-bcl-2-mouse monoclonal antibody were used to stain the 5pm sections. Staining was assessed by counting at least 500 cells from the area of the most intense staining in each tumour cell type, and this was scored semiquantitatively for intensity of staining on a 4 point scale. In addition, 30 primary GCTs were included in the mutational analysis: areas with p53 overexpression were identified and microdissected prior to DNA extraction. p53 exons 5-8 were amplified by polymerase chain reaction (PCR) followed by single strand conformation polymorphism analysis. Templates demonstrating band shifts on SSCP were subjected to direct DNA sequence analysis. None of the normal testes, 32/52 (62%) CIS, and 142/151 (94%) germ cell tumours exhibited p53 overexpression. p53 expression was significantly lower in mature teratomas (0.8 +/- 0.2) than in other germ cell tumour components (2.8 +/- 1.2, p > 0.001). PCR-SSCP did not reveal any missense mutations or deletions for the p53 gene. Bcl-2 protein expression was observed in none of the normal testes, in none of the CIS, and in 14/151 (9.3%) germ cell tumours. 13/14 germ cell tumours demonstrated bcl-2 expression only in the glandular and stromal elements of their teratomatous components whereas all other components were negative for bcl-2. Our results--p53 overexpression, lack of p53 mutations, undetectable bcl-2--are consistent with recent in vitro studies. High susceptibility of testicular cancer to drug-induced apoptosis appears to be the result of wild-type p53 and lack of bcl-2. Radiation and chemotherapeutic insensitivity of mature teratomas might be the result of bcl-2 overexpression and lack of p53 overexpression. Therefore, chemoresistance to DNA damaging agents might be reflected by the expression of p53 and bcl-2 and it might be useful to evaluate p53 and bcl-2 in primary tumours and metastatic lesions in order to identify patients early with primary or secondary chemoresistance.
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PMID:Immunohistochemical and mutational analysis of the p53 tumour suppressor gene and the bcl-2 oncogene in primary testicular germ cell tumours. 952 67

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.
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PMID:Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. 1128 Jul 90

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