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)

Adult human male germ cell tumors (GCTs) provide a unique opportunity to study the generation of a transformed pluripotential cell from a totipotential GC in lineage differentiation and on the path to gametogenesis. The pluripotentiality of the tumor cells manifests as histological differentiation into GC-like undifferentiated (SE), primitive zygotic (EC), embryonal-like somatically differentiated (TE), and extra-embryonally differentiated (CC, YST) phenotypes. The tumors and cell lines derived from them comprise exceptional model systems for the molecular analysis of human embryonal cell fate and lineage differentiation. The majority of GCTs show exquisite sensitivity to cisplatin-based treatment and have served as models for the development of chemotherapy for solid tumors. Until recently, the molecular mechanisms of GC transformation, GCT differentiation, or GCT chemotherapy sensitivity and resistance were understood poorly. Very recent studies of GCTs have suggested that: (a) overexpression of cyclin D2 is a very early, possibly the oncogenic, event in GC tumorigenesis; (b) differentiation in GCTs may be governed by several possibly interacting pathways, such as loss of regulators of GC totipotentiality and of embryonic development, and genomic imprinting; and (c) chemotherapy sensitivity and resistance may be rooted in part in a p53-dependent apoptotic pathway. In this review, these new data are discussed in the context of GC and GCT biology, and several novel testable genetic models are proposed.
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PMID:Genetics and biology of adult human male germ cell tumors. 1074 7

Inbred 129 strain mice are predisposed to developing male germ cell tumors (GCTs) of the testes. The inherent genetic defects that underlie male GCT susceptibility in the 129 mouse strain are unknown. GCT incidence is increased in 129 strain males that lack functional p53 protein, and we have used this finding to facilitate the generation of panels of GCT-bearing intercross and backcross mice for genetic mapping analysis. A 129 strain locus, designated pgct1, that segregates with the male GCT phenotype has been identified on chromosome 13 near D13Mit188. This region of murine chromosome 13 may be syntenic to a portion of human chromosome 5q that is implicated in male GCT susceptibility in humans.
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PMID:A male germ cell tumor-susceptibility-determining locus, pgct1, identified on murine chromosome 13. 1089 Aug 90

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

Testicular germ cell tumor comprises about 1% of all the malignancies of males in Japan, and occurs in only one over 100,000 males annually. A susceptibility gene may be located on the short arm of the chromosome 12. Among the genes in this region, the expression of the KRAS2 mRNA was increased in testicular cancer compared to the normal testicular tissue. By DNA typing, HLA-DR4 and 0405 allele in HLA-DRB1 showed high relative risk for testicular cancer. We analyzed the expression of the WT1 gene, reported to be a growth promoter for leukemia, by quantitative reverse transcription-PCR. Relative expression of the WT1 gene was significantly increased in high-stage cases than in low-stage cases, suggesting that WT1 could be useful as a tumor marker for progression of testicular cancers. Testicular germ cell tumors are usually very sensitive to chemotherapeutic agents such as cisplatin, and p53 has been reported to play an important role in chemosensitivity. Therefore, mutations of the p53 gene or other genes downstream may be responsible for their chemoresistance. The expression of the GML (GPI--anchored molecule like protein) gene was examined in testicular cancers. Its expression was not correlated with histology or stage. However, 4 refractory cases, 2 of which were recurrent cases from stage I and the others were at high stages, showed no expression of the GML mRNA. These interesting facts suggest that the expression of GML gene could be a good marker for the prognosis of testicular germ cell tumors.
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PMID:[A prospect of molecular biology in the field of urologic oncology: mechanisms of carcinogenesis or tumor development in testicular cancer]. 1177 Nov 75

Although intratubular embryonal carcinoma has been described adjacent to invasive embryonal carcinoma, to our knowledge it has not been reported as an isolated finding. We present in this report the histologic and immunohistochemical findings of 2 cases of intratubular embryonal carcinoma. One case was exclusively intratubular embryonal carcinoma without an invasive component in the same testis. A malignant mixed germ cell tumor in the contralateral testis had been previously excised. The second case is predominantly composed of intratubular embryonal carcinoma adjacent to a malignant mixed germ cell tumor. In one case, the intratubular embryonal carcinoma was immunoreactive for CD30, AE1/AE3, cytokeratin 7 focally, and p53. It was negative for cytokeratin 20, p21, and alpha-fetoprotein. These findings are strongly supportive of the opinion that intratubular embryonal carcinoma is the precursor of invasive embryonal carcinoma.
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PMID:Intratubular embryonal carcinoma. 1190 May 81

p19(ARF) is a key regulator of the p53-mediated apoptotic and tumor suppressor pathway. The proapoptotic Bax gene is a transcription target of p53, yet genetic studies in some animal models have suggested that Bax and p53 loss may cooperate in tumorigenesis. ARF-deficient mice are tumor prone, and to determine whether Bax loss could cooperate in the development of these tumors, we generated mice null for both ARF and Bax. The tumor latency of Bax+/+ARF-/-, Bax+/-ARF-/- and Bax-/-ARF-/- mice was similar with a mean survival of 48.9, 48.1, and 47.6 weeks, respectively. In Bax+/+ARF-/- mice, the predominant tumor type was B- and T-cell lymphoma followed by sarcomas and a lack of carcinomas. However, the frequency of lymphoma development dramatically decreased, whereas that of sarcomas and carcinomas increased, in a gene dosage-dependent manner in Bax+/-ARF-/- and Bax-/-ARF-/- mice. Furthermore, uncommon tumors of ARF-/- mice (osteosarcoma and hemangiosarcoma) were observed in Bax/ARF-double null mice, and tumor types not described previously in ARF-null mice (mixed germ cell tumor, Triton tumor, and histiocytic sarcoma) also developed in Bax-/-ARF-/- animals. Importantly, multiple primary malignant tumors of different lineage arose in 25% of the Bax-/-ARF-/- mice, whereas only one tumor type per animal was observed in Bax+/+ARF-null littermates. Finally, the wild-type Bax allele was retained in tumors arising in Bax+/-ARF-/- mice. Thus, Bax appears to function as a tumor modifier rather than as a classic tumor suppressor, and the combined loss of Bax and the ARF allows for the emergence of multiple malignant tumor types, an alteration of the tumor spectrum, and tumors not observed previously in ARF-null mice.
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PMID:Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. 1192 42

Twenty-nine pediatric immature teratomas were reviewed to determine the frequency and clinical significance of p53 expression. Tumors were stained for p53 expression by immunohistochemistry and results were correlated with the presence of other germ cell tumor elements and with outcome. Sequencing of p53 for mutations was performed on positive cases. Eighteen cases showed widespread positive p53 staining of the immature teratoma elements, 9 showed staining only in very occasional cells, and 2 cases showed no staining. Of the 18 positive cases, 5 recurred. All five were pure immature teratomas at diagnosis. Four recurred as immature or mature teratoma and one as a sarcoma; all except one showed frequent cells positive for p53 in the recurrent tumor. Another 5 of the 18 diffusely positive cases contained immature teratoma as well as other malignant germ cell elements at diagnosis; none of these recurred. None of the remaining eight cases with frequent positive cells, the nine cases with occasionally positive p53 staining, or the two cases with no staining recurred or demonstrated other germ cell tumor elements. We conclude that p53 expression is not unusual in immature teratoma and diffuse p53 immunopositivity is associated with recurrence or the presence of malignant elements in approximately 50% of cases. In only 1 of 29 cases tested was p53 immunopositivity associated with mutations in the p53 gene; hence, overexpression in the majority of cases is presumed to reflect increased half-life of the protein from undetermined stabilizing factors. Expression of p21, a p53 target gene, was only focal, suggesting impaired transcriptional activation by p53. The finding of frequent p53-positive cells in immature teratoma should prompt a search for malignant elements within the tumor and affected patients should be followed closely for evidence of recurrence.
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PMID:Significance of p53 expression in immature teratomas. 1220 94

There has been considerable variability in the reported results of immunohistochemical staining for some diagnostically relevant antigens. Our objectives in this study were to (1) use a multitumor tissue microarray with tissue from 351 cases received in our department, representing 16 normal tissues and 47 different tumor types, to compare immunohistochemical staining results in our laboratory with published data, using a panel of 22 antibodies; (2) assess interlaboratory variability of immunohistochemical staining for S-100 using this microarray; and (3) test the ability of hierarchical clustering analysis to group tumors by primary site, based on their immunostaining profile. Tissue microarrays consisting of duplicate 0.6-mm cores from blocks identified in the hospital archives were constructed and stained according to our usual protocols. Antibodies directed against the following antigens were used: B72.3, bcl-2, carcinoembryonic antigen, c-kit, pankeratin, CD 68, CD 99, CK 5/6, CK 7, CK 8/18, CK19, CK 20, CK 22, epithelial membrane antigen, estrogen receptor, melan-A, p53, placental alkaline phosphatase, S-100, synaptophysin, thyroid transcription factor-1, and vimentin. Staining results on the array cases were compared with published results, and hierarchical clustering analysis was performed based on the immunohistochemical staining results. Unstained slides of the multitumor tissue microarray were sent to five other diagnostic immunohistochemistry laboratories and stained for S-100 protein. The staining results from the different laboratories were compared. Staining results using our current methods and samples from our laboratory were compatible with those described in the literature for most antigens. Placental alkaline phosphatase staining was not specific with our protocol, showing staining of a broad spectrum of different tumors; this finding initiated a review of our recent requests for placental alkaline phosphatase immunostaining and revealed two instances in which placental alkaline phosphatase positivity was incorrectly interpreted as evidence of a germ cell tumor. S-100 staining was less sensitive but more specific for the diagnosis of melanoma or neural tumor in our laboratory, compared to some published reports. Assessment of interlaboratory variability of S-100 immunostaining showed that there was more frequent staining of carcinomas in some laboratories, resulting in decreased specificity of S-100 staining in distinguishing melanoma from carcinoma. Hierarchical clustering analysis showed a strong trend for tumors to cluster by tissue of origin, but there were significant exceptions. We conclude that multiple-tumor microarrays are an efficient method for assessing the sensitivity and specificity of staining with any antibody used diagnostically. As a tool for quality assurance, they offer the advantage of taking into account local differences in tissue fixation, processing, and staining. They also allow cost-effective assessment of interlaboratory variability in immunohistochemical staining. Results of hierarchical clustering analysis show the potential for panels of immunohistochemical stains to identify the primary site of metastatic carcinomas but also confirm the limitations of currently available antibodies in giving unequivocal tissue-specific staining patterns.
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PMID:Tissue microarrays are an effective quality assurance tool for diagnostic immunohistochemistry. 1248 Oct 20

We report a nephroblastoma arising in a germ cell tumor of testicular origin occurring in a 22-year-old man. Orchiectomy demonstrated a malignant mixed germ cell tumor composed of mature and immature teratoma with nephroblastoma and rhabdomyosarcoma. Following chemotherapy, the patient developed supraclavicular and retroperitoneal lymphadenopathy. Excision demonstrated metastatic teratoma at both sites. No recurrence was noted with 21 months of additional follow-up. Using tissue microdissection and loss of heterozygosity analysis, we investigated the clonality of the mature teratoma, immature teratoma, nephroblastoma, and rhabdomyosarcoma components of the primary tumor and of the metastatic mature teratoma at the two separate distant sites. Nine microsatellite polymorphic makers were used to examine the pattern of allelic loss in both primary and metastatic tumors. Loss of heterozygosity was found in 4 DNA loci, and the same pattern of allelic loss was demonstrated at all 4 loci in all of the different components of the primary tumor and the metastatic mature teratomas, supporting the germ cell tumor origin of the nephroblastoma component. Loss of heterozygosity on chromosome 17p13 (TP53) was detected in metastatic mature teratoma, but not in the primary tumor. Loss of heterozygosity was observed at 11p13, the locus of WT1 inactivation in patients genetically predisposed to nephroblastoma, and this loss may be an important genetic mechanism in nephroblastomatous differentiation of germ cell tumors. These data support a common clonal origin for nephroblastoma and the other germ cell tumor components.
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PMID:Nephroblastoma arising in a germ cell tumor of testicular origin. 1510 60

In the present study, we investigated the relation between p21 expression and the sensitivity of testicular germ cell tumor (TGCT) cells to apoptotic stimuli. Despite similar cisplatin-induced wild-type p53 accumulation, the TGCT cell lines Tera and Scha expressed low p21 protein and mRNA levels in comparison to A2780 ovarian cancer cells. Inhibition of the proteasome complex with MG-132 increased p21 protein levels in TGCT cells but much more in A2780 cells, whereas cisplatin had no additional effect on p21 protein levels. Inhibition of caspase-3 activity in TGCT cells with the broad-spectrum caspase inhibitor zVAD-fmk had no effect on p21 levels and also not upon cisplatin treatment. A similar induction of p53 irradiation, in contrast to cisplatin, substantially increased both p21 mRNA and protein expression in Tera cells. Cisplatin-treated Tera cells expressing low p21 protein levels were Fas-sensitive, while irradiation-induced p21, which was mainly localized in the cytosol, rendered irradiated Tera cells resistant to Fas-induced apoptosis. Sensitivity of irradiated Tera cells to Fas-induced apoptosis was restored by short interfering RNA-specific suppression of p21 expression. These results strongly indicate that the low p21 protein levels are caused by reduced p21 gene transcription and sensitize cisplatin-treated TGCT cells to the Fas death pathway.
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PMID:Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis. 1575 32


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