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)

Colorectal carcinoma is one of the most common primary malignancies in adults and occurs in older patients after pelvic radiation. It is rare in children and young adults. We report two cases of colonic adenocarcinoma which were second malignant neoplasms following treatment for early childhood malignancies. One child had Wilms' tumor at 9 months of age treated with preoperative radiation and surgery. He developed radiation colitis and multifocal intestinal adenocarcinomas 42 years later and died with abdominal carcinomatosis. The second child had retroperitoneal embryonal rhabdomyosarcoma at age 1 year and was treated with preoperative radiation, surgery, and chemotherapy. At age 2 years he had radiation colitis; at age 11 years he had rectal adenocarcinoma associated with adenomatous polyps, focal adenomatous change and radiation colitis. Immunohistochemical studies revealed p53 positivity in both adenocarcinomas and in adenomas from the second patient, suggesting that p53 mutation was involved in carcinogenesis. The history of high-dose radiation in early childhood and the multifocal lesions suggest the adenocarcinomas in both patients were second malignant neoplasms, with associated reactive and benign neoplastic and premalignant lesions well documented in one case. These two cases document the phenomenon of early onset of adult type tumors in survivors of childhood cancer and emphasize the need for continued clinical evaluation of patients at risk for second malignant neoplasms.
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PMID:Colorectal adenocarcinoma as a second malignant neoplasm following Wilms' tumor and rhabdomyosarcoma. 888 17

The product of the p53 tumor suppressor gene has a well-documented activity as a transcriptional activator, and several studies indicate that this function is at least in part essential for the ability of p53 to suppress cellular proliferation. However, there is growing evidence that some activities of wild-type p53 may be independent of its trans-activation function; in fact, recent investigations have indicated that the transcriptional repression function of p53, rather than its trans-activation function, may be influential in p53-mediated apoptosis. The focus of this study has been on the identification of genes that exhibit decreased expression during p53-dependent apoptosis, and therefore represent potential p53-repressed genes influential in programmed cell death. This report identifies the gene encoding the microtubule-associated protein MAP4 as one whose mRNA and protein expression decrease in cells following induction of wild-type p53. Importantly, decreased MAP4 expression following p53 induction can be inhibited by molecules that prevent p53-mediated transcriptional repression and apoptosis, such as the adenovirus E1B-19K protein and the Wilms tumor gene product WT1. Additionally, overexpression of MAP4 in cells induced to undergo p53-dependent apoptosis significantly delays this process, indicating that the negative regulation of this gene by p53 may be influential in the rapid progression of apoptosis.
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PMID:Wild-type p53 negatively regulates the expression of a microtubule-associated protein. 895 98

The Wilms tumour 1 (WT1) gene is believed to contribute to the growth and differentiation of certain tissues, including mesothelium. This study assessed WT1 gene status by mutational screening in 42 malignant mesotheliomas (MMs) and 3 MM cell lines and detected two tumours with identical heterozygous single nucleotide deletions in intron 7, with no apparent consequence for WT1 function. Furthermore, the expression pattern of the WT1 gene was studied in MMs and related lesions using three anti-WT1 monoclonal antibodies (MAbs). Strong to moderate nuclear immunoreactivity was noted in MM in situ (54/56), cultured mesothelioma cells (4/5), and hyperplastic and normal pleural (non-neoplastic, NNM) specimens. WT1 immunoreactivity was absent in all primary tumours of lung and in pleural metastases from adenocarcinomas of breast and colon; immunoreactivity was present in pleural metastases from renal carcinomas, melanomas, and papillary carcinomas of the ovary. Expression of the WT1 protein in MM was not correlated with survival. Coordinate expression of the WT1 protein and its putative transcriptional target genes was determined by correlating WT1 immunostaining with epidermal growth factor receptor (EGF-R) and insulin-like growth factor 1 receptor (IGF-1R) expression on MM and NNM; no significant correlation was found, irrespective of p53 expression status. Finally, the putative involvement of WT1 in cell-type transition was supported by this study, in that epithelial mesothelioma showed the strongest WT1 immunoreactivity while sarcomatous mesothelioma showed the least.
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PMID:WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis. 907 5

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-finger family. As a result of alternative RNA splicing, the gene can be expressed as four polypeptides that differ in the presence or absence of a stretch of 17 amino acids just NH2 terminal of the four zinc fingers and a stretch of three amino acids (+/-KTS) between zinc fingers 3 and 4. In this study, cDNA constructs encoding the four human Wilms' tumor 1 splice variants were transiently transfected into the p53-negative Hep3B and the p53-positive HepG2 hepatoma cell lines. Morphological assessment of the WT1-expressing cells showed that the WT1(-KTS) splice variants induced apoptosis in both cell lines, whereas the WT1(+KTS) isoforms did not. The induction of apoptosis by the WT1(-KTS) isoforms appears to be p53 independent in the hepatoma cell lines. Furthermore, it was found that the WT1(-KTS)-induced apoptosis could not be suppressed by coexpression of either the Mr 21,000 E1B, the Bcl-2, or the BAG-1 protein. Coexpression of either the epidermal growth factor receptor or the insulin receptor, however, partially rescued the cells from apoptosis.
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PMID:Wilms' tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. 910 24

WT1 encodes a zinc finger transcription factor that is expressed in the developing kidney and the inactivation of which leads to Wilms' tumor, a pediatric kidney cancer. We have recently shown that inducible expression of WT1 in osteosarcoma cells triggers programmed cell death, an effect that is associated with transcriptional repression of the endogenous epidermal growth factor receptor. We now show that WT1-mediated apoptosis is preceded by induction of the cyclin-dependent kinase inhibitor p21, associated with G1 phase arrest. This effect is only demonstrated by WT1 isoforms with an intact DNA binding domain, and it is associated with increased expression of endogenous p21 mRNA. WT1-mediated induction of p21 is independent of p53, another tumor suppressor gene known to regulate p21 expression. In the kidney, p21 is expressed in differentiating glomerular podocytes along with WT1. We conclude that induction of p21 expression may contribute to WT1-dependent differentiation pathways in the kidney and potentially to the function of WT1 as a tumor suppressor gene.
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PMID:Induction of p21 by the Wilms' tumor suppressor gene WT1. 910 40

One reason for the failure of chemotherapy is the overexpression of the multidrug resistance gene, MDR1. The product of this gene is the multidrug transporter P-glycoprotein, an ATP-dependent pump that extrudes drugs from the cytoplasm. Some tumors inherently express P-glycoprotein, whereas others acquire the ability to do so after exposure to certain chemotherapeutic agents, often by the mechanism of gene amplification. Classical Wilms' tumors (nephroblastoma) typically respond to therapy and have a good prognosis. On the contrary, anaplastic Wilms' tumors are generally refractory to chemotherapy. These anaplastic variants are rare (4.5% of all Wilms' tumors reported in the United States), aggressive, and often fatal forms of tumor, which are commonly thought to result from the progression of classical Wilms' tumors. To investigate the basis for this differential response to therapy, we examined a number of classical and anaplastic Wilms' tumors for the expression of the MDR1 gene by immunohistochemical and mRNA analysis. Classical Wilms' tumors consistently did not express P-glycoprotein except in areas of tubular differentiation, as in normal kidney. Similarly, two of three anaplastic tumors failed to show P-glycoprotein expression. In contrast, cultured cells derived from a third anaplastic tumor, W4, exhibited strong P-glycoprotein expression and were drug resistant in vitro. Southern analysis revealed that W4 cells contained a single copy of the MDR1 gene per haploid genome similar to normal cells, demonstrating that the overexpression of MDR1 was not caused by gene amplification. Transcriptional activation of the MDR1 gene would be in keeping with the concept that p53 might act as a transcriptional repressor of the MDR1 gene.
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PMID:Anaplasia and drug selection-independent overexpression of the multidrug resistance gene, MDR1, in Wilms' tumor. 912 18

The product of the WT1 Wilms tumor suppressor gene controls the expression of genes encoding components of the insulin-like growth factor and transforming growth factor beta signaling systems. The role of these growth factors in breast tumor growth led us to investigate possible WT1 gene expression in normal and cancerous breast tissue. WT1 was detected by immunohistochemistry in the normal mammary duct and lobule, and the patterns of expression were consistent with developmental regulation. In a survey of 21 infiltrating tumors, 40% lacked immunodetectable WT1 altogether and an additional 28% were primarily WT1-negative. Cytoplasmic, but not nuclear, localization of WT1 was noted in some tumor cells and WT1 was detected, sometimes at high levels, in more-advanced estrogen-receptor-negative tumors. In this highly malignant subset, the tumor suppressor protein p53, which can physically interact with WT1, was also sometimes detected. WT1 mRNA was detected in normal and tumor tissue by reverse transcription-coupled PCR. Alternative splicing of the WT1 mRNA may regulate gene targeting of the WT1 protein through changes either in its regulatory or zinc-finger domains. The relative proportions of WT1 mRNA splice variants were altered in a random sample of breast tumors, providing evidence that different tumors may share a common WT1-related defect resulting in altered regulation of target genes.
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PMID:Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer. 922 27

Lung cancer in the young, which has the characteristics of a higher incidence of adenocarcinoma, lower male-to-female ratio of the patients, and less frequent smoking history in the patients, may possibly be associated with genetic predisposition to cancers. We studied six microsatellite loci (D2S123, D3S659, D3S966, D5S346, WT1, and TP53) in 18 surgically treated lung cancer patients aged 25-40 years and nine control patients aged 62-74 to determine the presence of microsatellite instability (MSI) and to correlate its occurrence with clinicopathological characteristics. Of the 18 patients, 11 were female and seven were non-smokers. There were 15 adenocarcinomas and three squamous cell carcinomas, 15 (83%) of which had vascular invasion. MSI was positive in seven (39%) of 18 young patients and one (11%) of nine control patients. Moreover, MSIs in a half or more of six loci examined were demonstrated in five (28%) young patients, whereas no control patients showed such a high frequency of MSI. We observed no significant differences in clinical or pathologic parameters between cases with and without MSI. This result suggests that genetic factors play an important role in the development of lung cancer in young adults.
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PMID:Microsatellite instability in lung cancer patients 40 years of age or younger. 926 33

Alterations of the p53 gene have been extensively investigated in a wide variety of human malignancies. However, data on childhood malignant solid tumors are still limited. Mutations of the p53 gene on exons 5 through 8 were examined in 82 childhood malignant solid tumors by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of these mutations was confirmed by direct sequencing. The 82 tumors examined included neuroblastomas (n = 44), Wilms' tumors in = 13), hepatoblastomas (n = 11), rhabdomyosarcomas (n = 10), extraosseus Ewing sarcomas (n = 2), undifferentiated sarcoma of the liver (n = 1), and fibrosarcoma (n = 1). Two sarcoma samples were identified as having point mutations. One was a rhabdomyosarcoma with a missense mutation at codon 273, substituting histidine (His) for arginine (Arg). Another was an undifferentiated sarcoma of the liver with a missense mutation at codon 245, substituting serine (Ser) for glycine (Gly). No mutations were detected among neuroblastomas, Wilms' tumors, or hepatoblastomas. The two sarcomas with mutations were localized tumors. Both patients who had these tumors are disease free for 8 and 5 years after treatment, respectively. The overall incidence of p53 mutations was low (2.4%, 2 of 82). However, the incidence, when calculated for sarcomas, was higher at 14.3% (2 of 14). These data indicate that p53 mutations are generally uncommon in childhood malignant solid tumors examined. However, in some childhood sarcomas, p53 mutations appear to have a causative role in the development of these tumors.
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PMID:Mutation analysis of p53 gene in childhood malignant solid tumors. 926 65

The progress of fundamental research on the histopathological and molecular genetic properties, model systems, growth factor involvement, and tumor markers of clinical nephroblastoma (Wilms' tumor) are reviewed. Histologically, Wilms' tumor (WT) has been found to reveal a disorganized renal developmental process in which blastema and epithelia are randomly interspersed in varying amounts of stroma. Anaplasia is the only criterion for assigning a WT as having an "unfavorable histology." Cytogenetic analysis identified WT genes at chromosome 11p13 (WT1), 11p15 region (WT2), and 16q (WT3). Permanent in vitro WT cell lines and in vivo WT models, such as human xenografts, have been established which provide indefinite sources of tumor material for fundamental, as well as therapy-directed, research. Abnormalities of growth factor (GF) expression in WT indicate that GF may play an important role in WT pathogenesis. A series of monoclonal antibodies was tested in WT by immunohistochemical techniques to identify specific diagnostic and prognostic markers. p53 expression in anaplastic WT is significantly higher than in differentiated WTs, indicating p53 may be a prognostic marker. Although significant progress has been made in the fundamental research, our basic knowledge of this malignancy is still limited. The availability of suitable experimental models, particularly the human xenograft system, offers the opportunity for further study of the cell biological and molecular aspects of WT and its clinical progression.
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PMID:Progress of fundamental research in Wilms' tumor. 928 29


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