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)

Bcl-2 expression has been evaluated immunocytochemically in a series of 33 medullary thyroid carcinomas (MTC) with long-term (mean, 10.3 years) follow-up. Twenty-six of 33 cases showed intense bcl-2 immunoreactivity in more than 25% neoplastic cells. Bcl-2 immunoreactivity did not correlate with several clinicopathologic parameters including sex and age of the patients, sporadic or familial disease, tumor size and stage, amount of amyloid stroma, and immunoreactivity for calcitonin, chromogranin A, proliferating cell nuclear antigen (PCNA), N-myc, and p53. Lack of bcl-2 immunoreactivity, however, correlated significantly (P = .0001) with a shorter survival. Indeed, the seven patients with tumors devoid of bcl-2 immunoreactivity all died of disease within 8 years from the diagnosis. In multivariate analysis, lack of bcl-2 immunoreactivity was an independent predictor of worse prognosis (P = .001 for disease-free survival and P = .0001 for overall survival). None of the other clinicopathologic variable investigated proved to be an independent prognostic parameter. It is concluded that down-regulation of bcl-2 expression in MTC may identify a subset of tumors with a more aggressive clinical course.
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PMID:Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. 767 94

Although the occurrence of bladder cancer is common, the molecular events underlying the pathogenesis of this cancer remain ill-defined. A loss of heterozygosity (LOH) at specific chromosomal loci may predispose individuals to the development of bladder cancer but this has not been examined in detail. Furthermore, the role that deletion or inactivation of putative tumour suppressor genes might play in the genesis of bladder cancer has not been established. In this study, allelic deletion analysis on the short arm of chromosome 17 of patients with primary bladder tumours failed to show deletion at 17p13 (0/7), a region known to contain the p53 tumour suppressor gene. Chromosome 11p15 showed allelic deletion at the IGF2 locus (2/7: 29%) and the PTH locus (1/11: 9%). However, no deletion was observed at the CALCA locus (0/6). LOH at 11p13, a region containing the Wilm's tumour suppressor gene (WT1), was also studied. Analysis of LOH at 11p13 showed deletion at the CAT locus (13/18: 72%), the delta J/D11S414 locus (5/15: 33%), the WT1 locus (7/14: 50%) and the FSHB locus (6/16: 38%). The significance of these findings is discussed.
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PMID:Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma. 810 Feb 10

A case is presented of pulmonary blastoma occurring in the right upper lobe of a 25-year-old man without distinct clinical features and laboratory abnormality. Light microscopic analysis revealed that the tumor was composed of branching glands and morulae embedded in a primitive but bland mesenchyme. Immunohistochemically the epithelial cells were immunoreactive for cytokeratins, S-100 protein, protein gene product 9.5, chromogranin A, calcitonin, and Ki-67 (MIB-1); the mesenchymal cells were immunoreactive for vimentin, actin, cytokeratins, and Ki-67; and all the tumor cells were negative for p53, estrogen receptor protein, and human chorionic gonadotropin beta. Characteristically, many epithelial cells contained optically clear nuclei which were immunoreactive for biotin (M743). Electron microscopic analysis revealed that the optically clearing change was due to replacement of the central area of the nuclei by a mass of parallel-arranged 7- to 10-nm filaments, and biotin-immunoreactive products were mainly localized in the nuclear matrix. Additionally, spherical bodies were identified in the cytoplasm of the nuclear filament-aggregated cells, suggestive of an intimate pathogenetic association of the two morphological abnormalities. The similarity of the aggregated nuclear filaments to those observed in gestational endometrium and ovarian endometrioid carcinoma implies that a similar mechanism plays a role in the pathogenesis of these abnormalities.
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PMID:Pulmonary blastoma: an ultrastructural and immunohistochemical study with special reference to nuclear filament aggregation. 859 6

A unique thyroid tumor in a 62-year-old woman is reported. Foci of papillary carcinoma (PC), mucoepidermoid carcinoma (MEC) and undifferentiated carcinoma (UC) were found in the surgical specimen. Acid mucosubstances were observed in the two histologically differentiated areas of the neoplasia. The PC showed immunoreactivity for thyroglobulin, and both PC and MEC foci were positive for high-molecular-weight keratins. Papillary carcinoma, MEC and UC were stained with antibodies against keratin CAM 5.2, vimentin, S-100 protein and neuron-specific enolase. No immunoreactivity was found for calcitonin, calcitonin-gene-related peptide, chromogranin, keratin 1, carcinoembryonic antigen and p53 suppressor gene. The diagnosis of this peculiar carcinoma of the thyroid exhibiting papillary and mucoepidermoid features together with undifferentiated (anaplastic) areas, reinforces the existence of a close relationship between papillary carcinoma and mucoepidermoid carcinoma, and supports the importance that ultimobranchial multipotential stem cells may have in the histogenesis of thyroid carcinomas.
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PMID:Papillary and mucoepidermoid carcinoma of the thyroid with anaplastic transformation: a case report with histologic and immunohistochemical findings that support a provocative histogenetic hypothesis. 1594 30

In chronic myeloid leukaemia (CML), disease progression from the initial chronic phase to the acute phase or blast crisis has previously been shown to be correlated with progressive increases in hyper-methylation of the calcitonin gene, located at chromosome 11p15. However, sequential studies of individual patients were not performed in these investigations. We have analysed 44 samples from nine patients with typical Philadelphia chromosome positive CML throughout their disease progression to determine the methylation state of the calcitonin gene at these time points. Densitometry was used to quantitate the ratio of the normal 2.0 kb Hpa II fragments, indicating normal methylation status of the gene, compared to the intensity of the abnormal, hyper-methylated, 2.6-3.1 kb Hpa II fragments. We found a gradual increase in the ratio of methylated:unmethylated calcitonin gene during chronic phase with a dramatic rise at blast crisis. Further, the ratio of the abnormal hypermethylated 3.1 kb fragments to the methylated 2.6 kb fragment resulted in the identification of a clonal expansion of abnormally methylated cells. This expansion of cells with hypermethylation of the calcitonin gene during chronic phase was shown to coincide with the presence of a mutation in the p53 gene. The data presented in this study would suggest that an increased methylation status of the calcitonin gene during disease progression may indicate the expansion of abnormal blast cell populations and subsequent progression to blast crisis.
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PMID:Increasing methylation of the calcitonin gene during disease progression in sequential samples from CML patients. 894 87

Activation by point mutation of ras family genes as well as point mutations of the p53 tumor suppressor gene are found in many tumors. Here we describe a rare case of malignant neuroendocrine pancreatic tumor with multiple metastases in different organs showing strong positivity for synaptophysin, glucagon-like peptide 1, pan-cytokeratin, moderate positivity for chromogranin, Phe-5 and calcitonin and weak positivity for vasointestinal peptide. We found a point mutation at codon 61 of the c-N-ras oncogene, and point mutations in the p53 tumor suppressor gene in the primary tumor as well as in its metastases in liver. The mutation in the c-N-ras gene was a cytosine to adenine transversion, resulting in the amino-acid lysine. Allele specific hybridization showed that the mutation involved one of two c-N-ras alleles as the oligonucleotide for the normal codon also hybridized to amplified tumor DNA. Concomitant mutation of the p53 tumor suppressor gene at codons 248 and 249 was found. The mutation in codon 248 was a cytosine to guanine transversion resulting in the amino-acid glycine. The mutation in codon 249 was a third base, G- > T, transversion leading to a change from arginine to serine. This is the first time that concomitant point mutations in c-N-ras and p53 have been found in a neuroendocrine pancreatic tumor. Based upon these and our previous results, we concluded that these genetic changes may play a role in the development of this particular pancreatic tumor.
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PMID:Concomitant point mutation of tumor suppressor gene p53 and oncogene c-N-ras in malignant neuroendocrine pancreatic tumor. 904 54

The clinicopathologic features, including a detailed immunohistochemical, ultrastructural, and flow cytometric analysis, are described in three cases of atypical carcinoid tumor of the larynx. All patients had metastatic disease within cervical lymph nodes at presentation and eventually developed distant metastases. Special stains revealed focal intracytoplasmic mucin accumulation, and immunohistochemistry showed the tumors to be positive for CAM 5.2, CEA, chromogranin A, and calcitonin. In two cases, double-staining techniques revealed occasional cells that stained for both mucin and chromogranin A. The histochemical and immunohistochemical findings in these two cases were confirmed at the ultrastructural level, with most tumor cells containing many neurosecretory granules. Smaller numbers of cells contained mucin vacuoles and, in occasional cells, both mucin and neuroendocrine granules were identified. The three tumors exhibited positive staining with D07 (anti-p53), and flow cytometric analysis revealed DNA aneuploidy and polyploidy. The double-staining and ultrastructural features indicate that laryngeal atypical carcinoid qualifies for the designation of true amphicrine carcinoma. Further study is necessary to determine whether mutation of the p53 gene is important in the evolution of laryngeal neuroendocrine tumors and whether DNA aneuploidy or polyploidy identifies a subset of these tumors with a poor prognosis.
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PMID:Atypical carcinoid tumor of the larynx: an immunohistochemical, ultrastructural, and flow cytometric analysis. 927 73

We investigated the mechanisms by which calcitonin (CT) suppresses cellular proliferation, using HEK-293 cells stably transfected with either the rat C1a CT receptor (CTR) or the insert-negative form of the human CTR. CT treatment of clonal cell lines expressing either receptor type, but not untransfected HEK-293 cells, strongly suppressed cell growth in a concentration-dependent manner. The reduction in cell growth with CT treatment could not be attributed to cellular necrosis or apoptotic cell death, the latter assessed by both DNA fragmentation analysis and caspase 3 (CPP-32) assay. Growth inhibition was associated with an accumulation of cells in the G2 phase of the cell cycle. CT treatment of the human and rat CTR-expressing cell lines resulted in a rapid and sustained induction of mRNA encoding the cyclin-dependent kinase inhibitor, p21WAF1/CIP1, increased levels of which were maintained at least 48 h after initiation of treatment. Western blot analysis showed a rapid corresponding increase in p21WAF1/CIP1 protein, whereas protein levels of another member of the cyclin-dependent kinase inhibitor family, p27kip1, were unchanged. In parallel with the induction of p21, CT treatment reduced levels of p53 mRNA and protein. CT treatment resulted in a specific cell cycle block in G2, which was associated with inhibition of Cdc2/cyclin B kinase activity as measured by histone H1 phosphorylation. There was no evidence for p21 association with this complex despite the inhibition of Cdc2 activity. Evidence that p21 induction was causative of cell growth suppression was obtained from p21 antisense oligonucleotide experiments. Treatment with a p21 antisense oligonucleotide blocked induction of p21 expression and significantly reduced the CT-mediated growth inhibition. These observations suggest that p21 is required for the G2 arrest in response to CT, but argue against a direct role of p21 in the inhibition of Cdc2 activity. These studies suggest a novel regulation of cell cycle progression by CT and will provide a basis for detailed examination of the molecular mechanisms involved.
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PMID:Calcitonin receptor-mediated growth suppression of HEK-293 cells is accompanied by induction of p21WAF1/CIP1 and G2/M arrest. 1051 75

Normally, thyroid cancer is a disease with a good prognosis, but about 30% of the tumours dedifferentiate and may finally develop into highly malignant anaplastic thyroid carcinomas with a mean survival time of less than 8 months. Due to the loss of thyroid-specific functions associated with dedifferentiation, these tumours are inaccessible to standard therapeutic procedures such as radioiodide therapy and thyroxine-mediated thyrotrophin suppression. Medullary thyroid carcinomas are also highly aggressive. Here, therapy is limited to surgery, and no alternative is left if patients do not respond to this standard procedure. Obviously, new approaches would be desirable. Several novel approaches are currently being tested for the treatment of thyroid cancer. Many of them utilise methods of gene therapy, but follow different strategies: (1) reintroduction of the tumour suppressor p53 into a background lacking functional p53; (2) suicide gene therapy with ganciclovir and a transduced gene for herpes simplex virus thymidine kinase controlled by the thyroglobulin promoter; (3) strengthening of the antitumour immune response by expression of an adenovirus-delivered interleukin-2 (IL-2) gene; (4) induction of an immune response by DNA vaccination against the tumour marker calcitonin; (5) transduction of the thyroid sodium/iodide transporter gene to make tissues that do not accumulate iodide treatable by radioiodide therapy; (6) blocking of the expression of the oncogene c-myc by antisense oligonucleotides. While these approaches are still tested in vitro or in animal models, first results from pilot studies concerning other novel treatment modalities are available: (7) radioimmunotherapy exploits the carcinoembryonic antigen expressed on medullary thyroid carcinomas to target a radiolabelled antibody to the tumour; and (8) retinoic acid is used for a redifferentiation therapy in the case of thyroid cancer. Hopefully, one or the other of these novel strategies may probably extend after some time the current therapeutic repertoire for thyroid cancers and provide a perspective for otherwise untreatable patients.
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PMID:Innovative strategies for the treatment of thyroid cancer. 1087 26

The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is induced in many cell types in response to a variety of extracellular signals and causes cell cycle arrest in both the G1 and G2/M phases of the cell cycle. We reported previously that calcitonin (CT) receptor (CTR)-mediated growth inhibition of HEK-293 cells stably transfected with the human CTR is accompanied by a rapid and sustained induction of p21 and cell cycle arrest in G2. In the present study we have shown that CT stimulates transcription from a p21 promoter-luciferase construct. Using deletion and mutation analysis of the p21 promoter we have demonstrated that transcriptional activation of p21 by CT is p53-independent and is mediated through specific activation of Sp1-binding sites in a region of the promoter between -82 and -69, relative to the transcription start site. CTR-mediated transcriptional activation of p21 was specific for the insert-negative isoform of the human CTR. Butyrate, which was shown previously to activate the same Sp1 site, synergised with CT to increase further p21 promoter activity. These results provide the first demonstration that CTR can induce gene transcription through the constitutively expressed transcription factor Sp1, and define a mechanism of cell growth suppression that may have implications for other members of the seven-transmembrane domain G protein-coupled receptor superfamily.
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PMID:Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene. 1101 46


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