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)

Induction of apoptosis in malignant cells is a major goal of cancer therapy in general and of certain cancer gene therapy strategies in particular. Numerous apoptosis-regulating genes have been evaluated for this purpose. Besides the most prominent p53 gene others include p16, p21, p27, E2F genes, FHIT, PTEN and CASPASE genes. Recently, the potential for therapy of an adenoviral gene, E1A, known for a long time for its apoptosis-inducing activity, has been discovered. In experimental settings, these genes have proven their tumor-suppressive and apoptosis-inducing activity. Clinical trials are currently being performed with selected genes. By far the most studies transfer the p53 gene using retro- or adenoviral vectors. Disease stabilization or other benefits were observed in a limited number of patients when p53 was applied alone or in combination with cytotoxic drugs. A second proapoptotic gene that has entered clinical trials is adenovirus E1A. Here, too, disease stabilization as well as/or local regression in one case have been demonstrated in selected patients. In all cases, side effects were tolerable. To further improve E1A as a therapeutic transgene, we have deleted transforming domains from the adenovirus 5 and 12 13S cDNAs. Mutants were derived which had completely lost their transforming activity in combination with the E1B oncogene but retained a pronounced tumor-suppressive activity. Cells transduced with these constructs showed a highly reduced ability to grow in soft agar, and tumor growth in nude mice could be substantially suppressed. Outgrowing tumors had lost E1A expression when analyzed in Western blots. These E1A constructs may represent valuable tools for cancer gene therapy in the future.
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PMID:Apoptotic genes in cancer therapy. 1242 89

To investigate the etiological association of allelic loss at chromosomal regions containing tumor suppressor genes (TSGs) in non-small cell lung cancer (NSCLC) in Taiwan, we examined 48 microdissected NSCLC samples for loss of heterozygosity (LOH) at nine loci where TSGs are localized nearby. The associations of LOH at each locus with clinicoparameters and prognosis were also examined. The frequent LOH was observed using markers, D3S1285 near the FHIT gene (58.3%), D17S938 near the p53 gene (56.7%), D9S925 near the p16 gene (54.5%), and D13S153 near the RB gene (47.6%). The occurrence of LOH at each TSG locus was compared with the patients' clinicoparameters. The incidence of LOH at D17S938 (p53 gene) and D3S4545 (VHL gene) was significantly higher in squamous carcinoma tumors than in adenocarcinoma tumors (P = 0.003 and 0.024, respectively). LOH of these two loci also occurred frequently in tumors from smoker patients compared to that from nonsmoker patients (P = 0.013 and 0.025, respectively). LOH at D13S153 (RB gene) was also associated with smoking (P = 0.008). In addition, the prognostic analyses indicated that the patients with LOH at D18S535 (18q21, near the SMAD2/4 gene) had significantly longer post-operative survival time compared to those without LOH (P = 0.03). Our results suggested that LOH at FHIT, p53, and p16 genes may occur frequently in NSCLC patients in Taiwan. In addition, LOH at p53, RB, and VHL may associate with smoking or squamous carcinoma patients and LOH at SMAD2/4 may be correlated with better prognosis.
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PMID:Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer. 1251 64

The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16INK4, DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers.
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PMID:Genetic abnormalities in pancreatic cancer. 1253 85

It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are frequently associated with lung cancer. Although a complication with lung cancer is an important prognostic factor for IPF, standard treatments for lung cancer cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and lung cancer. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor (TGF)-beta 1 type II receptor, have been reported.
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PMID:[Idiopathic pulmonary fibrosis and lung cancer]. 1261 Aug 69

Despite high rates of loss of heterozygosity affecting various chromosomes, the number of tumor suppressor genes (TSGs) found to be consistently involved in primary liver cancer is low. In the past decade, characterization of homozygous deletions (HDs) in tumors has become instrumental to identify new TSGs or to reveal the influence of a particular TSG on the development of a specific tumor type. We performed a detailed HD profiling at 238 critical loci on a collection of 57 hepatobiliary tumor cell lines (hepatocellular, cholangiocellular, and bile duct carcinomas, hepatoblastomas, and immortalized hepatocytes). We identified HDs at 9 independent loci, the analysis of which was extended to 17 additional hepatobiliary tumor cell lines. In total, 34 homozygous losses involving 9 distinct genes were detected in the 74 cell lines analyzed. Besides expected deletions at the p16-INK4A/p14-ARF, FHIT, AXIN1, and p53 genes, we detected HDs at the PTEN, NF2, STK11, BAX, and LRPDIT genes that were formerly not known to be implicated in human liver tumorigenesis. In conclusion, our data suggest that these genes may represent novel liver tumor suppressive targets. Additional tumorigenic pathways should be carefully considered in hepatocarcinogenesis.
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PMID:Homozygous deletion scanning in hepatobiliary tumor cell lines reveals alternative pathways for liver carcinogenesis. 1266 63

The loss of tumour suppressor genes (TSGs) is a key event in many human cancers, including gastric carcinoma. Many TSG candidates have been studied, but their roles in gastric carcinogenesis remain unclear. To clarify the clinical significance of TSG expression in gastric carcinoma, the expression of various TSG candidates (p53, E-cadherin, FHIT, smad4, rb, VHL, PTEN, MGMT, p16, and KAI1), as well as other proteins (bcl-2, MUC1, MUC2, MUC5AC, MUC6, CEA, CD44, beta-catenin, C-erbB2, and cyclin B2), was evaluated immunohistochemically in 329 consecutive gastric carcinomas using the tissue array method. The overexpression of p53 and MUC1 (p < 0.01) and the loss of expression of smad4 (p = 0.04), FHIT (p = 0.03), MGMT (p = 0.01), E-cadherin, KAI1, and PTEN (p < 0.01) were found to be significantly associated with poor gastric carcinoma prognosis. Seven out of eight survival-associated proteins were found to be protein products of TSGs. The gastric carcinomas were divided into five groups according to the grade of alteration in TSG expression. No TSG expression loss was found in 32 cases (TSG1). One TSG loss was found in 47 cases (TSG2), two in 67 cases (TSG3), three or four in 64 cases (TSG4), and five, six, or seven in 38 cases (TSG5). The grade of TSG expression was confirmed to be significantly associated with WHO classification (p = 0.04), pTNM stage, lymphatic invasion, and patient survival (p < 0.01 for the latter three). By multivariate analysis, the grade of TSG expression was found to be significantly and independently associated with patient survival (p < 0.01). In conclusion, the findings of this study suggest that the cumulative loss of TSG expression in gastric carcinoma is important in determining patient survival.
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PMID:Tumour suppressor gene expression correlates with gastric cancer prognosis. 1269 39

In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.
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PMID:Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics. 1277 97

In this case of a dedifferentiated chondrosarcoma, we searched for genetic or epigenetic alterations in both components of the tumor, the low grade chondroblastic component, and the high grade osteosacomatouscomponent. To date, only little is known about aberrant patterns of DNA methylation in chondrosarcomas. Microdissection was used as a valuable method for clearly separating the tissues. We examined CpG island methylation of 8 tumor suppressor genes and candidate tumor suppressor genes, which are involved in different pathways: cell cycle (p21WAF1, p16INK4, p14ARF), apoptosis (DAPK, FHIT), DNA repair (hMLH1), and cell adherence (E-Cadherin). We found p16INK4 and E-cadherin promotor methylation in the low grade chondroid compartment of the dedifferentiated chondrosarcoma. P16INK4, FHIT, and E-cadherin were methylated in the highly malignant osteosarcomatous compartment of the tumor. Earlier investigations of this chondrosarcoma showed p53 mutation and p53-LOH in the anaplastic component. As shown in this case, it was accompanied by Rb-LOH. Early methylation of p16IK4 and E-cadherin in the chondroid compartment could point to the monoclonal origin of demonstrated dedifferentiated chondrosarcoma. Further alterations, as shown in p53, Rb and FHIT, are responsible for the "switch" to a high grade anaplastic sarcoma.
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PMID:Genetic and epigenetic alterations in tumor progression in a dedifferentiated chondrosarcoma. 1292 47

We investigated 31 cases of pleomorphic carcinomas of the lung, with a double component of neoplastic epithelial cells and of spindle and/or giant cells. To correlate the morphologic diversity of these two cell components with their immunophenotype, we evaluated the expression of several gene products involved in cell differentiation (cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, vimentin, S-100 protein, smooth muscle actin, desmin), cell cycle control and apoptosis (p53, p21Waf1, p27Kip1, FHIT), tumor growth (proliferative fraction, assessed by Ki-67 antigen, and microvascular density, assessed by CD34 immunostaining), and tumor cell motility (fascin). We found the epithelial component to be significantly more immunoreactive for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, cell cycle inhibitors p21Waf1, p27Kip1 and tumor suppressor gene FHIT, whereas the sarcomatoid component, independent of tumor stage and size, was more immunoreactive for vimentin, fascin, and microvascular density. Accordingly, we suggest a model of tumorigenesis whereby the mesenchymal phenotype of pleomorphic cells is likely induced by the selective activation and segregation of several molecules involved in cell differentiation, cell cycle control, and tumor cell growth and motility. Whether pleomorphic carcinomas of the lung are tumors with a dismal prognosis still remains an unsettled issue. In our series, however, stage I pleomorphic carcinomas have the same clinical behavior as ordinary non-small cell lung cancer, and only a high proliferative index (Ki-67 labeling index >35%) is associated with a worse prognosis in these tumors.
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PMID:Pleomorphic carcinomas of the lung show a selective distribution of gene products involved in cell differentiation, cell cycle control, tumor growth, and tumor cell motility: a clinicopathologic and immunohistochemical study of 31 cases. 1296 Aug 4

It is unclear how expression of the FHIT (fragile histidine triad) gene by the colorectal neoplasm correlates with histogenesis and progression of the disease. We studied the association between expression of Fhit protein and development of colorectal carcinoma (CRC). We also examined relations between Fhit protein expression, macroscopic type, Ki-67 labeling index (LI), and p53 overexpression in carcinoma in situ. We examined 27 colorectal adenomas, 82 carcinomas in situ and 21 invasive CRCs resected endoscopically or surgically. The carcinomas in situ comprised three macroscopic types: polypoid (n=27), superficial (flat elevated, n=27; depressed, n=10) and granulonodular laterally spreading tumor (G-LST, n=23). Fhit, Ki-67, and p53 overexpression were examined immunohistochemically. Levels of Fhit protein were lower in invasive CRC than in adenoma and carcinoma in situ (p<0.01). In carcinoma in situ, reduced Fhit expression was observed in 7 of 22 (31.8%) polypoid types, 13 of 27 (48.1%) superficial flat elevated types, 8 of 10 (80%) superficial depressed types and 7 of 23 (30.4%) G-LST. Frequencies of reduced Fhit expression were significantly higher in the polypoid type and G-LST lesions than in the depressed type (p<0.05). Reduced expression of Fhit protein was related significantly to Ki-67 LI and p53 overexpression in carcinoma in situ (p<0.01). The present findings suggest that reduced expression of Fhit protein is related to development of colorectal neoplasm. Polypoid CRC and G-LST appear to differ from superficial depressed CRC in terms of Fhit expression.
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PMID:Clinical significance of Fhit expression in development of colorectal carcinoma of various macroscopic types. 1296 15


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