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)

We ectopically expressed the transcription factor Pitx2a, one of the Pitx2 isoforms, in HeLa cells by using a tetracycline-inducible expression system and examined whether Pitx2a was capable of modulating Rho GTPase signaling and altering the cell's cytoskeleton. Ectopic expression of Pitx2a induced actin-myosin reorganization, leading to increased cell spreading, suppression of cell migration, and the strengthening of cell-cell adhesion, marked by the accumulation and localization of beta-catenin and N-cadherin to the sites of cell-cell contacts. Moreover, Pitx2a expression resulted in activation of the Rho GTPases Rac1 and RhoA, and the dominant negative Rac1 mutant N17Rac1 inhibited cell spreading and disrupted localization of beta-catenin to the sites of cell-cell contacts. Both reorganization of actin-myosin and cell spreading require phosphatidylinositol 3-kinase activity, which is also necessary for activation of the Rho GTPase proteins. Pitx2a induced the expression of Trio, a guanine nucleotide exchange factor for Rac1 and RhoA, which preceded cell spreading, and the expression of Trio protein was down-regulated after the changes in cell spreading and cell morphology were initiated. In addition, Pitx2a also induces cell cycle arrest at G0/G1, most likely due to the accumulation of the tumor suppressor proteins p53 and p21. Our data indicate that the transcriptional activities initiated in the nucleus by Pitx2a result in profound changes in HeLa cell morphology, migration, and proliferation.
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PMID:Pitx2a expression alters actin-myosin cytoskeleton and migration of HeLa cells through Rho GTPase signaling. 1185 22

Acinar cell carcinomas (ACCs) are rare malignant tumors of the exocrine pancreas. The specific molecular alterations that characterize ACCs have not yet been elucidated. ACCs are morphologically and genetically distinct from the more common pancreatic ductal adenocarcinomas. Instead, the morphological, immunohistochemical, and clinical features of ACCs overlap with those of another rare pancreatic neoplasm, pancreatoblastoma. We have recently demonstrated a high frequency of allelic loss on chromosome arm 11p and mutations in the APC/beta-catenin pathway in pancreatoblastomas, suggesting that similar alterations might also play a role in the pathogenesis of some ACCs. We analyzed a series of 21 ACCs for somatic alterations in the APC/beta-catenin pathway and for allelic loss on chromosome 11p. In addition, we evaluated the ACCs for alterations in p53 and Dpc4 expression using immunohistochemistry, and for microsatellite instability (MSI) using polymerase chain amplification of a panel of microsatellite markers. Allelic loss on chromosome 11p was the most common genetic alteration in ACCs, present in 50% (6 of 12 informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 23.5% (4 of 17) of the carcinomas, including one ACC with an activating mutation of the beta-catenin oncogene and three ACCs with truncating APC mutations. One ACC (1 of 13, 7.6%) showed allelic shifts in four of the five markers tested (MSI-high), two (15.4%) showed an allelic shift in only one of the five markers tested (MSI-low), and no shifts were detected in the remaining 10 cases. The MSI-high ACC showed medullary histological features. In contrast, no loss of Dpc4 protein expression or p53 accumulation was detected. These results indicate that ACCs are genetically distinct from pancreatic ductal adenocarcinomas, but some cases contain genetic alterations common to histologically similar pancreatoblastomas.
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PMID:Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. 1189 Nov 93

Post-transplantation lymphoproliferative disorder (PT-LPD) is characterized by lymphoid proliferation after organ or bone marrow transplantation. In Western countries, most cases of PT-LPD are B-cell-derived and Epstein-Barr virus-associated, in which alterations of c-myc, p53, and N-ras genes might play a role in disease progression. In Japan, PT-LPD of T- and NK/T-cell types are not uncommon in renal transplant patients. Mutations of p53 (exons 4 through 8), K-ras (exons 1 and 2), c-kit (exons 11 and 17), and beta-catenin genes (exon 3) in 12 cases of these diseases were analyzed by PCR single strand conformation polymorphism and then by direct sequencing. p53 gene mutations were detected in 5 of 5 cases of peripheral T-cell lymphoma, 3 (60%) of 5 cases of adult T-cell leukemia/lymphoma, and 1 of 2 cases of NK/T cell lymphoma. Twenty-five percent of T and NK/T cell lymphomas showed K-ras mutations. Mutations of c-kit and beta-catenin genes were found in 33% of cases. Among a total of 42 substitution mutations, 40 were transitions with involvement of CpG sites in 20 to 30% of cases. Most cases had at least one mutation that changed an amino acid, which might have provided the selection pressure for expansion. These findings suggested that p53 gene mutations might play a central role in development of peripheral T-cell lymphoma including adult T-cell leukemia/lymphoma in renal transplant patients.
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PMID:Gene mutations in lymphoproliferative disorders of T and NK/T cell phenotypes developing in renal transplant patients. 1189 4

Malignant lymphoma of the adrenal gland is a rare disease, usually with diffuse large cell morphology and B-cell immunophenotype, and often associated with Epstein-Barr virus infection. In this study, mutations of p53, c-kit, K-ras, and beta-catenin gene were analyzed in 17 cases (13 males and four females with ages ranging from 25 to 84 years) of such lymphomas by polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing. Selected exons in each gene, representing hot spots, were analyzed. All 44 mutations detected were single-nucleotide substitutions and 33 were missense mutations. Nineteen mutations were detected in exon 5 and / or 7 of the p53 gene in nine of 17 cases (52.9%) and 21 in exon 11 and / or 17 of the c-kit gene in 10 of 14 cases (71.4%). Bilateral adrenal lesions in one case who had not received any adjuvant therapy showed different mutational patterns of the p53 and c-kit genes, suggesting different clonal evolution of lymphoma between the left and right sides. Mutation at codon 13 of the K-ras gene was detected in one of 14 cases (7.1%), and in exon 3 of the beta-catenin gene in three of 12 cases (25%). All but one mutation were transition mutations, indicating that some endogenous mutagens act in lymphomagenesis in the adrenal gland. Our results suggest that p53 and c-kit gene mutations might play a role in adrenal lymphomagenesis.
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PMID:Mutations of p53, c-kit, K-ras, and beta-catenin gene in non-Hodgkin's lymphoma of adrenal gland. 1192 8

Solid-pseudopapillary tumors (SPTs) are unusual pancreatic neoplasms of low malignant potential that most frequently affect young women. Genetic events contributing to the development of SPTs are unknown. Whereas the more common ductal adenocarcinomas of the pancreas essentially never harbor beta-catenin or APC gene mutations, we have recently identified alterations of the APC/beta-catenin pathway in other nonductal pancreatic neoplasms including pancreatoblastomas and acinar cell carcinomas. We analyzed a series of 20 SPTs for somatic alterations of the APC/beta-catenin pathway using immunohistochemistry for beta-catenin protein accumulation, direct DNA sequencing of beta-catenin exon 3, and direct DNA sequencing of the mutation cluster region in exon 15 of the APC gene in those SPTs that did not harbor beta-catenin mutations. Immunohistochemical labeling for cyclin D1 was performed to evaluate the overexpression of this cell-cycle protein as one of the putative downstream effectors of beta-catenin dysregulation. In addition, we analyzed the SPTs for genetic alterations commonly found in pancreatic ductal adenocarcinomas, including mutations in the K-ras oncogene and p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of K-ras and immunostaining for p53 and Dpc4. Almost all SPTs harbored alterations in the APC/beta-catenin pathway. Nuclear accumulation of beta-catenin protein was present in 95% (19 of 20), and activating beta-catenin oncogene mutations were identified in 90% (18 of 20) of the SPTs. Seventy-four percent (14 of 19) showed overexpression of cyclin D1, ranging from 10 to 70% of tumor nuclei. In contrast, no K-ras mutations were present in any of the 20 SPTs, and Dpc4 expression was intact in all 16 SPTs for which immunohistochemical labeling was successful. Overexpression of p53 was limited to only 3 of 19 (15.8%) SPTs. These results emphasize the two distinct, divergent genetic pathways of neoplastic progression in pancreatic ductal and nonductal neoplasms.
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PMID:Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. 1194 21

E-cadherin and the catenins are responsible for inter-cellular adhesion in epithelial tissues. E-cadherin and/or catenin expression is often altered in malignancies, leading to increased invasiveness and metastatic activity of tumour cells. Intact adhesion molecules reduce the risk on distant metastases. This is confirmed by studies mostly performed on surgical series, correlating e-cadherin expression in tumours with prognosis and treatment outcome. It has become more apparent that anti-cancer treatment by itself can also affect the expression of adhesion molecules. We therefore suggest that the prognostic value of e-cadherin expression may depend on the treatment modality and the sequence of therapies administered for malignant tumours. We used paraffin embedded specimens from patients with rectal tumours and patients with laryngeal tumours treated by short course radiotherapy before definitive surgery. Expression of p53, e-cadherin, and beta-catenin was determined in pre-radiotherapy biopsies and in the surgical specimens. Material was available from 37 patients. We found no correlation between the expression of p53, e-cadherin or beta-catenin and pre-treatment parameters. Mutated p53 in pre-radiation biopsy correlated with increased occurrence of distant metastases and there was an unexpected trend for abnormal e-cadherin expression to correlate with reduced metastases. The prognostic value of p53 no longer existed after examination of the surgical specimens (post-radiotherapy). There was a trend for e-cadherin to reverse from abnormal to normal expression in laryngeal squamous cell carcinomas after radiotherapy, in 5/7 cases it was accompanied with p53 conversion from positive to negative expression. Based on this study it is suggested that the predictive value of the e-cadherin expression for the occurrence of distant metastases in tumours treated by radiotherapy before surgery may be different from that found in tumours treated by surgery only. This may be related to the influence of radiotherapy on e-cadherin expression, especially in squamous cell carcinomas. Alteration in p53 expression was of predictive value only in pre-treatment biopsies and the beta-catenin status did not correlate with treatment outcome in this series.
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PMID:The influence of pre-operative radiotherapy on the expression of p53 and adhesion molecules: correlation with treatment results in patients with squamous cell carcinoma or adenocarcinoma. 1195 39

It is still unclear as to whether the gene expression profile in HCV- or HBV-related HCC exhibits a degree of specificity and whether the development of HCC in a context of cirrhosis influences this gene profile. To address these issues, the expression profiles of 15 cases of HCC were analysed using cDNA macroarray. A global analysis and hierarchical clustering, demonstrated the heterogeneity of HCC patterns, with a majority of down-regulated genes. Statistical analysis clearly showed a distinction between the gene expression profiles of HCV- and HBV-related HCC. HBV-associated HCC exhibited involvement of different cellular pathways, those controlling apoptosis, p53 signalling and G1/S transition. In HCV-related HCC we identified a more heterogenous pattern with an over-expression of the TGF-beta induced gene. In HCC developing on non-cirrhotic tissues, beta-catenin encoding gene and genes implicated in the PKC pathway were specifically up-regulated. In addition, our investigation highlighted a distinct profiles of TGF-beta superfamily encoding genes in well, moderately or poorly differentiated HCC. Overall, our study supports the hypothesis that despite the heterogeneity of the HCC pattern, the large-scale screening of gene expression may provide data significant to our understanding of the mechanism of liver carcinogenesis.
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PMID:Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. 1197 55

The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that DeltaNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with DeltaNp63alpha and mediated its degradation. Here, we report that DeltaNp63 associates with the B56alpha regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3beta (GSK3beta), leading to a dramatic inhibition of PP2A-mediated GSK3beta reactivation. The inhibitory effect of DeltaNp63 on GSK3beta mediates a decrease in phosphorylation levels of beta-catenin, which induces intranuclear accumulation of beta-catenin and activates beta-catenin-dependent transcription. Our results suggest that DeltaNp63 isotypes act as positive regulators of the beta-catenin signaling pathway, providing a basis for their oncogenic properties.
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PMID:DeltaNp63 induces beta-catenin nuclear accumulation and signaling. 1208 51

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. Chronic infections with the hepatitis B virus (HBV) and the hepatitis C virus (HCV) have been implicated in about 80% of cases worldwide, and other known environmental risk factors, including alcohol abuse and dietary intake of aflatoxin B1, might synergize with viral infections. Recent insight into the molecular mechanisms leading to HCC development has been provided by the identification of major genetic abnormalities revealed by genomewide allelotype studies and molecular cytogenetic analysis. Moreover, several oncogenic pathways have been implicated in malignant transformation of liver cells. Inactivation of the p53 tumor suppressor gene by mutations and allelic deletions in about 30% of HCC cases has been associated predominantly with exposure to aflatoxin B1 and HBV infection. By contrast, a mutation in the beta-catenin gene in around 22% of HCCs is more rare in HBV-associated tumors. Activation of cyclin D1 and disruption of the Rb pathway are also commonly involved in liver tumorigenesis. New major challenges include the identification of candidate genes located in frequently altered chromosomal regions and that of oncogenic pathways driven by different risk factors. This search might shed some light on the tumorigenic role of HBV and HCV. It might also permit accurate evaluation of major targets for prognostic and therapeutic intervention.
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PMID:Genetic alterations and oncogenic pathways in hepatocellular carcinoma. 1209 25

Human cell lines established from biliary tract cancers are rare, and only five have been reported previously. We report the characterisation of six new six biliary tract cancer cell lines (designated SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079 and SNU-1196) established from primary tumour samples of Korean patients. The cell lines were isolated from two extrahepatic bile duct cancers (one adenocarcinoma of common bile duct, one hilar bile duct cancer), two adenocarcinomas of ampulla of Vater, one intrahepatic bile duct cancer (cholangiocarcinoma), and one adenocarcinoma of the gall bladder. The cell phenotypes, including the histopathology of the primary tumours and in vitro growth characteristics, were determined. We also performed molecular characterisation, including DNA fingerprinting analysis and abnormalities of K-ras, p15, p16, p53, hMLH1, hMSH2, DPC4, beta-catenin, E-cadherin, hOGG1, STK11, and TGF-betaRII genes by PCR-SSCP and sequencing analysis. In addition, we compared the genetic alterations in tumour cell lines and their corresponding tumour tissues. All lines grew as adherent cells. Population doubling times varied from 48-72 h. The culture success rate was 20% (six out of 30 attempts). All cell lines showed (i) relatively high viability; (ii) absence of mycoplasma or bacteria contamination; and (iii) genetic heterogeneity by DNA fingerprinting analysis. Among the lines, three lines had p53 mutations; and homozygous deletions in both p16 and p15 genes were found three and three lines, respectively; one line had a heterozygous missense mutation in hMLH1; E-cadherin gene was hypermethylated in two lines. Since the establishment of biliary tract cancer cell lines has been rarely reported in the literature, these newly established and well characterised biliary tract cancer cell lines would be very useful for studying the biology of biliary tract cancers, particularly those related to hypermethylation of E-cadherin gene in biliary tract cancer.
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PMID:Establishment and characterisation of six human biliary tract cancer cell lines. 1210 41


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