Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different studies of Wilms' tumours have demonstrated a loss of heterozygosity (LOH) of chromosome 16q ranging from 17 to 25%. In order to search for a potential tumour suppressor gene on 16q, we chose the calcium-dependent cell adhesion molecules E-cadherin and cadherin-11 as candidate genes, which are both located on the long arm of chromosome 16. E-cadherin is known to be expressed in epithelial structures, whereas cadherin-11 is supposed to be expressed in mesenchymal structures and developing epithelium, including renal tubules. For the present study, fresh frozen tissue from 30 Wilms' tumours and corresponding non-tumour tissues were analysed. Single nucleotide polymorphisms of the E-cadherin and cadherin-11 genes were chosen and analysed for allelic inactivation by polymerase chain reaction (PCR) amplification and sequence analysis. Loss of expression of one E-cadherin allele was seen in 10% (2/20) of the informative cases. Two out of 11 informative cases (18%) showed loss of expression of one cadherin-11 allele. No length alterations of either the E-cadherin or the cadherin-11 messenger RNAs were identified using reverse transcription PCR and agarose gel electrophoresis in tumour tissue. Sequencing of the entire E-cadherin coding region in seven cases showed the wild-type sequence. These data imply that E-cadherin and cadherin-11 are not likely to play typical tumour suppressor roles in Wilms' tumour. Interestingly, the E-cadherin immunohistochemistry showed a deviation from the normal reaction pattern in 50% of the cases, with 27% (8/30) showing an apical or cytoplasmic reaction and 23% (7/30) being completely negative. Northern blot analysis revealed that the overall expression of cadherin-11 is much stronger than that of E-cadherin. In several cases, the expression levels of the two genes were inversely correlated, suggesting the existence of a regulatory mechanism. Analysis of differential expression of the various cadherins and their subsequent signal transduction pathways might contribute to a better understanding of the complexity of Wilms' tumour formation.
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PMID:Molecular analysis of E-cadherin and cadherin-11 in Wilms' tumours. 1086 76

The existence of genetic alterations affecting genes involved in cellular proliferation and death, such as TP53 and K-ras, is one of the most common features of tumour cells. Recently, gene inactivation by promoter hypermethylation has been demonstrated. Methylation is the main epigenetic modification in mammals and abnormal methylation of the CpG islands located in the promoter region of the genes leads to transcriptional silencing. Examples include the p16INK4a, p15INK4B, p14ARF, Von Hippel-Lindau (VHL), the oestrogen and progesterone receptors, E-cadherin, death associated protein (DAP) kinase and the first tumour suppressor gene described, retinoblastoma (Rb) gene. In most cases, methylation involves loss of expression, absence of a coding mutation and restoration of transcription by the use of demethylating agents. However, is there a linkage between genetic and epigenetic alterations? Our results show one side of this puzzle demonstrating that epigenetic lesions drive genetic lesions in cancer. Four specific epigenetic lesions, promoter hypermethylation of the DNA mismatch repair gene hMLH1, the DNA alkyl-repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), the detoxifier glutathione S-transferase P1 (GSTP1) and the familial breast cancer gene BRCA1 may lead to four specific genetic lesions, microsatellite instability, G to A transitions, steroid-related adducts and double-strand breaks in DNA. This is probably only the beginning of an extensive list of epigenetic events that change and make the genetic environment of the transformed cell unstable.
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PMID:Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. 1109 2

beta-Catenin has an essential role in intercellular adhesion and signal transduction. beta-catenin functions as a transcriptional activator downstream in the Wnt signalling pathway. Cytoplasmic stabilisation of beta-catenin, mainly due to inactivating mutations of the adenomatous polyposis coli (APC) tumour suppressor gene or activating mutations in exon 3 of the beta-catenin gene, can activate this important pathway in the development of several carcinomas. To determine whether this pathway for malignant transformation is important in oesophageal cancer, we analysed 39 primary oesophageal squamous cell carcinomas (OSCC). Immunohistochemical expression of beta-catenin was studied in formalin-fixed, paraffin-embedded tissue samples. Results were correlated with clinicopathological parameters and immunohistochemical expression of the proteins p53, E-cadherin, bcl-2 and Ki-67. All examined OSCC had beta-catenin expression localised in the cellular membrane, frequently with a heterogeneous pattern. Seven (18%) cases also showed immunoexpression in the cytoplasm and nuclei of the tumour cells. These seven tumours were localised in the upper (three) or in the middle third (four) of the oesophagus. Only one patient had p53 expression and all had bcl-2 expression. The consensus sequence for glycogen synthase kinase (GSK) 3beta phosphorylation in exon 3 of the beta-catenin gene was studied using polymerase chain reaction and direct sequencing in the seven cases with nuclear beta-catenin expression. No genetic alteration was found. These results suggest that beta-catenin expression may characterise a subset of OSCC.
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PMID:beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. 1119 70

PKCdelta plays a fundamental role in cell cycle control. Consistent with its proposed tumour suppressor function, ras transfection of the human keratinocyte cell line HaCaT results in a loss of PKCdelta expression mediated by TGFalpha (Exp. Cell Res., 219, 299, 1995). To get more insight into the role of PKCdelta in keratinocytes, we investigated the effects of Rottlerin, a specific inhibitor of protein kinase Cdelta, in HaCaT cells. After Rottlerin treatment, HaCaT cells lost their cobble-stone morphology and displayed a spindle-shaped, fibroblastic phenotype. Additionally, the establishment of cell-cell contacts was prevented. This was caused by an internalization of E-cadherin and beta-catenin as assessed by immunofluorescence. A similar phenotype was observed in the presence of a neutralizing anti-E-cadherin antibody. Rottlerin-treated HaCaT cells proliferated like transformed cells in a three-dimensional cell culture system. We therefore conclude that PKCdelta is involved in mediating cell-cell contacts via E-cadherin and hence regulates differentiation in HaCaT cells.
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PMID:Rottlerin induces a transformed phenotype in human keratinocytes. 1140 99

E-cadherin is a calcium-dependent cell adhesion molecule which is important in cell-cell interactions in epithelium and plays a major role in maintaining the structure and integrity of epithelial sheets. The purpose of this study was to examine E-cadherin expression in normal and malignant oral epithelium. Ten specimens of normal oral epithelium, five specimens of hyperplastic epithelium and 15 squamous cell carcinomas were stained using a standard immunoperoxidase technique and a monoclonal antibody to E-cadherin. Normal and hyperplastic epithelium showed strong pericellular staining in the basal, suprabasal and prickle cell layers. The keratinising superficial layers were negative. E-cadherin expression did not correlate to the degree or pattern of keratinisation and was not altered in the hyperplastic epithelium. All cases of squamous cell carcinoma showed heterogenous staining with areas of loss or fragmentation of staining. No tumour was completely negative. The amount or pattern of loss showed no apparent correlation to the degree of tumour differentiation. These findings suggest that loss of E-cadherin is not essential for the acquisition of a malignant phenotype but may be important in the invasive process. This supports the view that E-cadherin may be the product of a tumour suppressor gene important in tumour progression.
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PMID:E-cadherin expression in normal, hyperplastic and malignant oral epithelium. 1170 26

Loss of heterozygosity at the long arm of chromosome 16 is one of the most frequent genetic events in breast cancer. In the search for tumour suppressor genes that are the target of loss of heterozygosity at 16q, the E-cadherin gene CDH1 was unveiled by the identification of truncating mutations in the retained copy. However, only lobular tumours showed E-cadherin mutations. Whereas investigations are still devoted to finding the target genes in the more frequent ductal breast cancers, other studies suspect the E-cadherin gene to also be the target in this tumour type. The present article discusses the plausibility of those two lines of thought.
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PMID:E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? 1187 52

Dominant oncogenes and tumour suppressor gene abnormalities are crucial events in human cancer. Many molecular techniques are used to identify these abnormalities, including single strand conformational polymorphism, the polymerase chain reaction, cloning, and sequencing, although the biological relevance of these changes is not always apparent. Immuno-histochemistry (ICH) or western blotting of abnormal gene products can provide information about their cellular localisation and expression in neoplastic versus normal cells, and can sometimes give a clue to their function. For example, ICH has shown how loss of the intercellular adhesion molecule E-cadherin, or abnormal localisation from the cell membrane to the cytoplasm, correlates with a diffuse tumour phenotype and a less favourable clinical outcome. Similarly, ICH of beta-catenin (a protein that binds E-cadherin and is essential for its function) has shown abnormal cellular localisation in the nucleus in a variety of human malignancies; in particular, colorectal carcinomas, where abnormal forms of the adenomatous polyposis coli gene product cause nuclear and cytoplasmic sequestration of beta-catenin. Such studies show how morphological assessment can sometimes provide insight into molecular function and dysfunction in human malignancy.
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PMID:Molecular histology in the study of solid tumours. 1195 Sep 53

Although most colorectal cancer develops based on the adenoma-adenocarcinoma sequence, morphologically, colorectal cancer is not a homogeneous disease entity. Generally, there are two distinct morphological types: polypoid and ulcerative colorectal tumours. Previous studies have demonstrated that K-ras codon 12 mutations are preferentially associated with polypoid growth of colorectal cancer; however, little is known about the molecular mechanism that determines ulcerative growth of colorectal cancer. beta-catenin complex plays a critical role both in tumorigenesis and morphogenesis. We examined the differential expression of beta-catenin and its related factors among different types of colorectal cancer in order to determine any relationship with gross tumour morphology. Immunohistochemical staining of beta-catenin, E-cadherin and MMP-7 was performed on 51 tumours, including 26 polypoid tumours and 25 ulcerative tumours. Protein truncation tests and single-strand conformational polymorphism for mutation of the adenomatous polyposis coli tumour suppressor gene, as well as single-strand conformational polymorphism for the mutation of beta-catenin exon 3 were also done. Nuclear expression of beta-catenin was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A significant relationship of nuclear beta-catenin expression with ulcerative colorectal cancer was found (P<0.001). However, this finding was independent of adenomatous polyposis coli tumour suppressor gene mutation and E-cadherin expression. Together with previous data, we propose that different combinations of genetic alterations may underlie different morphological types of colorectal cancer. These findings should be taken into consideration whenever developing a new genetic diagnosis or therapy for colorectal cancer.
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PMID:Nuclear beta-catenin expression is closely related to ulcerative growth of colorectal carcinoma. 1195 60

The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC binds to beta-catenin, a key component of the Wnt signalling pathway, and induces its degradation. APC interacts with microtubules and accumulates at their plus ends in membrane protrusions, and associates with the plasma membrane in an actin-dependent manner. In addition, APC interacts with the Rac-specific guanine nucleotide exchange factor Asef and stimulates its activity, thereby regulating the actin cytoskeletal network and cell morphology. Here we show that overexpression of Asef decreases E-cadherin-mediated cell-cell adhesion and promotes the migration of epithelial Madin-Darby canine kidney cells. Both of these activities are stimulated by truncated APC proteins expressed in colorectal tumour cells. Experiments based on RNA interference and dominant-negative mutants show that both Asef and mutated APC are required for the migration of colorectal tumour cells expressing truncated APC. These results suggest that the APC-Asef complex functions in cell migration as well as in E-cadherin-mediated cell-cell adhesion, and that truncated APC present in colorectal tumour cells contributes to their aberrant migratory properties.
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PMID:Mutated APC and Asef are involved in the migration of colorectal tumour cells. 1264 74

The tumour suppressor protein adenomatous polyposis coli (APC) regulates the level and the intracellular localisation of the proto-oncoprotein beta-catenin. There are indications that a region comprising seven homologous 20-amino acid residue repeats within the APC protein is responsible for the interaction with beta-catenin and that the phosphorylation of conserved serine residues within these repeats increases the affinity for beta-catenin. We used biophysical methods to analyse the beta-catenin binding of single repeats or repeat combinations as non-phosphorylated or phosphorylated recombinant proteins. The non-phosphorylated repeats showed similar affinities, no matter whether they were tested as single recombinant repeats or in combination with neighbouring repeats. This result makes a cooperative influence between the repetitive motifs unlikely. The phosphorylation of the APC protein was mimicked by specific serine/aspartate mutations, which align to serine residues in the cytoplasmic beta-catenin binding domain of E-cadherin. Remarkably, the mimicked phosphorylation of a serine, which is not involved in beta-catenin interaction in the E-cadherin/beta-catenin complex, led to a significant increase in the APC affinity for beta-catenin. These results indicate structural differences between the E-cadherin/beta-catenin and the APC/beta-catenin complexes and provide quantitative evidence for the importance of the APC phosphorylation for its interaction with beta-catenin.
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PMID:Differences between the interaction of beta-catenin with non-phosphorylated and single-mimicked phosphorylated 20-amino acid residue repeats of the APC protein. 1262 43


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