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)

One way of controlling the activity of E-cadherin--a protein that is, simultaneously, a major cell-adhesion molecule, a powerful tumour suppressor, a determinant of cell polarity and a partner to the potent catenin signalling molecules--is to keep it on the move. During the past two decades, many insights into the fundamental role of E-cadherin in these processes have been garnered. Studies during the past five years have begun to reveal the importance of intracellular trafficking as a means of regulating the functions of E-cadherin. E-cadherin is trafficked to and from the cell surface by exocytic and multiple endocytic pathways. In this article, we survey the vesicle-trafficking machinery that is responsible for the sorting, transport, actin association and vesicle targeting of E-cadherin to regulate its movement and function during growth and development and, possibly, in cancer.
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PMID:The ins and outs of E-cadherin trafficking. 1530 9

Cell migration is a process which is essential during embryonic development, throughout adult life and in some pathological conditions. Cadherins, and more specifically the neural cell adhesion molecule N-cadherin, play an important role in migration. In embryogenesis, N-cadherin is the key molecule during gastrulation and neural crest development. N-cadherin mediated contacts activate several pathways like Rho GTPases and function in tyrosine kinase signalling (for example via the fibroblast growth factor receptor). In cancer, cadherins control the balance between suppression and promotion of invasion. E-cadherin functions as an invasion suppressor and is downregulated in most carcinomas, while N-cadherin, as an invasion promoter, is frequently upregulated. Expression of N-cadherin in epithelial cells induces changes in morphology to a fibroblastic phenotype, rendering the cells more motile and invasive. However in some cancers, like osteosarcoma, N-cadherin may behave as a tumour suppressor. N-cadherin can have multiple functions: promoting adhesion or induction of migration dependent on the cellular context.
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PMID:N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling. 1534 21

CTCF is a ubiquitous 11-zinc-finger protein that plays a role in gene silencing or activation, chromatin insulation and genomic imprinting. The CTCF gene has been mapped to the chromosome band 16q22.1 that shows frequent loss of heterozygosity in breast cancer. The E-cadherin gene is the known tumour suppressor gene (TSG) at this region in lobular carcinomas; however, the target gene in the more frequent ductal tumours is still unknown. Since CTCF targets include TSGs and oncogenes and it has the ability to inhibit cell growth and proliferation, it has been suggested that it may be the target gene at the 16q22.1 in ductal carcinomas. In the present study, tissue microarray technology was used to study the expression pattern of CTCF immunohistochemically in 344 cases of invasive breast carcinoma and its expression was correlated with clinicopathological variables and patient outcome. Results showed that breast tissues express CTCF in the parenchymal cells of the normal ducts and lobules but with a variable percentage of positive cells. Staining of CTCF was detected in the nuclei and cytoplasm of the malignant cells, but no significant loss or decrease of expression was noticed in association with any specific tumour type. There was a significant correlation between expression of CTCF and histological grades; lower expression was associated with grade 3 tumours. Cytoplasmic expression was associated with increased tumour size and with the presence of vascular invasion. However, no association was found between CTCF expression and tumour type, lymph node stage, oestrogen receptor expression or patient outcome. In conclusion, the current results show that CTCF, although it may play a role in breast carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast cancer and thus another gene or genes at this region remain to be identified.
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PMID:Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1. 1535 17

Loss of the chromosomal material at 16q22.1 is one of the most frequent genetic aberrations found in both lobular and low-grade nonlobular invasive carcinoma of the breast, indicating the presence of a tumour suppressor gene (TSG) at this region in these tumours. However, the TSG (s) at the 16q22.1 in the more frequent nonlobular carcinomas is still unknown. Multiplex Amplifiable Probe Hybridisation (MAPH) is a simple, accurate and a high-resolution technique that provides an alternative approach to DNA copy-number measurement. The aim of our study was to examine the most likely candidate genes at 16q22.1 using MAPH assay combined with protein expression analysis by immunohistochemistry. We identified deletion at 16q22.1 that involves some or all of these genes. We also noticed that the smallest region of deletion at 16q22.1 could be delineated to a 3 Mb region centromeric to the P-cadherin gene. Apart from the correlation between E-cadherin protein expression and its gene copy number, no correlation was detected between the expression of E2F-4, CTCF, TRF2 or P-cadherin with their gene's copy number. In the malignant tissues, no significant loss or decrease of protein expression of any gene other than E-cadherin was seen in association with any specific tumour type. No expression of VE-cadherin or Ksp-cadherin was detected in the normal and/or malignant tissues of the breast in these cases. However, there was a correlation between increased nuclear expression of E2F-4 and tumours with higher histological grade (p = 0.04) and positive lymph node disease (p = 0.02), suggesting that it may have an oncogenic rather than a tumour suppressor role. The malignant breast tissues also showed abnormal cytoplasmic cellular localisation of CTCF, compared to its expression in the normal parenchymal cells. In conclusion, we have demonstrated that MAPH is a potential technique for assessment of genomic imbalances in malignant tissues. Although our results support E-cadherin as the TSG in invasive lobular carcinoma, they argue against the candidacy of E2F-4, CTCF, TRF2, P-cadherin, Ksp-cadherin and VE-cadherin as TSGs in breast cancer.
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PMID:High-resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry. 1560 12

The recent discovery of hypermethylation of the promoter of genes is a powerful epigenetic mechanism for the inactivation of tumour suppressor genes in colorectal and other cancers. Approximately 95% of hereditary non-polyposis colorectal cancers (HNPCCs) and 15% of sporadic colorectal cancers (CRCs) are replication error positive (RER(+)). Although DNA mutations are found in mismatch repair genes in the majority of HNPCC CRC, mutations are rare in sporadic RER(+) CRCs. We have shown that the principal cause of an RER(+) phenotype is hypermethylation of the promoter of hMLH1, resulting in the absence of hMLH1 protein. In contrast to sporadic RER(+) CRCs, we found that hypermethylation of hMLH1 does not occur in HNPCC CRC, suggesting the possibility of further differences between the two types of RER(+) tumours in the adenoma to carcinoma pathway. Other known tumour suppressor genes with few or no mutations may be candidates for epigenetic changes. One such gene is E-cadherin, and we described the first mutations of this gene in CRCs. Half of all CRCs were found to be hypermethylated in the Ecadherin promoter and this correlated with reduced E-cadherin expression. Epigenetic changes occur in CRCs and arise in different frequencies in separate genes. Hypermethylation of the promoter may be reversed and gene function restored to a cell, thus partially undoing the cancer phenotype.
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PMID:Epigenetics, mismatch repair genes and colorectal cancer. 1572 Sep 1

The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with < 1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression.
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PMID:Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. 1594 28

Upper gastrointestinal (GI) tract malignancies, including carcinomas of the esophagus, the GI junction and the stomach, are among the most common cancers worldwide. Overall survival is poor because many patients present with locally advanced and often incurable disease. This review focuses on the pathogenesis of adenocarcinomas of the stomach. It summarises recent findings on genetic predisposition to gastric cancer, in particular in relation to germline mutations in the E-cadherin gene. It also describes the molecular basis of sporadic gastric cancer, including alterations in oncogenes, tumour suppressor genes and growth factors, and discusses how these findings might be used in the clinic for improved diagnosis and therapy.
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PMID:Molecular medicine of gastric adenocarcinomas. 1615 4

Aberrant expression of some tumour suppressor genes and oncogenes by thymocytes had been involved in the development of primary thymic lymphomas induced by gamma-irradiation, but genetic alterations affecting critical genes expressed by stromal cells have not been yet explored. This paper analyzes a series of such tumours induced in C57BL/6J and in F1 hybrids of BALB/c and C57BL/6J mouse strains. As expected, hystopathological analyses revealed profound disorganizations within the thymus with a poor demarcation of the cortical and medullar areas. Immunological and quantitative on-line RT-PCR analyses confirm that E-cadherin (Cdh1) is essentially expressed by stromal cells of the thymus, while evidencing that the expression of this gene is significantly reduced in all tumours. In addition, and contrary to what one would expect, N-cadherin (Cdh2) that is exclusively expressed by stromal cells is likewise down-regulated in most of the thymic lymphomas. Although hypermethylation of the promoter region appears to be involved in the inactivation of Cdh2 in all tumours, additional epigenetic mechanisms mediated by repressors such as Snai1 may also play a role in Cdh1 silencing. These results represent the first reported case for tumour-associated gene alterations occurring not in the tumour cells per se, but in the stromal cells of primary thymic lymphomas. Additionally, since the expression of both genes is significantly up-regulated after a single high dose of gamma-radiation, but remained unchanged in treated thymic-lymphoma-free-mice, epigenetic down-regulation of E- and N-cadherin appears to occur concomitantly with the progression towards the most advanced stages of gamma-radiation-induced thymic lymphomas.
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PMID:Epigenetic silencing of E- and N-cadherins in the stroma of mouse thymic lymphomas. 2721 82

Methylation profiling of cancer tissues has identified this mechanism as an important component of carcinogenesis. Epigenetic silencing of tumour suppressor genes through promoter methylation has been investigated by a variety of means, the most recent of which is pyrosequencing. We have investigated quantitative methylation status in oral squamous cell carcinoma patients. Fresh tumour tissue and normal control tissue from resection margin was obtained from 79 consecutive patients undergoing resection of oral squamous cell carcinoma. DNA was extracted and bisulphite treated. PCR primers were designed to amplify 75-200 bp regions of the CpG rich gene promoters of p16, RARbeta, E-cadherin, cytoglobin and cyclinA1. Methylation status of 4-5 CpG sites per gene was determined by pyrosequencing. Significant CpG methylation of gene promoters within tumour specimens was found in 28% for p16, 73% for RARbeta, 42% for E-cadherin, 65% for cytoglobin and 53% for cyclinA1. Promoter methylation was significantly elevated in tumours compared to normal tissue for p16 (P = 0.048), cytoglobin (P = 0.002) and cyclin A1 (P = 0.001) but not in RARbeta (P = 0.088) or E-cadherin (P = 0.347). Concordant methylation was demonstrated in this tumour series (P = 0.03). Significant differences in degree of methylation of individual CpG sites were noted for all genes except RARbeta and these differences were in a characteristic pattern that was reproduced between tumour samples. Cyclin A1 promoter methylation showed an inverse trend with histological grade. Promoter methylation analysis using pyrosequencing reveals valuable quantitative data from several CpG sites. In contrast to qualitative data generated from methylation specific PCR, our data demonstrated p16 promoter methylation in a highly tumour specific pattern. Significant tumour specific methylation of cyclin A1 promoter was also seen. Cytoglobin is a novel candidate tumour suppressor gene highly methylated in upper aero-digestive tract squamous cancer.
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PMID:Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: quantitative evaluation using pyrosequencing. 1644 96

This review illustrates the relationships linking the ER and the ErbB family of receptor tyrosine kinases and their kinase pathways in breast cancer. The central role of the ER in activating tumour growth linked gene transcription as well as the cooperating nuclear co-factors very likely implicated in breast cancer tumourigenesis is discussed. The action of ErbB family members has been located upstream of the kinase pathways that begin at plasma membrane and end at the nucleus after complex interconnections with many factors, such as AP-1. The important role of MAPKs and PKB/Akt in cell survival and tumour proliferation is highlighted. Also other factors are discussed such as Fra-1 (a member of the AP-1 complex), E-cadherin (a tumour suppressor), and BRCA1 (another factor involved in tumour growth inhibition). Lactoferrin protein (characteristic of healthy tissues) and resistance proteins have also been briefly discussed.
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PMID:Breast cancer markers. 1653 Mar 25


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