Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the tumour suppressor gene adenomatous polyposis coli (Apc) are early and critical events in the development of colon cancer. In the absence of functional Apc, beta-catenin is not degraded in the cytoplasm and can be transported to the nucleus and turn on transcription of several genes, including the gap junction protein connexin43. Apc also stabilizes microtubules and regulates microtubule polymerization. Changes in Wnt signalling and microtubule function are reported to affect the connexin level. To study the effect of heterozygous Apc mutation we examined gap junctional intercellular communication (GJIC) in IMCE (Immorto-Min colonic epithelium) cells with one mutated Apc allele and in YAMC (Young adult mouse colon) cells with normal Apc function. IMCE cells had only half the GJIC level compared with YAMC cells. RT-PCR showed that both YAMC and IMCE cells express a common complement of seven connexin genes (Cx26, Cx31, Cx39, Cx40, Cx43, Cx45 and Cx50), with an additional Cx29 gene expression in YAMC cells. We found that the Cx43 level was correspondingly lower in IMCE cells as detected by western blotting and immunofluorescence. There were no differences in the level or localization of beta-catenin and the downstream gene E-cadherin between the cells, indicating no activation of the Wnt-signalling pathway in cells with one mutated Apc allele. We also examined the microtubule polymerization rate, and IMCE cells had markedly slower microtubule polymerization than YAMC cells. Hence, it appears that mutation in one Apc allele is sufficient to affect microtubule function, while inactivation of both wild-type Apc alleles may be necessary for activation of Wnt signalling. Reduction in GJIC and Cx43 level in IMCE cells may be caused by reduced Cx43 transport as a result of alterations in microtubule function.
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PMID:Cells heterozygous for the ApcMin mutation have decreased gap junctional intercellular communication and connexin43 level, and reduced microtubule polymerization. 1272 91

Human cancers frequently show a loss of heterozygosity on chromosome 7q31, which indicates the existence of broad-range tumour-suppressor gene(s) at this locus. Truncating mutations in the ST7 gene at this locus are seen frequently in primary colon cancer and breast cancer cell lines. Therefore, the ST7 gene represents a novel candidate gene for the tumour suppressor at this locus. However, more recent studies have reported that ST7 mutations are infrequent or absent in primary cancer and cell lines. To ascertain the frequency of mutations of the ST7 gene in cancer cells, we examined mutations in the ST7 coding sequence in 48 colorectal, 48 gastric, and 48 hepatocellular carcinomas using polymerase chain reaction-single-strand conformational polymorphism and direct sequencing. We detected somatic mutations, which were located near the exon-intron junction in intron 8, in only three out of 144 cases. We conclude that mutations in the ST7 gene are rare in primary colorectal, gastric, and hepatocellular carcinomas.
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PMID:Mutations in the ST7/RAY1/HELG locus rarely occur in primary colorectal, gastric, and hepatocellular carcinomas. 1279 35

The APC tumour suppressor gene is mutated in most colon cancers. A major role of APC is the downregulation of the beta-catenin/T-cell factor (Tcf)/lymphoid enhancer factor (LEF) signalling pathway; however, there are also suggestions that it plays a role in the organization of the cytoskeleton, and in cell adhesion and migration. For the first time, we have achieved stable expression of wild-type APC in SW480 colon cancer cells, which normally express a truncated form of APC. The ectopically expressed APC is functional, and results in the translocation of beta-catenin from the nucleus and cytoplasm to the cell periphery, and reduces beta-catenin/Tcf/LEF transcriptional signalling. E-cadherin is also translocated to the cell membrane, where it forms functional adherens junctions. Total cellular levels of E-cadherin are increased in the SW480APC cells and the altered charge distribution in the presence of full-length APC suggests that APC is involved in post-translational regulation of E-cadherin localization. Changes in the location of adherens junction proteins are associated with tighter cell-cell adhesion in SW480APC cells, with consequent changes in cell morphology, the actin cytoskeleton and cell migration in a wound assay. SW480APC cells have a reduced proliferation rate, a reduced ability to form colonies in soft agar and do not grow tumours in a xenograft mouse tumour model. By regulating the intracellular transport of junctional proteins, we propose that APC plays a role in cell adhesion in addition to its known role in beta-catenin transcriptional signalling.
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PMID:Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion. 1467 5

Defective DNA mismatch repair results from genetic or epigenetic alterations that most frequently inactivate the genes hMLH1 and hMSH2. This is thought to promote tumourigenesis by accumulation of mutations in oncogenes and tumour suppressor genes. This pathway, first reported in colon cancer, has been recently demonstrated in a subgroup of sporadic pancreatic adenocarcinomas. Intraductal papillary-mucinous neoplasms of the pancreas are a special type of pancreatic tumours, characterised by a spectrum of morphological changes from mild to moderate and to non-invasive, and they may associate with adenocarcinoma. An immunohistochemical study of hmlh1 and hmsh2 protein expression was performed on 26 intraductal papillary-mucinous neoplasms. All tumours showed nuclear expression of hmlh1 and hmsh2 proteins. There were two distinctive patterns of protein expression on the basis of the location of cells expressing these markers: the "normal" pattern, observed mainly in adenoma and rarely in intraductal papillary-mucinous neoplasms with moderate dysplasia and the "dysplastic" pattern, frequently encountered in moderate dysplasia neoplasms, non-invasive and invasive carcinomas. These findings suggest that defective DNA mismatch repair, due to inactivation of hMLH1 and hMSH2, does not play a significant role in the pathogenesis of intraductal papillary-mucinous neoplasms of the pancreas. Two patterns of protein expression were observed and were correlated with the progression of dysplasia in intraductal papillary mucinous neoplasms.
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PMID:Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas. 1476 May 34

E2F-1 is a pivotal transcription factor that integrates signals from a variety of G1/S phase regulators and modulates diverse cellular functions, such as DNA synthesis, repair, mitosis, and apoptosis. Its role in cellular proliferation and apoptosis, as depicted from experimental models and limited reports in human malignancies, remains a matter of debate. Recently, in non-small cell lung cancer, it was observed that E2F-1 overexpression was associated with tumour growth, implying an 'oncogenic' effect. To clarify further the role of E2F-1 in carcinogenesis, the investigation was expanded in four of the most common human malignancies by examining its expression status and putative impact on tumour kinetics. These issues were addressed by immunohistochemical and molecular means in 52 breast carcinomas, 42 prostate adenocarcinomas, 58 colon adenocarcinomas, and 77 superficial bladder transitional cell carcinomas (TCCs). The following results were found: (i). in breast carcinomas, E2F-1 expression correlated with proliferation (p < 0.001) and growth index (p = 0.001); (ii). in prostate adenocarcinomas, absence of E2F-1 was noted, in contrast to its expression in normal and hyperplastic glands; (iii). in colon adenocarcinomas, E2F-1 expression was inversely related to growth index (p = 0.001), being expressed in lesions with increased apoptosis (p = 0.001) and low proliferation (p < 0.001); and (iv) in superficial TCCs, E2F-1 expression correlated with proliferation (p = 0.002). Taken together, these results suggest that E2F-1 has a growth-promoting effect in breast carcinomas and superficial TCC, whereas the opposite seems to be the case for colon and prostate cancer. To interpret the above findings, the status of the pRb and p53 tumour suppressor pathways, which are known to affect E2F-1 activity, was further investigated. The results suggest that the actions of E2F-1 are mainly dependent on the functionality of these pathways. Nevertheless, the data also imply that p53-independent pathways may play a nodal role in the function of E2F-1 in colon cancer.
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PMID:Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas. 1522 33

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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PMID:Colon cancer: genomics and apoptotic events. 1525 76

The majority of human tumour cells are aneuploid owing to an underlying chromosome instability phenotype. While the genetic lesions that cause chromosome instability remain undefined, mouse ES cells harbouring homozygous adenomatous polyposis coli (APC) mutations are frequently tetraploid. In addition, colon cancer cells with APC mutations have weakened kinetochore-microtubule interactions. Furthermore, mitotic spindles assembled in APC-depleted Xenopus egg extracts are aberrant. Therefore, to determine whether APC mutations can initiate chromosome instability in human cells, we expressed N-terminal APC fragments in HCT-116 cells, a near diploid colon cancer cell line with two wild-type APC alleles. We show that cells expressing N-APC mutants exit mitosis prematurely in the presence of spindle toxins, consistent with a spindle checkpoint defect. In addition, N-APC cells show enhanced survival following prolonged spindle damage. In contrast to controls, the N-APC survivors frequently contain dicentric chromosomes and then go on to become highly aneuploid. These observations suggest that truncating APC mutations can exert dominant effects which in turn can initiate chromosome instability. As such, APC mutation not only compromises tumour suppressor function but may also have oncogenic properties. We suggest therefore that the initial APC mutation acts as a 'double whammy', destabilising the genome and setting the stage for deregulated proliferation upon loss of the second APC allele.
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PMID:Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability. 1556 72

SLC5A8 is a candidate tumour suppressor gene that is silenced in colon cancer, gastric cancer and possibly other cancers in humans. This gene codes for a transporter belonging to the Na(+)/glucose co-transporter gene family (SLC5). The cancer-associated silencing of the gene involves hypermethylation of CpG islands present in exon 1 of the gene. SLC5A8 is expressed in colon, ileum, kidney and thyroid gland. The protein coded by the gene mediates the Na(+)-coupled and electrogenic transport of a variety of monocarboxylates, including short-chain fatty acids, lactate and nicotinate. It may also transport iodide. The normal physiological function of this transporter in the intestinal tract and kidney is likely to facilitate the active absorption of short-chain fatty acids, lactate and nicotinate. One of the short-chain fatty acids that serves as a substrate for SLC5A8 is butyrate. This fatty acid is an inhibitor of histone deacetylases and is known to induce apoptosis in a variety of tumours including colonic tumour. Since butyrate is produced in the colonic lumen at high concentrations by bacterial fermentation of dietary fibre, we speculate that the ability of SLC5A8 to mediate the entry of this short-chain fatty acid into colonic epithelial cells underlies the potential tumour suppressor function of this transporter.
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PMID:Biological functions of SLC5A8, a candidate tumour suppressor. 1566 16

Adenomatous polyposis coli (APC) is a tumour suppressor involved in colon cancer progression. We and others previously described nuclear-cytoplasmic shuttling of APC. However, there are conflicting reports concerning the localization of endogenous wild-type and tumour-associated, truncated APC. To resolve this issue, we compared APC localization using immunofluorescence (IF) microscopy and cell fractionation with nine different APC antibodies. We found that three commonly used APC antibodies showed nonspecific nuclear staining by IF and validated this conclusion in cells where APC was inactivated using small interfering RNA or Cre/Flox. Fractionation showed that wild-type and truncated APC from colon cancer cells were primarily cytoplasmic, but increased in the nucleus after leptomycin B treatment, consistent with CRM1-dependent nuclear export. In contrast to recent reports, our biochemical data indicate that APC nuclear localization is not regulated by changes in cell density, and that APC nuclear export is not prevented by truncating mutations in cancer. These results verify that the bulk of APC resides in the cytoplasm and indicate the need for caution when evaluating the nuclear accumulation of APC.
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PMID:Redefining the subcellular location and transport of APC: new insights using a panel of antibodies. 1567 62

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.
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PMID:A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer. 1567 31


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