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)

Allele imbalance at chromosome 15q14-q22 is seen in a high proportion of sporadic colorectal cancers encompassing the colorectal adenoma and carcinoma susceptibility locus. The FLJ12973 gene, which has recently been identified as a candidate tumour suppressor, maps to 15q15 and encodes a WD-repeat protein with structural similarity to the small subunit of the xeroderma pigmentosum E (XP-E) complex. To examine the proposition that FLJ12973 is involved in colorectal cancer we analysed 31 tumours for sequence variation. No missense changes or pathogenic mutations--truncating or splice site--were detected in any of the tumours. While epigenetic effects on FLJ12973 cannot be excluded, these results show that it is not a common target for mutations in colorectal cancers.
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PMID:Mutations in the candidate tumour suppressor gene FLJ12973 on chromosome 15q15 are rare in colorectal cancer. 1286 Feb 91

Prospective cohort and case-control studies suggest an association between low folate intake and increased risk of colo-rectal adenoma and cancer. Some, but not all, animal studies indicate that folate supplementation protects against the development of colo-rectal neoplasms, although supraphysiological folate doses have been shown to enhance tumour growth. Folate is a methyl donor for nucleotide synthesis and biological methylation reactions, including DNA methylation. A low dietary folate intake may increase the risk of colo-rectal neoplasia by inducing genomic DNA hypomethylation, which can affect the expression of proto-oncogenes and tumour suppressor genes associated with the development of cancer. Common polymorphisms in genes involved in the methylation pathway, such as methylenetetrahydrofolate reductase and methionine synthase, have been shown to influence risk of colo-rectal neoplasia, with interactions dependent on folate status and/or alcohol intake, which is known to antagonise methyl group availability. There is some evidence to show that DNA from normal-appearing colo-rectal mucosa in individuals with colo-rectal cancer is hypomethylated. In a case-control study DNA methylation in normal-appearing colo-rectal mucosa has been shown to be lower in individuals with colo-rectal cancer (P = 0.08) and colo-rectal adenoma (P = 0.009) than in controls free of colo-rectal abnormalities. Human intervention trials to date suggest that supraphysiological doses of folate can reverse DNA hypomethylation in colo-rectal mucosa of individuals with colo-rectal neoplasia. In a double-blind randomised placebo-controlled study folate supplementation at physiological doses has been shown to increase DNA methylation in leucocytes (P = 0.05) and colonic mucosa (P = 0.09). Further studies are required to confirm these findings in larger populations and to define abnormal ranges of DNA methylation.
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PMID:Folate, DNA methylation and colo-rectal cancer. 1450 92

Malignant pituitary tumours are rare and their pathogenesis is not fully understood. We have performed genetic analyses on tissues arising from a pituitary carcinoma that initially presented as a silent corticotroph adenoma but which failed to respond to repeated, aggressive surgical and medical therapy. Loss of heterozygosity (LOH) of known or putative tumour suppressor genes (TSG) was assessed by microsatellite analysis of microdissected tumour and matched patient blood DNA. Clonality of the pituitary tumour samples was analysed by two PCR-based techniques; one employing the highly polymorphic short tandem repeat (STR) within the human androgen receptor allele (HUMARA), another based on a restriction fragment length polymorphism of the X chromosome phosphoglycerokinase (PGK-1) gene. Screening with 9 microsatellite markers demonstrated allelic loss at 3 sites (D1S190, D3S1283 and D10S297) in all tumour samples except the presenting pituitary tumour. X chromosome inactivation analysis demonstrated polyclonality in the original presenting tumour and a metastatic deposit but monoclonality in tissue samples from a second and third transsphenoidal resection. In these cases of tumour recurrence both LOH and X chromosome inactivation suggest that monoclonality arose from preferential clonal growth from the original polyclonal tumour. Polyclonality of the metastatic deposit suggests that this was derived from the presenting tumour, although the LOH pattern indicates that a single clone dominates. The data are consistent with increasing allelic loss associated with tumour dedifferentiation and malignant transformation.
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PMID:Corticotroph carcinoma presenting as a silent corticotroph adenoma. 1467 23

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

T-cell factor (Tcf)-4 is a main transcription factor to pass on Wnt/beta-catenin signalling. The tumour suppressor protein p53 contributes as a transcription factor to cell-cycle arrest and apoptosis induction. Mutations of components in p53 and Wnt/beta-catenin signalling networks play a part in tumour formation. Here, we identify the Tcf-4 gene as a downstream effector of p53. Induction of wild-type p53 in a tet-off regulated human colon cell system leads to the reduction of Tcf-4 mRNA and protein levels. Also, mRNA of the Tcf-4 target gene uPAR is downregulated after p53 induction. Expression of a luciferase reporter controlled by the Tcf-4 promoter is repressed by wild-type p53, but not by a p53 mutant deficient in DNA binding. Such a regulation is seen in cell lines of different origin. These findings directly link Wnt/beta-catenin signalling and p53 tumour suppressor function and may provide a mechanism by which loss of p53 function contributes to progression in the adenoma/carcinoma sequence in colon tumours. Furthermore, since Tcf-4 is expressed in many tissues and downregulation of Tcf-4 by p53 is seen in several different cell types, this regulation likely plays a role in proliferation control of all tissues that can express p53 and Tcf-4.
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PMID:Identification of Tcf-4 as a transcriptional target of p53 signalling. 1499 Sep 88

The expression of the protein DCC (deleted in colorectal cancer) is lost or markedly reduced in numerous cancers and in the majority of colorectal cancers due to loss of heterozygosity in chromosome 18q, and has therefore been proposed to be a tumour suppressor. However, the rarity of mutations found in DCC, the lack of cancer predisposition of DCC mutant mice, and the presence of other tumour suppressor genes in 18q have raised doubts about the function of DCC as a tumour suppressor. Unlike classical tumour suppressors, DCC has been shown to induce apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless DCC is engaged by its ligand, netrin-1 (ref. 3). Here we show that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract leads to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engenders aggressive adenocarcinomatous malignancies. These data demonstrate that netrin-1 can promote intestinal tumour development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumour suppressors.
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PMID:Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. 1534 20

Methylthioadenosine phosphorylase (MTAP) is known as a ubiquitously expressed house keeping gene important in biochemical salvage processes. The MTAP gene is localized on the human chromosomal region 9p21, a region often deleted in cancer. Recently, several groups including our own have shown that MTAP serves as a tumour suppressor gene. The aim of this study was to analyse the role of MTAP in colon carcinoma and normal colon epithelium and the regulation of gene expression. To examine MTAP RNA and protein expression, we screened six colon carcinoma cell lines and human primary colon epithelial cells by RT-PCR and immunoblotting. MTAP expression was confirmed in vivo by immunohistochemical staining of normal colon tissue compared to adenoma and colon carcinoma. Interestingly, we found strong MTAP mRNA and protein expression by colon carcinoma cell lines but no expression by colonic epithelial cells. To analyse the regulation of MTAP expression, promoter studies were performed and revealed control of MTAP expression by LEF/TCF/beta-catenin. Furthermore, we demonstrated a significant correlation between MTAP protein expression and tumour progression as the intensity of MTAP protein staining increased from normal tissue to carcinoma. In addition, the recently postulated association between MTAP activity and interferon (IFN) sensitivity was confirmed in colon epithelial cells showing only little response to IFN-gamma, in contrast to the carcinoma cell lines. In summary, these data indicate for the first time that MTAP is not expressed in normal human colonic epithelium but is strongly upregulated in colon carcinoma. This finding may be of clinical significance concerning the homeostasis of normal colon epithelium and potential treatment of colon carcinoma.
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PMID:Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin. 1549 51

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 human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription-polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression.
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PMID:Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. 1573 78

DNA methylation is an epigenetic mechanism involved in transcriptional silencing of imprinted genes, genes located on the inactive X chromosome, and a number of tumour suppressor genes in cancer. MBD (methyl-CpG-binding domain) proteins selectively bind to methylated DNA and recruit chromatin remodelling and transcriptional repressor complexes, thereby establishing a repressive chromatin state. MBD2, a member of the MBD protein family, binds to methylated promoter CpG islands (clusters of high-density CpG dinucleotides) and acts as a methylation-dependent transcriptional repressor. Previous work has demonstrated that decreased CpG island methylation in mice lacking the DNA methyltransferase DNMT1 is associated with impaired tumorigenesis when crossed on the tumour-susceptible Apc(Min/+) background. Mbd2 deficiency also dramatically reduces adenoma burden and extends life span in a gene dosage-dependent manner in this mouse model. Mbd2 is therefore essential for tumorigenesis in the murine intestine, although it is dispensable for the viability of the host animals. These findings validate MBD2 as a potential target for therapeutic intervention in colorectal cancer.
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PMID:Role of MBD2 in gene regulation and tumorigenesis. 1624 64


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