UNIPROT:P43146 - FACTA Search

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)

Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families with opposing effects which are referred to as "essential fatty acids" (EFA): arachidonic acid (AA) and pentaene (eicosapentaenoic acid: EPA) and hexaene (docosahexaenoic acid: DHA) acids. The role of EFA is crucial, without a source of AA or compounds which can be converted into AA, synthesis of prostaglandins (PGs) by a cyclooxygenase (COX) enzyme would be compromised, and this would seriously affect many normal metabolic processes. COX, also known as prostaglandin endoperoxide synthase (Pghs) or as prostaglandin G/H synthase, is a key membrane bound enzyme responsible for the oxidation of AA to PGs. Two COX isoforms have been identified, COX-1 and COX-2 that form PGH2, a common precursor for the biosynthesis of thromboxane A2 (TxA2), prostacyclin (PGI2) and PGs (PGD2, PGE2, PGF2alpha. COX-1 enzyme is expressed constitutively in most cells and tissues. Its expression remains constant under either physiological or pathological conditions controlling synthesis of those PGs primarily involved in the regulation of homeostatic functions. In contrast, COX-2 is an intermediate response gene that encodes a 71-kDa protein. COX-2 is normally absent from most cells but highly inducible in certain cells in response to inflammatory stimuli resulting in enhanced PG release. PGs formed by COX-2 primarily mediate pain and inflammation but have multiple effects that can favour tumorigenesis. They are more abundant in cancers than in normal tissues from which the cancers arise. COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC (Adenomatous Polyposis Coli) tumour suppressor gene is the initiating event. In addition, COX-2 up-regulation and elevated PGE2 levels are involved in breast carcinogenesis. It seems that there is a correlation between COX-2 level of expression and the size of the tumours and their propensity to invade underlying tissue. Inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) of COX enzymes which significantly suppress PGE2 levels, reduced breast cancer incidence and protected against colorectal cancer. Therefore it is suggested that consumption of a diet enriched in n-3 PUFA (specifically EPA and DHA) and inhibition of COX-2 by NSAIDs may confer cardioprotective effects and provide a significant mechanism for the prevention and treatment of human cancers.
...
PMID:Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. 1219 20

LT97, a permanent cell line consisting of epithelial cells with an early premalignant genotype was established from small colorectal polyps. LT97 cells have lost both alleles of the APC tumour suppressor gene. In addition, they carry a mutated Ki-ras oncogene, while TP53 is normal. LT97 growth characteristics are thus representative of early adenomas. They had to be passaged as multicellular aggregates indicating a dependency of survival on cell-cell contact and in accordance with their premalignant genotype were not capable of growth in soft agar. LT97 cells did express both the EGF-receptor and small amounts of TGF(alpha) establishing an autocrine growth or survival pathway. However, in spite of autocrine TGF(alpha) production, growth was strongly dependent on exogenous growth factors--mainly EGF, insulin and HGF. Inhibition of the EGF-receptor kinase induced apoptosis at an IC(50) concentration of 4 micromolar indicating that TGF(alpha) activated survival pathways in the early adenoma cell.
...
PMID:Cells obtained from colorectal microadenomas mirror early premalignant growth patterns in vitro. 1220 77

Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.
...
PMID:Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. 1254 68

Many genetic and environmental factors contribute to development of cancer, but DNA methylation may provide a link between these influences. Genome stability and normal gene expression are largely maintained by a fixed and predetermined pattern of DNA methylation. In cancer, this idealistic scenario is disrupted by an interesting phenomenon: the hypermethylation of regulatory regions called CpG islands in some tumour suppressor genes--eg, BRCA1, hMLH1, p16INK4a, APC, VHL--which causes their inactivation. Development of new techniques that couple bisulphite modification with PCR has enabled these alterations to be studied in all types of biological fluids and archived tissues. Potentially, there are four types of translational studies that can be used to investigate the aberrant pattern of DNA methylation in cancer. First, CpG island hypermethylation can be used as a marker to identify cancer cells from biological samples, eg, serum and urine. This technique is highly sensitive and informative because profiles of tumour-suppressor-gene inactivation are specific to particular cancers. Second, single and combined genes that are inactivated by promoter hypermethylation, such as p16INK4a and DAPK, can be used as prognostic factors. Third, products of genes that are silenced by DNA methylation can be used as biomarkers of response to chemotherapy or hormone therapy--eg, the DNA repair O6-methylguanine-DNA methyltransferase and the oestrogen receptor. Finally, dormant tumour suppressor genes can be reactivated by DNA demethylating drugs, with the aim of reversing the neoplastic phenotype. These are new avenues worth exploring in the fight against cancer.
...
PMID:Relevance of DNA methylation in the management of cancer. 1278 7

The site of the 'first hit' in the APC tumour suppressor gene determines the type of the 'second hit', both in familial adenomatous polyposis (FAP) and sporadic colorectal tumours. Mutations near codon 1300 are associated with loss of heterozygosity (LOH) of the wild-type allele; other tumours tend to have two protein-truncating mutations. In this study, we have confirmed and refined the LOH-associated region in colorectal FAP: allelic loss in adenomatous polyps tended to occur when the germline mutation lay in the region of the APC gene between the first and second beta-catenin degradation repeats (codons 1285-1378). LOH generally occurred by mitotic recombination, leaving two identical alleles, each encoding a protein with one remaining beta-catenin degradation repeat. For patients with germline mutations that truncated the protein before the first repeat (codon 1264), LOH was very rare and tumours generally acquired a somatic mutation which left two, or less often one, repeats remaining in the protein. In our sample set, patients with germline mutations after the second beta-catenin degradation repeat tended to have undetectable, presumably cryptic, somatic mutations in their polyps. Exceptions to these rules were, however, not uncommon. Although the site of the germline mutation was the strongest determinant of the somatic mutation in FAP tumours and most patients showed no clear tendency to acquire specific types of truncating 'second hit', a minority of patients did have unusual somatic mutation spectra in their polyps. Thus, some individuals may be predisposed to particular types of 'second hit' (for example, frameshift rather than nonsense changes). Overall, disease severity (polyp number) did not vary with individuals' spectrum of somatic APC mutations, providing no clear evidence for modifier genes that influence disease severity in this fashion. Our data are consistent with the hypothesis that there exists an optimal level of beta-catenin signalling in colorectal tumours and that the APC mutation spectrum principally reflects this fact. The association between 'first hits' and 'second hits' at APC is not, however, so strong as to suggest that tumorigenesis only occurs if the genotype is optimum; we suggest 'relaxed' terminology, the 'loose fit' model, to describe this situation.
...
PMID:Refining the relation between 'first hits' and 'second hits' at the APC locus: the 'loose fit' model and evidence for differences in somatic mutation spectra among patients. 1283 48

Two versions of the PDZ2 domain of the protein tyrosine phosphatase PTP-Bas/human PTP-BL are generated by alternative splicing. The domains differ by the insertion of five amino acid residues and their affinity to the tumour suppressor protein APC. Whereas PDZ2a is able to bind APC in the nanomolar range, PDZ2b shows no apparent interaction with APC. Here the solution structure of the splicing variant of PDZ2 with the insertion has been determined using 2D and 3D heteronuclear NMR experiments. The structural reason for the changed binding specificity is the reorientation of the loop with extra five amino acid residues, which folds back onto beta-strands two and three. In addition the side-chain of Lys32 closes the binding site of the APC binding protein and the two helices, especially alpha-helix 2, change their relative position to the protein core. Consecutively, the binding site is sterically no longer fully accessible. From the NMR-titration studies with a C-terminal APC-peptide the affinity of the peptide with the protein can be estimated as 540(+/-40)microM. The binding site encompasses part of the analogous binding site of PDZ2a as already described previously, yet specific interaction sites are abolished by the insertion of amino acids in PDZ2b. As shown by high-affinity chromatography, GST-PDZ2b and GST-PDZ2a bind to phosphatidylinositol 4,5-bisphosphate (PIP(2)) micelles with a dissociation constant K(D) of 21 microM and 55 microM, respectively. In line with these data PDZ2b binds isolated, dissolved PIP(2) and PIP(3) (phosphatidylinositol 3,4,5-trisphosphate) molecules specifically with a lower K(D) of 230(+/-20)microM as detected by NMR spectroscopy. The binding site could be located by our studies and involves the residues Ile24, Val26, Val70, Asn71, Gly77, Ala78, Glu85, Arg88, Gly91 and Gln92. PIP(2) and PIP(3) binding takes place in the groove of the PDZ domain that is normally part of the APC binding site.
...
PMID:Structure determination and ligand interactions of the PDZ2b domain of PTP-Bas (hPTP1E): splicing-induced modulation of ligand specificity. 1459 6

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.
...
PMID:Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion. 1467 5

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.
...
PMID:Colon cancer: genomics and apoptotic events. 1525 76

Most hereditary predispositions to tumours affect only one particular cell type of the body but the genes bearing the relevant germ-line mutation are not cell-type-specific. Some predisposition syndromes include increased risks of lesions (developmental or tumourous) of unrelated cell types, in any individual predisposed to the main lesion (e.g. osteosarcoma in patients predisposed to retinoblastoma). Other predispositions to additional lesions occur only in members of some families with the predisposition to the basic lesion (e.g. Gardner's syndrome in some families suffering familial adenomatous polyposis). In yet other predisposition syndromes, different mutations of the same gene are associated with markedly differing family-specific clinical syndromes. In particular, identical germline mutations (e.g. in APC, RET and PTEN genes), have been found associated with differing clinical syndromes in different families. This paper reviews previously suggested mechanisms of the cell-type specificity of inherited predispositions to tumour. Models of tumour formation in predisposition syndromes are discussed, especially those involving a germline mutation (the first 'hit') of a tumour suppressor gene (TSG) and a second (somatic) hit on the second allele of the same TSG. A modified model is suggested, such that the second hit is a co-mutation of the second allele of the TSG and a regulator which is specific for growth and/or differentiation of the cell type which is susceptible to the tumour predisposition. In some cases of tumour, the second hit may be large enough to be associated with a cytogenetically-demonstrable abnormality of the part of the chromosome carrying the TSG, but in other cases, the co-mutation may be of 'sub-cytogenetic' size (i.e. 10(2)-10(5) bases). For the latter, mutational mechanisms of frameshift and impaired fidelity of replication of DNA by DNA polyerases may sometimes be involved. Candidate cell-type-specific regulators may include microRNAs and perhaps transcription factors. It is suggested that searching the introns within 10(5)-10(6) bases either side of known of exonic mutations of TSGs associated with inherited tumour predisposition might reveal microRNA cell-type-specific regulators. Additional investigations may involve fluorescent in situ hybridisations on interphase tumour nuclei.
...
PMID:The cell-type-specificity of inherited predispositions to tumours: review and hypothesis. 1553 89

The use of mouse models to study neoplasia is proving particularly powerful in dissecting the mechanisms underlying disease initiation and progression. However, the majority of these models have been somewhat limited in studying the very early effects of loss of gene function, as tumour initiation relies upon either constitutive loss of gene function or spontaneous somatic loss of function. We have therefore adopted a strategy of using an inducible Cre-lox-based system to analyse the effects of loss of gene function, the use of which is reviewed here for the intestinal tumour suppressor APC (adenomatous polyposis coli). Using this approach, we have conditionally and synchronously inactivated APC in virtually all the epithelial cells of the adult murine small intestine. After 5 days following induction of Cre-mediated recombination, mice show grossly altered crypt/villus architecture. Deficiency in APC perturbs migration, alters the normal programme of differentiation and results in increased proliferation and apoptosis. Microarray analysis reveals the transcriptome to be significantly altered; reflecting both gross phenotypic changes and changes in transcriptional activation. These findings demonstrate that APC is indeed the critical determinant of cell fate in the intestinal epithelium, explaining its role as the cellular 'gatekeeper' in preventing neoplasia.
...
PMID:Studying the consequences of immediate loss of gene function in the intestine: APC. 1604 69

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>