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)

Intestinal stem cells are adult, tissue-based stem cells located at the base of the intestinal crypt and are capable of regenerating all intestinal cell types. The progeny of mutated stem cells can expand to fill an entire crypt as a consequence of genetic drift, selective advantage or hitchhiking-eventually forming a clonal crypt population by a process called "niche succession". Cancer is believed to be a disease of stem cells. The digestive tract has a very high cancer prevalence partly due to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes, including familial adenomatous polyposis (FAP), has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the "gatekeeper" tumour suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are non-random events, selected for by the position of the germline mutation. The early growth of adenomas is contentious, with two main theories, the "top-down" and "bottom-up" hypotheses, attempting to explain the spread of dysplastic tissue in the bowel. Initial X chromosome inactivation studies suggested that colorectal tumours were monoclonal; however, work on a rare XO/XY human patient with FAP and chimeric Min mice showed that approximately 76% of adenomas were polyclonal. A reduction in tumour multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumour resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumour polyclonality.
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PMID:Expansion of a mutated clone: from stem cell to tumour. 1746 95

The aim of our group is to identify PKC (protein kinase C) in vivo function by analysing individual PKC knockouts we have generated over the past few years. The general approach we are using to identify target tissues and/or defined cell populations within the mouse for further investigation is a detailed expression analysis of individual PKC isoforms. For these purposes, we have established several specific tools in the past that allow us to follow up isoform-specific PKC expression on a very precise level. Doing so, we have started to investigate PKC expression profiles under various tumour conditions in mice. As predicted, we were able to identify various PKC isoforms to be either up- or down-regulated during the development and progression of certain tumours, implying that these isoforms are substantially linked to the biology of these tumours. In order to prove this hypothesis, we then crossed relevant PKC knockout lines on the appropriate tumour background and analysed tumour growth and progression under PKC-deficient conditions. Exemplary of this approach, recent data generated with PKCalpha-deficient APC(Min) (adenomatous polyposis coli) mice identify PKCalpha in this system acting as a tumour suppressor instead of being a promoter as suggested from PMA data.
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PMID:Functional PKC in vivo analysis using deficient mouse models. 1795 67

RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.
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PMID:Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. 1845 62

The adenomatous polyposis coli (APC) tumour suppressor is a multifunctional protein involved in the regulation of Wnt signalling and cytoskeletal dynamics. Little is known about how APC controls these disparate functions. In this study, we have used APC- and axin-fluorescent fusion proteins to examine the interactions between these proteins and show that the functionally distinct populations of APC are also spatially separate. Axin-RFP forms cytoplasmic punctate structures, similar to endogenous axin puncta. Axin-RFP recruits beta-catenin destruction complex proteins, including APC, beta-catenin, glycogen synthase kinase-3-beta (GSK3-beta) and casein kinase-1-alpha (CK1-alpha). Recruitment into axin-RFP puncta sequesters APC from clusters at cell extensions and this prevents its microtubule-associated functions. The interaction between APC-GFP and axin-RFP within the cytoplasmic puncta is direct and dramatically alters the dynamic properties of APC-GFP. However, recruitment of APC to axin puncta is not absolutely required for beta-catenin degradation. Instead, formation of axin puncta, mediated by the DIX domain, is required for beta-catenin degradation. An axinDeltaDIX mutant did not form puncta, but still mediated recruitment of destruction complex proteins and phosphorylation of beta-catenin. We conclude that there are distinct pools of APC and that the formation of axin puncta, rather than the axin/APC complex, is essential for beta-catenin destruction.
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PMID:Recruitment of adenomatous polyposis coli and beta-catenin to axin-puncta. 1859 34

Human placentation displays many similarities with tumourigenesis, including rapid cell division, migration and invasion, overlapping gene expression profiles and escape from immune detection. Recent data have identified promoter methylation in the Ras association factor and adenomatous polyposis coli tumour suppressor genes as part of this process. However, the extent of tumour-associated methylation in the placenta remains unclear. Using whole genome methylation data as a starting point, we have examined this phenomenon in placental tissue. We found no evidence for methylation of the majority of common tumour suppressor genes in term placentas, but identified methylation in several genes previously described in some human tumours. Notably, promoter methylation of four independent negative regulators of Wnt signalling has now been identified in human placental tissue and purified trophoblasts. Methylation is present in baboon, but not in mouse placentas. This supports a role for elevated Wnt signalling in primate trophoblast invasiveness and placentation. Examination of invasive choriocarcinoma cell lines revealed altered methylation patterns consistent with a role of methylation change in gestational trophoblastic disease. This distinct pattern of tumour-associated methylation implicates a coordinated series of epigenetic silencing events, similar to those associated with some tumours, in the distinct features of normal human placental invasion and function.
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PMID:Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts. 1870 52

The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
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PMID:E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. 1881 47

Colorectal cancer is a major health problem worldwide. Aberrant activation of the Wingless-type mouse mammary tumour virus integration site family (Wnt)/beta-catenin signalling pathway due to mutation of adenomatous polyposis coli (APC), beta-catenin (CTNNB1) or AXIN genes is the most common and initial alteration in sporadic colorectal tumours. Numerous epidemiological and experimental studies have indicated a protective action of vitamin D against colorectal cancer. Previous work has demonstrated that the most active vitamin D metabolite, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits beta-catenin transcriptional activity by promoting vitamin D receptor (VDR) binding to beta-catenin and the induction of E-cadherin expression. Recently, 1,25(OH)2D3 has been shown to distinctly regulate two genes encoding the extracellular Wnt inhibitors DICKKOPF-1 and DICKKOPF-4 (DKK-1, DKK-4). By an indirect transcriptional mechanism, 1,25(OH)2D3 increases the expression of DKK-1 RNA and protein, which acts as a tumour suppressor in human colon cancer cells harbouring endogenous mutations in the Wnt/beta-catenin pathway. In contrast, 1,25(OH)2D3 represses DKK-4 transcription by inducing direct VDR binding to its promoter. Unexpectedly, DKK-4 is a target of the Wnt/beta-catenin pathway and is up-regulated in colorectal tumours, and it has been shown to increase cell migration and invasion and to promote a proangiogenic phenotype. Together, these results show that 1,25(OH)2D3 exerts a complex set of regulatory actions leading to the inhibition of the Wnt/beta-catenin pathway in colon cancer cells that is in line with its protective effect against this neoplasia.
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PMID:Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. 1903 86

The Discs Large (Dlg) protein is known to be involved in the regulation of cellular proliferation and polarity in a variety of tissues. The human homologue DLG1 is thought to be a tumour suppressor, through formation of a complex with the APC (adenomatous polyposis coli) protein, causing negative regulation of the cell cycle. An alternative oncogenic role has also been proposed, in which the PI3-kinase pathway is activated under the influence of the adenovirus E4 ORF1 protein. The differing roles seem to be related to differences in the precise pattern of expression. However, the biochemical pathways involved in regulating DLG1 function during different phases of the cell cycle remain unclear. In this study we show that phosphorylation is a major post-translational modification of the protein and it affects both location and function. DLG1 lies at the cellular junctions in G1, is enriched in the cytoplasm in S phase and locates to the mitotic spindle in M phase. We also show that DLG1 is phosphorylated by both CDK1 and CDK2 on Ser158 and Ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on Ser158 and Ser442 in its putative nuclear functions as a tumour suppressor. In addition, the mutants at these sites demonstrate different half-lives as well as different susceptibilities to ubiquitylation, suggesting a role for these phosphorylation events in controlling DLG1 protein stability. These findings establish phosphorylation events as key regulators of DLG1 localisation and function.
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PMID:CDK phosphorylation of the discs large tumour suppressor controls its localisation and stability. 1906 88

The adenomatous polyposis coli (APC) tumour suppressor gene is mutated in the majority of colon cancers. APC is a multi-domain protein whose distribution at different subcellular locations correlates with unique cellular processes. Our laboratory has focused on the link between APC subcellular location and function, and has characterized pathways for the trafficking of APC both into and out of the nucleus. Antibody specificity is an important factor in the determination of APC localization, and in this chapter we outline a strategy for the unambiguous detection of APC using a combination of biochemical and cell biology approaches.
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PMID:Detection of cytoplasmic and nuclear localization of adenomatous polyposis coli (APC) protein in cells. 1909 47

The Wnt/beta-catenin signalling pathway has important roles in normal cellular proliferation, development and angiogenesis. Many malignant transformations, including sporadic colorectal tumours, are caused by constitutive activation of the Wnt route due to mutations in the tumour suppressor protein adenomatous polyposis coli (APC) or the beta-catenin oncogene, ultimately resulting in reduced beta-catenin degradation by the ubiquitin (Ub) proteasome system (UPS). The COP9 signalosome (CSN) regulates the UPS by controlling cullin-RING Ub ligases (CRLs). We show here that the CSN and the beta-catenin destruction complex cooperate in targeting beta-catenin for degradation by the UPS. Together with the CRL that ubiquitinates beta-catenin, they form a supercomplex responsible for beta-catenin degradation. Wnt3A, glycogen synthase kinase 3beta inhibitors or mutation of CSN-mediated deneddylation induce the disassembly of the supercomplex and the accumulation of beta-catenin. Likewise, downregulation of the CSN in HeLa cells leads to retarded degradation of beta-catenin. Additionally, we found that the knockdown of the CSN causes accelerated proteolysis of APC, an essential component of the beta-catenin destruction complex, which is degraded by the UPS as beta-catenin. We show here that APC is stabilised by the Ub-specific protease 15 (USP15) associated with the CSN. This is demonstrated by over-expression of siRNA oligonucleotides against USP15 or by over-expression of an USP15 mutant, which is unable to degrade poly-Ub chains. Thus, the CSN controls the Wnt/beta-catenin signalling by assisting the assembly of beta-catenin-degrading supercomplexes by deneddylation and, simultaneously, by stabilising APC via CSN-associated USP15. The CSN regulates the balance between beta-catenin and APC. Disturbance of this balance can cause cancer by driving cell transformation, tumour angiogenesis and metastasis. A model is provided that proposes a role of CSN-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound APC via CSN-associated USP15.
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PMID:The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. 1957 24


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