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)

The tumour suppressor APC is truncated in most colon cancers, which leads to the stabilization of beta-catenin and to the constitutive activation of Wnt signalling. However, it is not clear why colon cancer cells retain the truncated APC fragment. Here, we show that a decrease of APC levels achieved by RNA interference impairs cell proliferation and DNA replication, not only in 293 cells that express a wild-type protein, but also in SW480 colon cancer cells that express exclusively a truncated APC fragment. This correlates with a reduction of the levels of cyclin A, cyclin A-dependent kinase activity, p27(kip1) and the catalytic subunit of DNA polymerase delta. Thus, our data suggest that colon cancer cells retain a truncated APC fragment because it is essential for cell proliferation.
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PMID:Truncated APC is required for cell proliferation and DNA replication. 1645 Mar 83

Our previous studies have implicated the Wnt antagonist, sFRP1, as a tumour suppressor gene in advanced colorectal cancer. In this study, we set out to investigate the relationship between sFRP1 expression and large bowel adenomas, a precursor of colorectal cancer. The induction of beta-catenin/TCF mediated transcription is both a frequent early event in colorectal neoplasia, and a key downstream effect of wnt growth factor signalling. Lithium treatment of a small bowel mucosal cell line (FHs 74 int) induced sFRP1 within 8 h, indicating that this gene is positively regulated by beta-catenin, contrasting with the suppression of sFRP1 expression, we saw previously in advanced colorectal cancers. We therefore investigated a series of 12 adenomas and matched large bowel mucosa samples. Real-time RT-PCR analysis showed a reduction in sFRP1 expression in all 12 dysplastic lesions (median 485-fold, IQR 120- to 1500-fold), indicating factors other than beta-catenin influence sFRP1 levels. In a second series of 11 adenomas, we identified methylation of the sFRP1 promotor region in all 11 samples, and this was increased compared with the surrounding normal mucosa in seven cases. Immunohistochemical analysis using a polyclonal antibody supported these findings, with sFRP1 expression reduced in many of the adenoma samples examined. sFRP1 staining in normal mucosa adjacent to the dysplastic tissue was also reduced compared with the normal controls, suggesting that sFRP1 expression may be suppressed in a field of mucosa rather than in individual cells. This study identifies sFRP1 inactivation at the premalignant stage of colorectal cancer development, indicating that these pathways may be useful targets for chemoprevention strategies in this common solid tumour.
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PMID:The Wnt antagonist sFRP1 is downregulated in premalignant large bowel adenomas. 1652 2

Overexpression of the transcriptional activator beta-catenin, mostly owing to loss-of-function mutations of the adenomatous polyposis coli (APC) tumour suppressor gene, is crucial for the initiation and progression of human colorectal carcinogenesis. Securin is a regulator of chromosome separation and its overexpression has been shown to be involved in different tumour-promoting processes, like transformation, hyperproliferation and angiogenesis, and correlates with tumour cell invasion. However, the molecular mechanism leading to securin overexpression in human colorectal cancer is unknown. Here we show a correlated high expression of beta-catenin and securin (hPTTG1) in colorectal adenomas and carcinomas and further demonstrate that securin is a target of beta-catenin transcriptional activation. This implies that deregulation of the beta-catenin/T-cell factor-signalling pathway leads to overexpression of securin in human colorectal cancer, which subsequently may contribute to tumour progression.
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PMID:Securin (hPTTG1) expression is regulated by beta-catenin/TCF in human colorectal carcinoma. 1670 13

The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC binds to beta-catenin, a key component of the Wnt signalling pathway, and induces its degradation. In addition to this role, there is increasing evidence for additional roles of APC, including the organization of cytoskeletal networks. APC interacts with microtubules and accumulates at their plus ends in membrane protrusions. Also, it has been reported that APC is associated with the plasma membrane in an actin-dependent manner. Moreover, APC interacts with IQGAP1, an effector of Rac1 and Cdc42, and APC-stimulated guanine nucleotide exchange factor (Asef), a Rac1-specific guanine nucleotide exchange factor (GEF). IQGAP1 mediates association of APC with cortical actin in the leading edge of migrating cell and both proteins are required for cell polarization and directional migration. APC interacts with Asef and stimulates its activity, thereby regulating the actin cytoskeletal network, cell morphology, adhesion and migration. Truncated mutant APCs present in colorectal tumour cells activate Asef constitutively and contribute to their aberrant migratory properties, which may be important for adenoma formation as well as tumour progression to invasive malignancy.
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PMID:Wnt signalling and the actin cytoskeleton. 1714 98

Most colon cancer cells express truncated versions of the tumour suppressor Adenomatous Polyposis Coli (APC). These molecules are selected during tumourigenesis for impaired beta-catenin degrading activity. In this study, we describe that truncated APC can still control the activity of beta-catenin in colon cancer cell lines via its first 20 amino acid repeat. First, we show that both endogenous and ectopically expressed truncated APC molecules can bind to beta-catenin. Second, reduction of the levels of truncated APC by RNA interference increases the activity of a beta-catenin-dependent reporter gene and stimulates the expression of the beta-catenin target gene AXIN2/conductin. This occurs without alterations of the amounts of cytosolic beta-catenin. Conversely, ectopic expression of truncated APC decreases beta-catenin-dependent transcription without affecting the intensity of immunofluorescence staining of beta-catenin in transfected cells. Third, we reveal that the APC level increases when cells reach the G1-S boundary during cell cycle progression. Simultaneously, the amount of beta-catenin bound to APC increases and the transcriptional activity of beta-catenin drops in an APC-dependent manner. Again, this occurs independently of the amounts of either total or phosphorylated cytosolic beta-catenin. Together, these results indicate that truncated APC controls the ability of beta-catenin to activate transcription. As we also show that the inhibition involves the first 20 amino acid repeat of APC, our data suggest that colon cancer cells retain a truncated APC molecule containing at least the first 20 amino acid repeat to modulate the transcriptional activity of beta-catenin in a cell cycle-dependent manner.
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PMID:Truncated APC regulates the transcriptional activity of beta-catenin in a cell cycle dependent manner. 1718 93

Smad4 is a tumour suppressor gene frequently deleted in pancreatic cancer. To investigate the roles of Smad4 deficiency in invasive and matastatic capabilities of pancreatic cancer, we examined the effects of Smad4 deficiency on regulation of the invasion suppressor E-cadherin in pancreatic cancer cell line PANC-1. TGF-beta decreased expression of E-cadherin and beta-catenin proteins at the plasma membrane, increased Snail and Slug mRNA expression, and induced fibroblastoid morphology in PANC-1 cells. These effects of TGF-beta were abrogated in Smad4-knocked-down PANC-1 cells. We also found that TGF-beta-induced down-regulation of E-cadherin expression was partially inhibited in Snail- and Slug-knocked-down PANC-1 cells. Thus, Smad4 mediates down-regulation of E-cadherin induced by TGF-beta in PANC-1 cells, at least in part, through Snail and Slug induction. These results suggest that Smad4 deficiency observed in invasive and metastatic pancreatic cancer might not be linked to the loss of E-cadherin.
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PMID:Smad4 is essential for down-regulation of E-cadherin induced by TGF-beta in pancreatic cancer cell line PANC-1. 1730 Oct 79

The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers, and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.
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PMID:Myc deletion rescues Apc deficiency in the small intestine. 1737 31

Approximately 10% of all colorectal carcinomas are mucinous carcinomas, characterized by extracellular mucin. Occasionally, mucin accumulates intracellularly in these tumours, causing signet ring cell differentiation. We hypothesized that signet ring cells arise from a separate genetic pathway. In this study the molecular background of signet ring cell differentiation was investigated by analysing genetic changes, changes in the expression of adhesion molecules, and mucin content. Furthermore, its clinical relevance was addressed. Cell lines of colorectal tumours with non-mucinous (AC), mucinous (MC), and signet ring cell phenotype (MCSRC) were used for Multiplex Ligation-dependent Probe Amplification to detect deletions and amplifications in specific oncogenes and tumour suppressor genes. Furthermore, the expression of E-cadherin, beta-catenin, ITF (intestinal trefoil factor), and MUC2 in signet ring cells was studied by immunohistochemistry, immunofluorescence, and mRNA in situ hybridization. Results were validated using a large cohort of rectal carcinomas from which clinicopathological data were available. Specific amplifications and deletions in cell lines of AC, MC, and MCSRC were detected. Bcl-2 was amplified in MCSRC and MC cell lines, but not in AC cell lines. Bcl-2 FISH analysis confirmed this in patient material. Signet ring cells had decreased expression of adhesion molecules (E-cadherin, beta-catenin) and were strongly positive for ITF and MUC2, two peptides which are normally only produced by goblet cells. RNA in situ hybridization confirmed the production of ITF. Mucinous carcinomas with signet ring cell differentiation presented at a higher T stage than adenocarcinomas and mucinous carcinomas (16% pT4 versus 3-5%, p<0.001) and were more frequently node positive (77% vs 39-44%; p<0.001). Prognosis was significantly worse. In conclusion, the presence of signet ring cells in carcinomas with mucinous differentiation correlates with increased T-stage and poor prognosis. These cells, characterized by ITF and MUC2 production, show disruption of the E-cadherin/beta-catenin complex, as well as amplification of Bcl-2.
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PMID:Signet ring cell differentiation in mucinous colorectal carcinoma. 1747 75

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog.
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PMID:Tumour suppressors in liver carcinogenesis. 1793 20

Adenomatous polyposis coli (APC), whose mutation causes colorectal cancers, is a key player in the Wnt signaling pathway. While the role of APC in inhibition of beta-catenin/LEF1-dependent activation of transformation-inducing genes has been intensively studied and well established, regulation of APC expression at the protein level is only partially understood. Here we report that APC is up-regulated by EDD, the mammalian orthologue of Drosophila melanogaster"hyperplastic discs" gene (hyd) that is considered to be a putative tumor suppressor. Screening of APC immunocomplexes by mass spectrometry identified EDD as a putative APC-interacting protein. Exogenously expressed and endogenous APC interacted with EDD in vivo. Indirect immunofluorescent analyses demonstrated that APC and EDD co-localized in the cytoplasm of the cell. Over-expression of EDD enhanced the protein expression level of APC and its binding partner Axin, resulting in inhibition of Wnt signaling downstream of beta-catenin. Conversely, siRNA knock-down of EDD down-regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of beta-catenin. Thus, through protein-protein interaction, EDD stabilizes APC and up-regulates APC's function to inhibit beta-catenin, suggesting that EDD could act as a colorectal tumor suppressor.
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PMID:Putative tumor suppressor EDD interacts with and up-regulates APC. 1807 71


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