Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relatively little is known about molecular genetic events that participate in the genesis and progression of hemangiopericytoma. In this study, we describe two cases of hemangiopericytoma accompanied by severe hypoglycemia. Tumor cells from patient 1 exhibited insulin-growth factor I (IGF I) and insulin-like growth factor I receptor (IGF IR) mRNA transcripts. Tumor cells from patient 2 exhibited IGF II, IGF IR and IGF binding proteins 1-3 mRNA. Serum from patient 2 contained IGF II, mostly in a large molecular form ("big" IGF II); the IGF II level did not change after the tumor removal. The presence of IGF IR in tumor cells was confirmed by immunoprecipitation with antibodies that recognize human IGF IR subunit (visualized as a 460-kDa band). The hemangiopericytoma cells derived from patient 1 expressed 210000 IGF I receptors/cell. Specific binding of IGF I to the tumor cell membrane fraction was higher in tissue from patient 1, while the tissue of patient 2 showed relatively low IGF I binding. In contrast, IGF II binding was much higher in tissue from patient 2. Both tumor tissues showed positive immunostaining for c-Jun; one tumor showed strong immunostaining for c-Myc, H-Ras and p53, while the other exhibited strong reaction with H-Ras antibodies only. No loss of the heterozygosity at the genes APC, NFI and nm23-H1 loci in tumor tissue obtained from patient 1 was found. In effect, our results suggest multiple molecular genetic changes in hemangiopericytoma -- activation of some oncogenes and the IGF growth factor family. IGF ligands together with IGF IR could be responsible for hypoglycemia and perhaps the transformed phenotype.
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PMID:Molecular pathology of hemangiopericytomas accompanied by severe hypoglycemia: oncogenes, tumor-suppressor genes and the insulin-like growth factor family. 969 37

A general increase in protein synthesis and a specific increase in the synthesis of growth-promoting proteins are necessary for mitogenesis. Regulation of protein synthesis, as well as preferential translation of some mRNAs coding for growth promoting proteins (e.g. cyclin D1), involves the essential protein synthesis initiation factor eIF-4E. This factor is induced by various oncoproteins, and, when overexpressed, it can transform cultured cells. In this report we explore the roles of eIF-4E in human neoplastic disorders of the colon and in the regulation of general and specific protein synthesis. We find that eIF-4E is increased in colon adenomas and carcinomas, and this increase is accompanied in most but not all cases by elevation of cyclin D1 levels. While general protein synthesis is increased by eIF-4E overexpression in cultured cells, only a small proportion of proteins is preferentially upregulated by eIF-4E, as revealed by two-dimensional gel electrophoresis. These results are consistent with the view that eIF-4E plays a role in carcinogenesis by increasing general protein synthesis and by preferentially upregulating a subset of putative growth promoting proteins. Our results, taken together with the recent findings that c-myc transcription is negatively regulated by APC and our earlier data on transcriptional activation of eIF-4E expression by c-Myc suggest that eIF-4E is a downstream target of the APC/beta-catenin/Tcf-4 pathway, and is strongly involved in colon tumorigenesis.
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PMID:Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. 1022 2

beta-Catenin and gamma-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or beta-catenin's amino terminus stabilize beta-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though beta- and gamma-catenin have analogous structures and functions and like binding to APC, evidence that gamma-catenin has an important role in cancer has been lacking. We report here that APC regulates both beta- and gamma-catenin and gamma-catenin functions as an oncogene. In contrast to beta-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of gamma-catenin had similar transforming activity. gamma-Catenin's transforming activity, like beta-catenin's, was dependent on Tcf/Lef function. However, in contrast to beta-catenin, gamma-catenin strongly activated c-Myc expression and c-Myc function was crucial for gamma-catenin transformation. Our findings suggest APC mutations alter regulation of both beta- and gamma-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of beta-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both beta- and gamma-catenin. Furthermore, the data imply beta- and gamma-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.
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PMID:gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. 1083 25

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.
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PMID:Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines. 1117 84

Alterations of the Wnt/beta-catenin signaling pathway are known to occur in mutations of the component genes such as APC, Axin, and beta-catenin, and play a pathogenetic role in tumorigenesis. Activated Wnt signaling stabilizes beta-catenin, which associates with T cell factor, resulting in transactivation of the downstream target genes including c-myc and cyclin D1. To investigate the involvement of Wnt/beta-catenin signaling pathway in thyroid tumorigenesis, we analyzed its activation and localization in 5 human thyroid cancer cell lines and 132 thyroid tumor tissue samples. Dislocalization of beta-catenin was observed in all cell lines. Constitutive activation of T cell factor in two of four thyroid cancer cell lines was observed using reporter gene assay. Furthermore, high expression levels of c-Myc and cyclin D1 were observed in cell lines that showed cytoplasmic or nuclear accumulation of beta-catenin. In 132 paraffin-embedded thyroid carcinoma tissue samples, cytoplasmic beta-catenin was immunohistochemically observed in 52 out of 78 (67%) papillary thyroid cancers, but only in 3 of 34 (9%) follicular adenomas and 5 of 20 (25%) follicular cancers. Cytoplasmic localization of beta-catenin significantly correlated with overexpression of cyclin D1 in papillary carcinomas. Our results suggest that aberrant activation of Wnt/beta-catenin signaling is strongly involved in thyroid tumorigenesis.
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PMID:Aberrant localization of beta-catenin correlates with overexpression of its target gene in human papillary thyroid cancer. 1210 63

To elucidate early molecular events related to colon carcinogenesis, we examined alterations in the expression of colon cancer-related genes such as cyclooxygenase (COX)-2, APC and c-Myc, cell proliferation and apoptosis in the background colon mucosa, and K-ras mutation at aberrant crypt foci (ACF) in the colons of azoxymethane (AOM)-treated rats 4 weeks after the first exposure to AOM. About 40 ACF/colon were induced in the colons of rats treated with AOM (Group 1); however, rats not treated with AOM (Group 2) showed no ACF formation in the colon. The level of AgNORs in the colonic mucosa was significantly higher in Group 1 than in Group 2 (P<0.01). The colonic mucosa in Group 1 looked macroscopically and histologically normal, but the proliferative activity of the mucosa of rats treated with AOM was clearly elevated. COX-2 mRNA expression was not detected in normal colonic mucosa in Group 2, but 3 out of 10 rats in Group 1 showed COX-2 mRNA expression in their colons by reverse transcription (RT)-polymerase chain reaction (PCR). There was a tendency toward an increased expression level of COX-2 in the AOM-treated group. The level of APC mRNA expression in Group 1 was significantly lower than that in Group 2 (P<0.01). Moreover, the level of c-Myc mRNA expression in Group 1 was significantly higher than that in Group 2 (P<0.01). An average of 0.034+/-0.006% apoptosis in colonic mucosa was detected in Group 1; the incidence of apoptosis in Group 2 was 0.021+/-0.005%. The difference between Groups 1 and 2 was significant (P<0.01). These results indicate that apoptosis was possibly induced to eliminate cells damaged by AOM administration. Six out of 22 (27%) ACF with 4 or more crypts showed K-ras mutations at codon 12; all mutations were G to A transitions (GGT to GAT). ACF with 1-3 crypts showed no mutations in the K-ras gene. In conclusion, AOM caused an increase in COX-2 and c-Myc mRNA expression, a decrease in APC mRNA expression, induction of apoptosis in normal-appearing colonic mucosa, and a K-ras mutation in ACF with 4 or more crypts. These findings may help to identify key targets in the early steps of colon carcinogenesis, against which drugs that would be broadly effective for chemoprevention of colon cancer could be developed.
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PMID:Molecular changes in the early stage of colon carcinogenesis in rats treated with azoxymethane. 1214 79

The development of nontoxic natural agents with chemopreventive activity against colon cancer is the focus of investigation in many laboratories. Curcumin (feruylmethane), a natural plant product, possesses such chemopreventive activity, but the mechanisms by which it prevents cancer growth are not well understood. In the present study, we examined the mechanisms by which curcumin treatment affects the growth of colon cancer cells in vitro. Results showed that curcumin treatment causes p53- and p21-independent G(2)/M phase arrest and apoptosis in HCT-116(p53(+/+)), HCT-116(p53(-/-)) and HCT-116(p21(-/-)) cell lines. We further investigated the association of the beta-catenin-mediated c-Myc expression and the cell-cell adhesion pathways in curcumin-induced G(2)/M arrest and apoptosis in HCT-116 cells. Results described a caspase-3-mediated cleavage of beta-catenin, decreased transactivation of beta-catenin/Tcf-Lef, decreased promoter DNA binding activity of the beta-catenin/Tcf-Lef complex, and decreased levels of c-Myc protein. These activities were linked with decreased Cdc2/cyclin B1 kinase activity, a function of the G(2)/M phase arrest. The decreased transactivation of beta-catenin in curcumin-treated HCT-116 cells was unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though the curcumin-induced cleavage of beta-catenin was blocked in Z-DEVD-fmk pretreated cells. The curcumin treatment also induced caspase-3-mediated degradation of cell-cell adhesion proteins beta-catenin, E-cadherin and APC, which were linked with apoptosis, and this degradation was prevented with the caspase-3 inhibitor. Our results suggest that curcumin treatment impairs both Wnt signaling and cell-cell adhesion pathways, resulting in G(2)/M phase arrest and apoptosis in HCT-116 cells.
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PMID:Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. 1246 62

Murine models of familial adenomatous polyposis harbor a germinal heterozygous mutation on Apc tumor suppressor gene. They are valuable tools for studying intestinal carcinogenesis, as most human sporadic cancers contain inactivating mutations of APC. However, Apc(+/-) mice, such as the well-characterized Apc(Min/+) model, develop cancers principally in the small intestine, while humans develop mainly colorectal cancers. We used a Cre-loxP strategy to achieve a new model of germline Apc invalidation in which exon 14 is deleted. We compared the phenotype of these Apc(Delta14/+) mice to that of the classical Apc(Min/+). The main phenotypic difference is the shift of the tumors in the distal colon and rectum, often associated with a rectal prolapse. Thus, the severity of the colorectal phenotype is partly due to the particular mutation Delta14, but also to environmental parameters, as mice raised in conventional conditions developed more colon cancers than those raised in pathogen-free conditions. All lesions, including early lesions, revealed Apc LOH and loss of Apc gene expression. They accumulated beta-catenin, overexpressed the beta-catenin target genes cyclin D1 and c-Myc, and the distribution pattern of glutamine synthetase, a beta-catenin target gene recently identified in the liver, was mosaic in intestinal adenomas. The Apc(Delta14/+) model is thus a useful new tool for studies on the molecular mechanisms of colorectal tumorigenesis.
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PMID:Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. 1550 62

The APC tumor suppressor controls the stability and nuclear export of beta-catenin (beta-cat), a transcriptional coactivator of LEF-1/TCF HMG proteins in the Wnt/Wg signaling pathway. We show here that beta-cat and APC have opposing actions at Wnt target genes in vivo. The beta-cat C-terminal activation domain associates with TRRAP/TIP60 and mixed-lineage-leukemia (MLL1/MLL2) SET1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes H3K4 trimethylation at the c-Myc gene in vivo. H3K4 trimethylation in vivo requires prior ubiquitination of H2B, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits Pygopus, Bcl-9/Legless, and MLL/SET1-type complexes to the c-Myc enhancer together with the negative Wnt regulators, APC, and betaTrCP. Interestingly, APC-mediated repression of c-Myc transcription in HT29-APC colorectal cancer cells is initiated by the transient binding of APC, betaTrCP, and the CtBP corepressor to the c-Myc enhancer, followed by stable binding of the TLE-1 and HDAC1 corepressors. Moreover, nuclear CtBP physically associates with full-length APC, but not with mutant SW480 or HT29 APC proteins. We conclude that, in addition to regulating the stability of beta-cat, APC facilitates CtBP-mediated repression of Wnt target genes in normal, but not in colorectal cancer cells.
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PMID:The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. 1651 Aug 74

PPAR-gamma has been known to induce suppression, differentiation and reversal of malignant changes in colon cancer in vitro. However, there are several reports that PPAR-gamma ligands enhance colon polyp development in APCmin mice in vivo. These contradictory results have not yet been thoroughly explained. To explain the contradictory results, we analyzed the effects of different concentrations of the PPAR-gamma agonist, 15-deoxy-D12, 14-prostaglandin (15-d Delta PGJ2) and pioglitazone, on APC gene-mutated colon cancer cell lines (HT-29). We measured cell growth and suppression by cell count and MTT assay and analyzed the expression of beta-catenin and c-Myc protein by Western blot. In addition, we inoculated HT-29 cells into APCmin mice to compare tumor size. High concentrations (10-100 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand suppressed growth, while low concentrations (0.01-1 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand promoted growth. In particular, the effects of 0.1 microM/L 15-d Delta PGJ2 and pioglitazone on cell growth were statistically significant (P = 0.003, P = 0.001, respectively). Tumor growth was associated with an increase in beta-catenin and c-Myc expression. The growth of xenograft tumors was greater in PPAR-gamma ligand-treated mice than in control mice (control vs day 14: P = 0.024, control vs day 28: P = 0.007). The expression of beta-catenin and c-Myc protein were also elevated in PPAR-gamma-treated mouse tissues. PPAR-gamma ligand can promote the growth of APC-mutated HT-29 colon cancer cells in vitro and in vivo. In addition, the tumor promoting effect seems to be associated with an increase in beta-catenin and c-Myc expression. We think that well-controlled clinical trials should be conducted to confirm our results and to verify clinical applications.
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PMID:PPAR-gamma ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo. 1816 Oct 4


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