Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Axin antagonizes the developmental effects of Wnt in vertebrates. We show here that Axin simultaneously binds two components of the Wnt pathway, beta-catenin and its negative regulator glycogen synthase kinase-3beta. In mammalian cells, Axin inhibits Wnt-1 stimulation of beta-catenin/lymphoid enhancer factor 1-dependent transcription. Axin also blocks beta-catenin-mediated transcription in colon cancer cells that have a mutation in the adenomatous polyposis coli gene. These findings suggest that Axin, by forming a complex with beta-catenin and glycogen synthase kinase-3beta, can block signaling stimulated by Wnt or by adenomatous polyposis coli mutations.
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PMID:Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. 950 Dec 8

The interaction between beta-catenin and LEF-1/TCF transcription factors plays a pivotal role in the Wnt-1 signaling pathway. The level of beta-catenin is regulated by partner proteins, including glycogen synthase kinase-3beta (GSK-3beta) and the adenomatous polyposis coli (APC) tumor suppressor protein. Genetic defects in APC are responsible for a heritable predisposition to colon cancer. APC protein and GSK-3beta bind beta-catenin, retain it in the cytoplasm, and facilitate the proteolytic degradation of beta-catenin. Abrogation of this negative regulation allows beta-catenin to translocate to the nucleus and to form a transcriptional activator complex with the DNA-binding protein lymphoid-enhancing factor 1 (LEF-1). This complex is thought to be involved in tumorigenesis. Here we show that covalent linkage of LEF-1 to beta-catenin and to transcriptional activation domains derived from the estrogen receptor or the herpes simplex virus protein VP16 generates transcriptional regulators that induce oncogenic transformation of chicken embryo fibroblasts. The chimeras between LEF-1 and beta-catenin or VP16 are constitutively active, whereas fusions of LEF-1 to the estrogen receptor are regulatable by estrogen. These experiments document the oncogenicity of transactivating LEF-1 and show that the transactivation domain normally provided by beta-catenin can be replaced by heterologous activation domains. These results suggest that the transactivating function of the LEF-1/beta-catenin complex is critical for tumorigenesis and that this complex transforms cells by activating specific LEF-1 target genes.
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PMID:Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. 987 85

The tumor suppressor function of the adenomatous polyposis coli protein (APC) depends, in part, on its ability to bind and regulate the multifunctional protein, beta-catenin. beta-Catenin binds the high mobility group box transcription factors, lymphocyte enhancer-binding factor (LEF) and T-cell factor, to directly regulate gene transcription. Using LEF reporter assays we find that APC-mediated down-regulation of beta-catenin-LEF signaling is reversed by proteasomal inhibitors in a dose-dependent manner. APC down-regulates signaling induced by wild type beta-catenin but not by the non-ubiquitinatable S37A mutant, beta-catenin. Bisindoylmaleimide-type protein kinase C inhibitors, which prevent beta-catenin ubiquitination, decrease the ability of APC to down-regulate beta-catenin-LEF signaling. All these effects on LEF signaling are paralleled by changes in beta-catenin protein levels. Lithium, an inhibitor of glycogen synthase kinase-3beta, does not alter the ability of APC to down-regulate beta-catenin protein and beta-catenin-LEF signaling in the colon cancer cells that were tested. These results point to a role for beta-catenin ubiquitination, proteasomal degradation, and potentially a serine kinase other than glycogen synthase kinase-3beta in the tumor-suppressive actions of APC.
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PMID:The ubiquitin-proteasome pathway and serine kinase activity modulate adenomatous polyposis coli protein-mediated regulation of beta-catenin-lymphocyte enhancer-binding factor signaling. 1034 31

Colon carcinoma and melanoma cells containing either a deletion of the adenomatous polyposis coli tumor suppressor protein (APC) or mutation of the site in beta-catenin phosphorylated by glycogen synthase kinase-3beta (GSK-3beta) display elevated levels of detergent-soluble beta-catenin due to insensitivity of the cytosolic protein to proteasome-dependent degradation. In this study, we have examined the effect of beta-catenin mutation (S37F) or APC loss on the proteasome sensitivity of additional subcellular beta-catenin pools in melanoma cells. In contrast to detergent-soluble beta-catenin, the detergent-insoluble protein remains proteasome-sensitive irrespective of S37F mutation or APC status. This insoluble component appears associated primarily with nuclear cytoskeletal elements. In addition, DNase I treatment solubilized a portion of detergent-insoluble beta-catenin, suggesting that this fraction also contains chromatin-associated protein, and correlating with a proteasome-sensitive elevation in beta-catenin-stimulated reporter activity. Since the detergent-insoluble nuclear component of beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity, distinct from the soluble nuclear and cytosolic pools of this protein, regulation of beta-catenin proteasome sensitivity and the contribution of this process to beta-catenin function may be more complex than previously appreciated.
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PMID:Nuclear beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity in melanoma cells. 1069 68

Alteration of adenomatous polyposis coli (APC) is known to be an early event in neoplasia, causing activation of the beta-catenin / Tcf pathway. Although it is thought that alterations in APC and beta- catenin may complement one another, the contribution of beta-catenin mutations to colorectal carcinogenesis remains unclear. We therefore performed PCR-single strand conformation polymorphism analysis and direct sequencing of exon 3 of beta-catenin gene in adenomas, adenocarcinomas, and aberrant crypt foci (ACF), considered to be putative precursor lesions of colorectal neoplasias, in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) treated F344 rats. beta-Catenin mutations were identified in all of 7 adenomas (100%) and 6 of 12 (50%) adenocarcinomas. All of the mutations were found in codons 32 through 34, the serine encoded by codon 33 being an important phosphorylation site by glycogen synthase kinase-3beta. Regarding ACF, 14 of 46 (30.4%) were found to be mutated, eleven (78%) in codon 34, and the others in codon 45 (frequently altered in human colon cancer), and codons 47 and 56 (which have not been previously reported). The frequency of beta-catenin mutations in adenomas was significantly higher than in ACF (P < 0.001) and adenocarcinomas (P < 0.05). Thus, beta-catenin mutations may have more importance in the genesis of adenomas than ACF or adenocarcinomas in rat colon carcinogens by PhIP.
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PMID:More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats. 1096 19

Analysis of the glycogen synthase kinase-3beta (GSK-33) activity in several colon cancer cell lines suggested a correlation between comparatively low enzyme activity and moderate to high differentiation status. Treatment of LIM2537 cells, a poorly differentiated colon cancer cell line, with the potent differentiating agent sodium butyrate resulted in 34% reduction in GSK-3beta activity in the treated cells (P < 0.028, n = 3). Decreases in GSK-3beta activity were paralleled by stabilization of cytoplasmic beta-catenin, a hallmark of Wnt signaling. However, in contrast to Wnt signaling, expression of the beta-catenin/ TCF target genes c-myc and cyclin D1 did not appear to be increased in the sodium butyrate-treated cells. Interestingly, expression of membrane-bound beta-catenin was increased in the sodium butyrate-treated cells. This suggests that, in the context of cellular differentiation, increases in beta-catenin expression may be sequestered at the cell membrane and suggests that a possible role of sodium butyrate in promoting differentiation may be via increasing the levels of beta-catenin available for cell adhesion.
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PMID:Sodium butyrate-induced differentiation of human LIM2537 colon cancer cells decreases GSK-3beta activity and increases levels of both membrane-bound and Apc/axin/GSK-3beta complex-associated pools of beta-catenin. 1134 69

Mutations in human Adenomatous Polyposis Coli (APC) gene are associated with both familial and sporadic colorectal tumors. APC is known to down regulate beta-catenin levels, a transducer of Wnt signaling. The aim of this study is to provide transgenic Drosophila expressing either full-length or truncated forms of human APC (hAPC) protein and methods for using them in functional genomics and drug screening. Consistent with its biochemical properties, targeted expression of either full-length hAPC or its beta-catenin binding domain alone negatively regulated the function of the beta-catenin homologue, Armadillo (Arm) and thereby, inhibited Wnt/Wg signaling during fly development. hAPC inhibited Arm function even in the absence of GSK-3beta activity, although the latter was required to mediate the degradation of Arm. Consistent with this, hAPC suppressed the phenotypes induced by the over-expression of degradation-resistant forms of Arm. Subsequently, using hAPC-induced eye phenotypes as the assay in a suppressor-enhancer screen, we have identified two new loci in Drosophila, which modulate Wnt/Wg signaling. In addition, an anti-colon cancer drug, indomethacin, specifically enhanced hAPC-induced phenotypes.
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PMID:Studies on human colon cancer gene APC by targeted expression in Drosophila. 1168 66

A novel phosphorylation-specific antibody (alphapbeta-catenin) was generated against a peptide corresponding to amino acids 33-45 of human beta-catenin, which contained phosphorylated serines at positions 33 and 37. This antibody is specific to phosphorylated beta-catenin and reacts neither with the non-phosphorylated protein nor with phosphorylated or non-phosphorylated plakoglobin. It weakly interacts with S33Y beta-catenin but not with the S37A mutant. pbeta-catenin is hardly detectable in normal cultured cells and accumulates (up to 55% of total beta-catenin) upon overexpression of the protein or after blocking its degradation by the proteasome. Inhibition of both GSK-3beta and the proteasome resulted in a rapid (t1/2=10 minutes) and reversible reduction in pbeta-catenin levels, suggesting that the protein can undergo dephosphorylation in live cells, at a rate comparable to its phosphorylation by GSK-3beta. pbeta-catenin interacts with LEF-1, but fails to form a ternary complex with DNA, suggesting that it is transcriptionally inactive. Immunofluorescence microscopy indicated that pbeta-catenin accumulates in the nuclei of MDCK and BCAP cells when overexpressed and is transiently associated with adherens junctions shortly after their formation. pbeta-catenin only weakly interacts with co-transfected N-cadherin, although it forms a complex with the ubiquitin ligase component beta-TrCP. SW480 colon cancer cells that express a truncated APC, at position 1338, contain high levels of pbeta-catenin, whereas HT29 cells, expressing APC truncated at position 1555, accumulate non-phosphorylated beta-catenin, suggesting that the 1338-1555 amino acid region of APC is involved in the differential regulation of the dephosphorylation and degradation of pbeta-catenin.
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PMID:Regulation of S33/S37 phosphorylated beta-catenin in normal and transformed cells. 1207 67

The intestinal mucosa is a rapidly-renewing tissue characterized by cell proliferation, differentiation, and eventual apoptosis with progression up the vertical gut axis. The inhibition of phosphatidylinositol (PI) 3-kinase by specific chemical inhibitors or overexpression of the lipid phosphatase PTEN enhances enterocyte-like differentiation in human colon cancer cell models of intestinal differentiation. In this report, we examined the role of PI 3-kinase inhibition in the regulation of apoptotic gene expression in human colon cancer cell lines HT29, HCT-116, and Caco-2. Inhibition of PI 3-kinase with the chemical inhibitor wortmannin increased TNF-related apoptosis-inducing ligand (TRAIL; Apo2) mRNA and protein expression. Similarly, overexpression of the tumor suppressor protein PTEN, an antagonist of PI 3-kinase signaling, resulted in the increased expression of TRAIL. Activation of PI 3-kinase by pretreatment with IGF-1, a gut trophic factor, markedly attenuated the induction of TRAIL by wortmannin. Moreover, overexpression of active Akt, a downstream target of PI 3-kinase, or inhibition of GSK-3, a downstream target of active Akt, completely blocked the induction of TRAIL by wortmannin. Consistent with findings that TRAIL is induced by agents that enhance intestinal cell differentiation, TRAIL expression was specifically localized to the differentiated cells of the colon and small bowel. Adenovirus-mediated overexpression of TRAIL increased DNA fragmentation of HCT-116 cells, demonstrating the functional activity of TRAIL induction. Taken together, our findings demonstrate induction of the TRAIL by inhibition of PI 3-kinase in colon cancer cell lines. These results identify TRAIL, a novel TNF family member, as a downstream target of the PI 3-kinase/Akt/GSK-3 pathway and may have important implications for better understanding the role of the PI 3-kinase pathway in intestinal cell homeostasis.
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PMID:Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. 1214 Feb 94

Constitutive activation of the Wnt/beta-catenin pathway is thought to play a central role in colorectal carcinogenesis. A key output in this pathway is the nuclear level of beta-catenin, which determines the transcription of T-cell transcription factor (TCF)/lymphoid enhancer-binding factor-responsive target genes. In unstimulated cells, beta-catenin is continuously targeted for ubiquitin-dependent degradation, which depends on its NH(2)-terminal phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) in association with a multiprotein complex. Previously, we have shown that the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin down-regulate beta-catenin/TCF signaling in colorectal cancer cells. Here, we demonstrate that the reduced signaling activity of beta-catenin in response to NSAIDs is a result of its enhanced phosphorylation. In SW948 and SW480 colorectal cancer cells, phosphorylation of NH(2)-terminal S/T residues time dependently increased in response to aspirin and indomethacin. In contrast, in 293 cells, NSAID treatment failed to induce detectable levels of beta-catenin phosphorylation but resulted in degradation of beta-catenin within 24 h in serum-deprived cells. The aspirin-induced beta-catenin phosphorylation in colon cancer cells preceded down-regulation of beta-catenin/TCF signaling, suggesting a causal relationship. Inhibition of this process by LiCl pointed to participation of GSK-3beta. Unexpectedly, GSK-3beta was also phosphorylated upon aspirin treatment in six colorectal cancer cell lines. We present evidence that inactivation of a phosphatase rather than stimulation of a kinase or interference with the ubiquitination machinery may be the cause of the stabilized phosphorylation. The data emphasize the importance of beta-catenin in the pathogenesis of colorectal cancer and define it as a key target for anticancer therapeutics.
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PMID:Reduction of beta-catenin/T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin. 1281 29


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