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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wnt signaling pathway is central to the development of all animals and to cancer progression, yet largely unknown are the pairings of secreted Wnt ligands to their respective Frizzled transmembrane receptors or, in many cases, the relative contributions of canonical (beta-catenin/LEF/TCF) versus noncanonical Wnt signals. Specifically, in the kidney where Wnt-4 is essential for the mesenchymal to epithelial transition that generates the tissue's collecting tubules, the corresponding Frizzled receptor(s) and downstream signaling mechanism(s) are unclear. In this report, we addressed these issues using Madin-Darby Canine Kidney (MDCK) cells, which are competent to form tubules in vitro. Employing established reporter constructs of canonical Wnt/beta-catenin pathway activity, we have determined that MDCK cells are highly responsive to Wnt-4, -1, and -3A, but not to Wnt-5A and control conditions, precisely reflecting functional findings from Wnt-4 null kidney mesenchyme ex vivo rescue studies. We have confirmed that Wnt-4's canonical signaling activity in MDCK cells is mediated by downstream effectors of the Wnt/beta-catenin pathway using beta-Engrailed and dnTCF-4 constructs that suppress this pathway. We have further found that MDCK cells express the Frizzled-6 receptor and that Wnt-4 forms a biochemical complex with the Frizzled-6 CRD. Since Frizzled-6 did not appear to transduce Wnt-4's canonical signal, data supported recently by Golan et al., there presumably exists another as yet unknown Frizzled receptor(s) mediating Wnt-4 activation of beta-catenin/LEF/TCF. Finally, we report that canonical Wnt/beta-catenin signals cells help maintain cell growth and survival in MDCK cells but do not contribute to standard HGF-induced (nonphysiologic) tubule formation. Our results in combination with work from Xenopus laevis (not shown) lead us to believe that Wnt-4 binds both canonical and noncanonical Frizzled receptors, thereby activating Wnt signaling pathways that may each contribute to kidney tubulogenesis.
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PMID:Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells. 1526 86

The Wnt signalling system controls many fundamental processes during animal development and its deregulation has been causally linked to colorectal cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA-binding factors and the subsequent activation of target genes. Using genetic assays in Drosophila, we have recently identified a presumptive adaptor protein, Legless (Lgs), that binds to beta-catenin and mediates signalling activity by recruiting the transcriptional activator Pygopus (Pygo). Here, we characterize the beta-catenin/Lgs interaction and show: (1) that it is critically dependent on two acidic amino acid residues in the first Armadillo repeat of beta-catenin; (2) that it is spatially and functionally separable from the binding sites for TCF factors, APC and E-cadherin; (3) that it is required in endogenous as well as constitutively active forms of beta-catenin for Wingless signalling output in Drosophila; and (4) that in its absence animals develop with the same phenotypic consequences as animals lacking Lgs altogether. Based on these findings, and because Lgs and Pygo have human homologues that can substitute for their Drosophila counterparts, we infer that the beta-catenin/Lgs binding site may thus serve as an attractive drug target for therapeutic intervention in beta-catenin-dependent cancer progression.
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PMID:Identification and in vivo role of the Armadillo-Legless interaction. 1529 66

Dysregulation of Wnt signaling appears to be a critical event in the formation of intestinal tumors and some other cancers. Accumulating data from preclinical studies strongly suggest that targeted disruption of beta-catenin-mediated TCF signaling is a promising strategy for early chemopreventive intervention, particularly with respect to intestinal tumorigenesis. While the search for potent inhibitors is just getting underway, the ability of several synthetic and naturally occurring agents to decrease the transcriptional activity of a luciferase reporter plasmid under the control of TCF-4 regulatory elements (pTOPFLASH) has been demonstrated already. Additional enthusiasm for this approach is provided by data from several groups, which indicate that sulindac, sulindac sulfone and indomethacin can modulate the subcellular localization of beta-catenin in vivo, resulting in either decreased nuclear compartmentalization or enhanced localization of beta-catenin to the plasma membrane. Although the mechanism by which agents disrupt beta-catenin-mediated TCF signaling remains to be elucidated, possibilities include: (1) physical inhibition of the beta-catenin/TCF complex formation, (2) upregulation of the ubiquitin-mediated proteosomal degradation of beta-catenin, (3) accelerated nuclear export of beta-catenin and (4) enhanced sequestration of beta-catenin by E-cadherin. The common role of beta-catenin in both Wnt signaling and cell adhesion provides a unique opportunity to develop chemopreventive therapies that both prevent the development of cancer and delay tumor progression.
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PMID:beta-catenin-mediated signaling: a molecular target for early chemopreventive intervention. 1547 53

FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression. In addition to mitogens, various toxicants and carcinogens persistently induce FRA-1 expression in vitro and in vivo. Although the mitogen induced expression of c-FOS is relatively well understood, it is poorly defined in the case of FRA-1. Our recent analysis of the FRA-1 promoter has shown a critical role for a TRE located at -318 in mediating the TPA-induced expression. The -379 to -283 bp promoter segment containing a critical TRE (-318), however, is insufficient for the induction of FRA-1 promoter. Here, we show that a 40-bp (-276/-237) segment, comprising a TCF binding site and the CArG box (collectively known as serum response element, SRE), and an ATF site, is also necessary for the FRA-1 induction by TPA and EGF. Interestingly, the -283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene. However, in association with the -318 TRE, the SRE and ATF sites imparted a strong TPA-inducibility to the reporter. Similarly, EGF also required these motifs for the full induction of this gene. Using ChIP assays we show that, in contrast to c-Jun, SRF, Elk1, ATF1 and CREB proteins bind to SRE and ATF sites of the FRA-1 promoter, constitutively. RNAi-mediated knockdown of endogenous SRF, ELK1 and c-JUN protein expression significantly reduced TPA-stimulated FRA-1 promoter activity. Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens.
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PMID:Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements. 1580 62

While Wnt and Ras signaling pathways are activated during progression of colorectal cancers, many of their important downstream targets remain to be elucidated. The gastrin gene encodes for a family of peptide growth factors that are commonly upregulated in colorectal neoplasia. Previously, we showed that the Wnt signaling pathway moderately stimulates the gastrin promoter. To determine whether Ras signaling can cooperate with Wnt signaling in transcriptional regulation of gastrin gene expression, we have analyzed the response of murine gastrin promoter-reporter gene constructs to combinations of oncogenic stimulation in transient transfection assays. We found a strong (25- to 40-fold) synergistic stimulation of the gastrin promoter by the combination of oncogenic beta-catenin and K-ras overexpression. Deletion analysis localized the response element to an area between -140 and -110bp upstream in the murine gastrin promoter. Electrophoretic mobility shift assays detected a complex containing beta-catenin/TCF, AP1, and SMAD3/4 transcription factors that bound to a DNA element through AP1 and SMAD binding sites. Gastrin promoter activation could be further enhanced or suppressed by the co-expression of wild type SMAD4 or dominant negative mutant of SMAD4, respectively, and abrogated by the PI3K inhibitor, LY20004, but not by the MEK inhibitor, PD98059. Taken together, our data strongly suggest that oncogenic Wnt and Ras signaling pathways can synergistically induce gastrin expression, possibly contributing to neoplastic progression.
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PMID:Synergistic activation of the murine gastrin promoter by oncogenic Ras and beta-catenin involves SMAD recruitment. 1613

E-cadherin mediates homophilic adhesion of epithelial cells and is a major determinant of epithelial differentiation during embryonic development and tumor progression. At cell junctions, E-cadherin associates with beta-catenin, which also functions as a transcriptional co-activator of the canonical Wnt signaling pathway by interacting with TCF transcription factors. Here, we have analyzed whether E-cadherin plays a role in the control of gene expression in Wnt-dependent and -independent cellular systems. In DLD-1 colorectal cancer cells, which show constitutive activation of Wnt signaling and exhibit E-cadherin-based cell contacts, the siRNA-mediated knock-down of E-cadherin led to the disturbance of cell junctions, translocation of beta-catenin to the nucleus and an enhancement of beta-catenin/TCF-dependent reporter activity. In L929 fibroblasts, which are deficient in Wnt signaling and E-cadherin-mediated cell adhesion, ectopic expression of E-cadherin induced the stabilization of beta-catenin at the cell junctions and caused marked alterations in cellular morphology and phenotype. However, E-cadherin did not significantly change the transcriptional program of these cells as revealed by DNA microarray analysis. Our data indicate that E-cadherin may modulate Wnt-dependent gene expression by regulating the availability of beta-catenin but has a surprisingly small impact on gene expression in the absence of Wnt signaling.
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PMID:E-cadherin modulates Wnt-dependent transcription in colorectal cancer cells but does not alter Wnt-independent gene expression in fibroblasts. 1636 35

The beta-catenin signaling pathway is dysregulated in most cases of colon cancer resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumor progression. This study examines the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h. Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid "X" receptor (RXR)-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXRalpha small interfering RNA (siRNA). The RXR pan-antagonist and RXRalpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFlash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc. These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving RXR.
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PMID:Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. 1721 22

Although the role of Wnt signalling in breast cancer is far from being fully understood, in the last years its importance has been reported frequently. Besides stimulation by canonical Wnt signalling, the downstream effectors beta-catenin and the transcriptional modulators of the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family can also be activated by other inputs including the TGF-beta pathway. Wnt and TGF-beta signalling are both major signal transduction pathways, which provide important cues during development and tumor progression. However, particularly TGF-beta has a complicated influence on oncogenesis, which ranges from suppressive to promoting activity. Signalling pathways activated in parallel with TGF-beta might determine the oncogenic influence, and therefore place signals cooperating with TGF-beta into the limelight. During early development Wnt and TGF-beta signalling collaborate extensively. Here we provide an overview of the known interactions of Wnt with TGF-beta signalling in development and metastasis, particularly in breast cancer. We want to focus on the Wnt-activated transcription factor complex beta-catenin/LEF-1, its upstream activators, its downstream targets and consequences on the cellular level in response to beta-catenin/LEF-1 activation.
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PMID:Beta-catenin/LEF-1 signalling in breast cancer--central players activated by a plethora of inputs. 1758 8

The epithelial-to-mesenchymal transition (EMT) is a crucial process, occurring both during development and tumor progression, by which an epithelial cell undergoes a conversion to a mesenchymal phenotype, dissociates from initial contacts and migrates to secondary sites. We recently reported that in hepatocytes the multifunctional cytokine TGFbeta induces a full EMT characterized by (i) Snail induction, (ii) E-cadherin delocalization and down-regulation, (iii) down-regulation of the hepatocyte transcriptional factor HNF4alpha and (iv) up-regulation of mesenchymal and invasiveness markers. In particular, we showed that Snail directly causes the transcriptional down-regulation of E-cadherin and HNF4, while it is not sufficient for the up-regulation of mesenchymal and invasiveness EMT markers. In this paper, we show that in hepatocytes TGFbeta induces a Src-dependent activation of the focal adhesion protein FAK. More relevantly, we gathered results indicating that FAK signaling is required for (i) transcriptional up-regulation of mesenchymal and invasiveness markers and (ii) delocalization of membrane-bound E-cadherin. Our results provide the first evidence of FAK functional role in TGFbeta-mediated EMT in hepatocytes.
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PMID:TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling. 1794 12

The constitutive activation of beta-catenin-dependent ('canonical') Wnt signalling is a necessary initiating event in the genesis of most colorectal cancers. As this constitutive activation occurs through genetic mutation of one of the down-stream components of the signalling pathway, it was presumed that additional regulation of beta-catenin-dependent Wnt signalling would be inconsequential. However, it is now recognised that additional modulation of beta-catenin-dependent Wnt signalling is involved in tumour progression, and many of the genes associated with tumour invasion and metastasis are beta-catenin/TCF transcriptional target genes that are dynamically regulated during cancer progression. Intriguingly, the demonstration that naturally occurring inhibitors of Wnt-Frizzled (FZD) interaction are bona fide tumour suppressors in this cancer suggests that additional modulation of Wnt signalling is via the upstream components of the pathway. This is corroborated by recent studies that demonstrate tumour-promoting roles for Wnt and FZD per se. Moreover, both beta-catenin-dependent and beta-catenin-independent Wnt/FZD-mediated signalling is implicated during the dynamic and reversible EMT and MET that underscore colorectal cancer progression. Importantly, therapeutic targeting of the Wnt signalling pathway at the plasma membrane is clearly indicated by the profound anti-tumour activity of small molecule inhibitors and dominant-negative receptor constructs that target the receptor complex. The potential to effectively target EMT and MET processes at the plasma membrane via the upstream components of the Wnt signalling pathway offers new hope for anti-cancer therapy.
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PMID:The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. 1835 Feb 53


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