The first five years of the Wnt targetome

Vlad, Annica; Röhrs, Sonja; Klein-Hitpaß, Ludger; Müller, Oliver

doi:10.1016/j.cellsig.2007.10.031

Cited by 115 publications

(101 citation statements)

References 38 publications

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“…Finally, suppression of endogenous SRp20 by RNA interference prevents the b-catenin/ TCF4-induced changes in alternative splicing. Vlad et al 2008), SFSR3 has not been included in these gene lists. We observed an about twofold increase in SRp20 transcripts in our experiments, which is close to the threshold value set in most microarray experiments.…”

Section: Discussionmentioning

confidence: 99%

The β-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression

Gonçalves¹,

Matos²,

Jordan³

2008

RNA

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Gene expression programs can become activated in response to extracellular signals. One evolutionarily conserved example is binding of Wnt glycoproteins to their receptor, which triggers a signal transduction cascade that stabilizes cytoplasmic bcatenin protein, allowing it to translocate into the nucleus. There, b-catenin binds to TCF/Lef family transcription factors and promotes the expression of target genes. Mutations in either the b-catenin gene itself or its partner protein APC are responsible for the oncogenic activation of this pathway in colorectal tumors. Here we report the splicing factor SRp20 as a novel target gene of b-catenin/TCF4 signaling. Transfection of activated b-catenin mutants into colorectal cells increased expression of endogenous SRp20 transcript and protein and also stimulated a luciferase reporter construct containing the SRp20 gene promoter. In contrast, inhibition of endogenous b-catenin signaling by a dominant-negative TCF4 construct down-regulated both luciferase reporter and SRp20 expression. We further demonstrate that the b-catenin/TCF4-mediated increase in SRp20 protein levels is sufficient to modulate alternative splicing decisions in the cells. In particular, we observed a change in the alternative splicing pattern in a control minigene reporter as well as in the endogenous SRp20-regulated CD44 cell adhesion protein. These results demonstrate that the b-catenin/TCF4 pathway not only stimulates gene transcription, but also promotes the generation of transcript variants through alternative splicing. Our data support the recent notion that transcription and alternative splicing represent two different layers of gene expression and that signaling pathways act upon a coordinated network of transcripts in each layer.

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Section: Discussionmentioning

confidence: 99%

The β-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression

Gonçalves¹,

Matos²,

Jordan³

2008

RNA

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“…Most CRCs are caused by aberrant Wnt signaling that fuel excessive cell growth through increased activity of growth-stimulating genes while keeping negative growth regulators (for example, FOXO3A, DAPK2, HATH1 and CDKN1A/p21) in check through direct and indirect mechanisms (van de Wetering et al, 2002;Tsuchiya et al, 2007;Dehner et al, 2008;Li et al, 2009). The widespread effects on gene expression imposed by the Wnt signaling pathway is initially executed by the bipartite transcription factor complex beta-catenin/TCF that recruits numerous auxiliary co-regulators to achieve activation or inhibition of target gene promoters in an often context-dependent manner (van de Wetering et al, 2002;Theisen et al, 2007;Blauwkamp et al, 2008;Cselenyi and Lee, 2008;Vlad et al, 2008;Railo et al, 2009). Interestingly, recent studies have hinted at the tantalizing possibility that microRNAs (miRNAs), often functioning as negative posttranscriptional regulators (Filipowicz et al, 2008), are also embedded in the Wnt signaling network.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

et al. 2011

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“…The canonical Wnt pathway from the IPA database was slightly modified to accommodate additional Wnt target genes. 11,12 The signaling network is represented graphically as nodes (symbols representing genes) and lines/arrows (biological relationship between the genes according to the legend). Red and green gene symbols denote up-and down-regulated genes, respectively.…”

Section: The Conserved Cross-species Signature As a Tool To Differentmentioning

confidence: 99%

“…10 Loss of APC function or oncogenic activation of ␤-catenin, as observed in the vast majority of the sporadic CRC cases, leads to intracellular accumulation of ␤-catenin and its translocation to the nucleus, where it binds to transcription factors of the T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family and modulates transcription of a broad spectrum of downstream target genes. 11,12 The vast majority (70 to 90%) of FAP patients have been shown to carry germline APC mutations. 13 More recently, biallelic mutations in the base excision repair gene MYH were found in a subset of polyposis families with attenuated clinical presentation and an autosomal recessive inheritance pattern, often referred to as MAP (MYH-associated polyposis).…”

mentioning

confidence: 99%

Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli (APC)-Driven Tumorigenesis

Gaspar

Cardoso

Franken

et al. 2008

The American Journal of Pathology

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Expression profiling is a well established tool for the genome-wide analysis of human cancers. However, the high sensitivity of this approach combined with the well known cellular and molecular heterogeneity of cancer often result in extremely complex expression signatures that are difficult to interpret functionally. The majority of sporadic colorectal cancers are triggered by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, leading to the constitutive activation of the Wnt/␤-catenin signaling pathway and formation of adenomas. Despite this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate, and malignancy potential. Here, we applied a cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations and from mice carrying a targeted inactivating mutation in the mouse homologue Apc. This comparative approach resulted in the establishment of a conserved signature of 166 genes that were differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analyses of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/␤-catenin signaling pathway. Moreover, the conserved signature was able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic inactivation of the MYH gene, supporting the usefulness of such comparisons to discriminate among patients with distinct genetic defects.

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The first five years of the Wnt targetome

Cited by 115 publications

References 38 publications

The β-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression

The β-catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression

Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes

Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli (APC)-Driven Tumorigenesis

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