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Wnt in human embryonic carcinoma cells

ABSTRACT: Background Wnt signaling is implicated in many developmental decisions, including stem cell control, as well as in cancer. There are relatively few target genes known of the Wnt pathway. Results We have identified target genes of Wnt signaling using microarray technology and human embryonal carcinoma cells stimulated with active Wnt protein. The ~50 genes upregulated early after Wnt addition include the previously known Wnt targets Cyclin D1, MYC, ID2 and beta TRCP. The newly identified targets, which include MSX1, MSX2, Nucleophosmin, Follistatin, TLE/Groucho, Ubc4/5E2, CBP/P300, Frizzled and REST/NRSF, have important implications for understanding the roles of Wnts in development and cancer. The protein synthesis inhibitor cycloheximide blocks induction by Wnt, consistent with a requirement for newly synthesized beta - catenin protein prior to target gene activation. The promoters of nearly all the target genes we identified have putative TCF binding sites; and we show that the TCF binding site is required for induction of Follistatin. Several of the target genes have a cooperative response to a combination of Wnt and BMP. Conclusion Wnt signaling activates genes that promote stem cell fate and inhibit cellular differentiation; and regulates a remarkable number of genes involved in its own signaling system. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set

ORGANISM(S): Homo sapiens

PROVIDER: GSE3262 | GEO | 2005/09/08

SECONDARY ACCESSION(S): PRJNA92917

REPOSITORIES: GEO

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Project description:Sivakumar2011_WntSignalingPathway The secreted protein Wnt activates the heptahelical receptor Frizzled on nieghboring cells. Activation of Frizzled causes the recruitment of additional membrane proteins which in turn result in 1) the activation of the protein Dishevelled via phosphorylation and 2) the activation of a heterotrimeric G protein of unknown type. Activation of Dishevelled results in the down-regulation of the Beta-Catenin destruction complex which causes ubiquitination of Beta-Catenin and its ultimate degradation via the proteasome. Inhibition of the Beta-Catenin destruction complex yields a higher cytosolic concentration of Beta-Catenin, which enters the nucleus, binds various transcriptional regulatory molecules including the TCF/LEF class of proteins, and results in the transcription of TCF/LEF target genes. Activation of the heterotrimeric G-protein pathway in turn activates Phospholipase C which in turn catalyzes the catalysis of PI(4,5)P2 into DAG and IP3. Reference: The Wnt signalling pathway. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Wnt signaling pathway. This model is described in the article: A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways. Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S. OMICS 2011 Oct; 15(10): 729-737 Abstract: The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs. This model is hosted on BioModels Database and identified by: BIOMD0000000397. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Wnt in human embryonic carcinoma cells

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