The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells
Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways may lead to the development of colorectal cancer (CRC). In CRC the Apc/β-catenin genes in the Wnt signaling pathway are frequently mutated and active Notch signaling contributes to tumorigenesis by...
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| Veröffentlicht in: | PloS one 2011-03, Vol.6 (3), p.e17957-e17957 |
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| description | Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways may lead to the development of colorectal cancer (CRC). In CRC the Apc/β-catenin genes in the Wnt signaling pathway are frequently mutated and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has previously been suggested in normal development as well as in cancer.
In this study, in silico analysis of putative promoters involved in transcriptional regulation of genes coding for proteins in the Notch signaling pathway revealed several putative LEF-1/TCF sites as potential targets for β-catenin and canonical Wnt signaling. Further results from competitive electrophoretic mobility-shift assay (EMSA) studies suggest binding of several putative sites in Notch pathway gene promoters to in vitro translated β-catenin/Lef-1. Wild type (wt)-Apc negatively regulates β-catenin. By induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Finally, active Notch signaling was verified in the Apc(Min/+) mouse model where Hes-1 mRNA levels were found significantly upregulated in intestinal tumors compared to normal intestinal mucosa. Luciferase assays showed an increased activity for the core and proximal Notch-2 promoter upon co-transfection of HCT116 cells with high expression recombinant Tcf-4, Lef-1 or β-catenin.
In this paper, we identified Notch-2 as a novel target for β-catenin-dependent Wnt signaling. Furthermore our data supports the notion that additional genes in the Notch pathway might be transcriptionally regulated by Wnt signaling in colorectal cancer. |
| doi_str_mv | 10.1371/journal.pone.0017957 |
| format | Article |
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In this study, in silico analysis of putative promoters involved in transcriptional regulation of genes coding for proteins in the Notch signaling pathway revealed several putative LEF-1/TCF sites as potential targets for β-catenin and canonical Wnt signaling. Further results from competitive electrophoretic mobility-shift assay (EMSA) studies suggest binding of several putative sites in Notch pathway gene promoters to in vitro translated β-catenin/Lef-1. Wild type (wt)-Apc negatively regulates β-catenin. By induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Finally, active Notch signaling was verified in the Apc(Min/+) mouse model where Hes-1 mRNA levels were found significantly upregulated in intestinal tumors compared to normal intestinal mucosa. Luciferase assays showed an increased activity for the core and proximal Notch-2 promoter upon co-transfection of HCT116 cells with high expression recombinant Tcf-4, Lef-1 or β-catenin.
In this paper, we identified Notch-2 as a novel target for β-catenin-dependent Wnt signaling. Furthermore our data supports the notion that additional genes in the Notch pathway might be transcriptionally regulated by Wnt signaling in colorectal cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0017957</identifier><identifier>PMID: 21437251</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoma ; Adenoma - genetics ; Adenomatous polyposis coli ; Analysis ; Animals ; Base Sequence ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; beta Catenin - metabolism ; Binding Sites ; Biology ; Cancer ; Cancer genetics ; Cell growth ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Computational Biology ; Crosstalk ; Electrophoretic mobility ; Epithelial cells ; Gastrointestinal diseases ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Genes ; Genetic aspects ; HCT116 Cells ; Health sciences ; Heparan sulfate ; Homeostasis ; HT29 Cells ; Humans ; Intestine ; Kinases ; LEF protein ; Ligands ; Luciferases - genetics ; Lymphoid Enhancer-Binding Factor 1 - metabolism ; Mammals ; MEDICIN ; MEDICINE ; Mice ; Molecular Sequence Data ; Mucosa ; Notch protein ; Promoter Regions, Genetic - genetics ; Promoters ; Protein Binding ; Proteins ; Receptor, Notch2 - genetics ; Receptor, Notch2 - metabolism ; RNA ; Signal transduction ; Signal Transduction - genetics ; Signaling ; Transcription ; Transcription (Genetics) ; Transcription Factor 4 ; Transcription factors ; Transcription Factors - metabolism ; Transcriptional Activation - genetics ; Transfection ; Tumorigenesis ; Tumors ; Wnt protein ; Wnt Proteins - metabolism ; β-Catenin</subject><ispartof>PloS one, 2011-03, Vol.6 (3), p.e17957-e17957</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>Copyright Public Library of Science Mar 2011</rights><rights>Ungerbäck et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c760t-bf50c9a7b6468a99ea22e65223e3c6c8987a8c4bac5d5e1abc486eda3691fdeb3</citedby><cites>FETCH-LOGICAL-c760t-bf50c9a7b6468a99ea22e65223e3c6c8987a8c4bac5d5e1abc486eda3691fdeb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060910/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060910/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21437251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-67155$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Ungerbäck, Jonas</creatorcontrib><creatorcontrib>Elander, Nils</creatorcontrib><creatorcontrib>Grünberg, John</creatorcontrib><creatorcontrib>Sigvardsson, Mikael</creatorcontrib><creatorcontrib>Söderkvist, Peter</creatorcontrib><title>The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways may lead to the development of colorectal cancer (CRC). In CRC the Apc/β-catenin genes in the Wnt signaling pathway are frequently mutated and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has previously been suggested in normal development as well as in cancer.
In this study, in silico analysis of putative promoters involved in transcriptional regulation of genes coding for proteins in the Notch signaling pathway revealed several putative LEF-1/TCF sites as potential targets for β-catenin and canonical Wnt signaling. Further results from competitive electrophoretic mobility-shift assay (EMSA) studies suggest binding of several putative sites in Notch pathway gene promoters to in vitro translated β-catenin/Lef-1. Wild type (wt)-Apc negatively regulates β-catenin. By induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Finally, active Notch signaling was verified in the Apc(Min/+) mouse model where Hes-1 mRNA levels were found significantly upregulated in intestinal tumors compared to normal intestinal mucosa. Luciferase assays showed an increased activity for the core and proximal Notch-2 promoter upon co-transfection of HCT116 cells with high expression recombinant Tcf-4, Lef-1 or β-catenin.
In this paper, we identified Notch-2 as a novel target for β-catenin-dependent Wnt signaling. Furthermore our data supports the notion that additional genes in the Notch pathway might be transcriptionally regulated by Wnt signaling in colorectal cancer.</description><subject>Adenoma</subject><subject>Adenoma - genetics</subject><subject>Adenomatous polyposis coli</subject><subject>Analysis</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>beta Catenin - metabolism</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Cell growth</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Computational Biology</subject><subject>Crosstalk</subject><subject>Electrophoretic mobility</subject><subject>Epithelial cells</subject><subject>Gastrointestinal diseases</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>HCT116 Cells</subject><subject>Health sciences</subject><subject>Heparan sulfate</subject><subject>Homeostasis</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Intestine</subject><subject>Kinases</subject><subject>LEF protein</subject><subject>Ligands</subject><subject>Luciferases - genetics</subject><subject>Lymphoid Enhancer-Binding Factor 1 - metabolism</subject><subject>Mammals</subject><subject>MEDICIN</subject><subject>MEDICINE</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Mucosa</subject><subject>Notch protein</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Promoters</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Receptor, Notch2 - genetics</subject><subject>Receptor, Notch2 - metabolism</subject><subject>RNA</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><subject>Transcription Factor 4</subject><subject>Transcription factors</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional Activation - genetics</subject><subject>Transfection</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt Proteins - 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In CRC the Apc/β-catenin genes in the Wnt signaling pathway are frequently mutated and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has previously been suggested in normal development as well as in cancer.
In this study, in silico analysis of putative promoters involved in transcriptional regulation of genes coding for proteins in the Notch signaling pathway revealed several putative LEF-1/TCF sites as potential targets for β-catenin and canonical Wnt signaling. Further results from competitive electrophoretic mobility-shift assay (EMSA) studies suggest binding of several putative sites in Notch pathway gene promoters to in vitro translated β-catenin/Lef-1. Wild type (wt)-Apc negatively regulates β-catenin. By induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Finally, active Notch signaling was verified in the Apc(Min/+) mouse model where Hes-1 mRNA levels were found significantly upregulated in intestinal tumors compared to normal intestinal mucosa. Luciferase assays showed an increased activity for the core and proximal Notch-2 promoter upon co-transfection of HCT116 cells with high expression recombinant Tcf-4, Lef-1 or β-catenin.
In this paper, we identified Notch-2 as a novel target for β-catenin-dependent Wnt signaling. Furthermore our data supports the notion that additional genes in the Notch pathway might be transcriptionally regulated by Wnt signaling in colorectal cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21437251</pmid><doi>10.1371/journal.pone.0017957</doi><tpages>e17957</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1292884895 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenoma Adenoma - genetics Adenomatous polyposis coli Analysis Animals Base Sequence Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism beta Catenin - metabolism Binding Sites Biology Cancer Cancer genetics Cell growth Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics Computational Biology Crosstalk Electrophoretic mobility Epithelial cells Gastrointestinal diseases Gene expression Gene Expression Regulation, Neoplastic Gene regulation Genes Genetic aspects HCT116 Cells Health sciences Heparan sulfate Homeostasis HT29 Cells Humans Intestine Kinases LEF protein Ligands Luciferases - genetics Lymphoid Enhancer-Binding Factor 1 - metabolism Mammals MEDICIN MEDICINE Mice Molecular Sequence Data Mucosa Notch protein Promoter Regions, Genetic - genetics Promoters Protein Binding Proteins Receptor, Notch2 - genetics Receptor, Notch2 - metabolism RNA Signal transduction Signal Transduction - genetics Signaling Transcription Transcription (Genetics) Transcription Factor 4 Transcription factors Transcription Factors - metabolism Transcriptional Activation - genetics Transfection Tumorigenesis Tumors Wnt protein Wnt Proteins - metabolism β-Catenin |
| title | The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T05%3A24%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Notch-2%20gene%20is%20regulated%20by%20Wnt%20signaling%20in%20cultured%20colorectal%20cancer%20cells&rft.jtitle=PloS%20one&rft.au=Ungerb%C3%A4ck,%20Jonas&rft.date=2011-03-18&rft.volume=6&rft.issue=3&rft.spage=e17957&rft.epage=e17957&rft.pages=e17957-e17957&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0017957&rft_dat=%3Cgale_plos_%3EA476900169%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1292884895&rft_id=info:pmid/21437251&rft_galeid=A476900169&rft_doaj_id=oai_doaj_org_article_55acb1644f1e4a1dbd62a02c2f9ff372&rfr_iscdi=true |