The Notch-2 Gene Is Regulated by Wnt Signaling in Cultured Colorectal Cancer Cells
2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 3, 0017957- p.Article in journal (Refereed) Published
Background: 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/beta-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. Principal Findings: 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 beta-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 beta-catenin/Lef-1. Wild type (wt)-Apc negatively regulates beta-catenin. By induction of wt-Apc or beta-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 beta-catenin. Conclusions: In this paper, we identified Notch-2 as a novel target for beta-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.
Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2011. Vol. 6, no 3, 0017957- p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-67155DOI: 10.1371/journal.pone.0017957ISI: 000288545100048OAI: oai:DiVA.org:liu-67155DiVA: diva2:407806
Jonas Ungerbäck, Nils Elander, John Grunberg, Mikael Sigvardsson and Peter Söderkvist, The Notch-2 Gene Is Regulated by Wnt Signaling in Cultured Colorectal Cancer Cells, 2011, PLOS ONE, (6), 3, 0017957.
Licensee: Public Library of Science (PLoS)