title: The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways.
abstract: Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, USA. mbordonaro@tcmedc.org
authors.forename: Michael
authors.initials: M
authors.lastname: Bordonaro
authors.forename: Shruti
authors.initials: S
authors.lastname: Tewari
authors.forename: Wafa
authors.initials: W
authors.lastname: Atamna
authors.forename: Darina L
authors.initials: DL
authors.lastname: Lazarova
mesh_terms: D028341:Activins / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D002087:Butyrates; C526317:CCN2 protein, human; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D028341:Activins; D055513:Connective Tissue Growth Factor; D008156:Luciferases