title: Colocalization of β-catenin with Notch intracellular domain in colon cancer: a possible role of Notch1 signaling in activation of CyclinD1-mediated cell proliferation.
abstract: The Wnt and Notch1 signaling pathways play major roles in intestinal development and tumorigenesis. Sub-cellular localization of β-catenin has been implicated in colorectal carcinogenesis. However, the β-catenin and Notch intracellular domain (NICD) interaction has to be addressed. Immunohistochemistries of β-catenin, NICD, and dual immunofluorescence of β-catenin and NICD were analyzed in colorectal tissues and HT29 cell line. Moreover, real-time PCR analysis of CyclinD1, Hes1 and MUC2 was done in HT29 cells upon N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment. Dual staining emphasized the strong interaction of β-catenin and NICD in adenoma and adenocarcinoma than in normal tissues. Hes1 transcript levels were decreased 1.5- and 7.1-fold in 12.5 and 25 µM DAPT-treated HT29 cells. CyclinD1 transcript levels decreased 1.2- and 1.6-fold, and MUC2 transcript level increased 4.3- and 7.5-fold in 12.5 and 25 µM DAPT-treated HT29 cells. The results of this study showed that the sub-cellular localization of β-catenin converges with NICD inducing proliferation through the activation of CyclinD1 and Hes1. Moreover, the inhibition of Notch1 signaling by DAPT leads to the arrest of cell proliferation and induces apoptosis leading to the upregulation of MUC2, a secretory cell lineage marker.
authors: Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India.
authors: Natarajan
authors: N
authors: Gopalakrishnan
authors: Marimuthu
authors: M
authors: Saravanakumar
authors: Perumal
authors: P
authors: Madankumar
authors: Mani
authors: M
authors: Thiyagu
authors: Halagowder
authors: H
authors: Devaraj
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D004151:Dipeptides; D018398:Homeodomain Proteins; D055262:Mucin-2; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D051176:beta Catenin; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; C524625:MUC2 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C078493:HES1 protein, human