title: Increased beta-catenin expression and nuclear translocation accompany cellular hyperproliferation in vivo.
abstract: Beta-catenin performs critical roles in development and cellular adhesion. More recently, an oncogenic role has been described. In colon cancer, decreased E-cadherin/beta-catenin association is causally linked to increased beta-catenin-regulated gene expression and increased cellular division. Whether the same pathway is active in native epithelia remains unknown. To address this question, we used the transmissible murine colonic hyperplasia model to measure changes in beta-catenin abundance, nuclear partitioning, target gene (c-myc and cyclin D1) expression, and subcellular distribution. Colonocyte hyperproliferation was associated with a 4.3 +/- 0.56 (SD)-fold increase in total cellular beta-catenin protein content, whereas modest changes in gamma-catenin and E-cadherin expression were recorded. The beta-catenin signal increased before changes in mucosal crypt length, a gross index of cellular proliferation/apoptosis. Beta-catenin detected in Triton X-100-soluble (cytosolic) cellular fractions was enriched 4.3 +/- 0.9 (SD)-fold, whereas a modest decrease of 0.9 +/- 0.09 (SD)-fold was recorded in Triton X-100-insoluble (cytoskeletal) fractions. After these changes, nuclear beta-catenin partitioning increased 2.4 +/- 0.4 (SD)-fold, accompanied by 2.5 +/- 0.4- and 4.0 +/- 0.8-fold (SD) increases in cellular c-myc and cyclin D1 levels, respectively. Thus, increased cellular cytosolic and nuclear beta-catenin levels were associated with increased beta-catenin target protein expression. Significant alterations in beta-catenin subcellular distribution were also recorded immunohistochemically. Apical/lateral junctional labeling was observed in normal crypts with increased lateral membrane staining within the upper regions. During transmissible murine colonic hyperplasia, these gradients were dissipated, and basilar plaques were formed within a subset of basal crypt cells. These findings predict that an oncogenic signaling mechanism related to non-E-cadherin-bound beta-catenin is active in hyperproliferating native colonocytes and is similar to that recorded during the early stages of colon carcinogenesis.
authors: Department of Internal Medicine, The University of Texas Medical School-Houston, 77030, USA.
authors: J H
authors: JH
authors: Sellin
authors: S
authors: S
authors: Umar
authors: J
authors: J
authors: Xiao
authors: A P
authors: AP
authors: Morris
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D016971:Citrobacter freundii; D003106:Colon / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004756:Enterobacteriaceae Infections / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000378:metabolism / Q000382:microbiology; D007150:Immunohistochemistry; D051379:Mice; D011230:Precancerous Conditions / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin