title: Progressive changes in adherens junction structure during intestinal adenoma formation in Apc mutant mice.
abstract: The C57BL/6J-Min/+ (Min/+) mouse bears a mutant Apc gene and therefore is an important in vivo model of intestinal tumorigenesis. Min/+ mice develop adenomas that exhibit loss of the wild-type Apc allele (Apc(Min/-)). Previously, we found that histologically normal enterocytes bearing a truncated Apc protein (Apc(Min/+)) migrated more slowly in vivo than enterocytes with either wild-type Apc (Apc(+/+)) or with heterozygous loss of Apc protein (Apc(1638N)). To study this phenotype further, we determined the effect of the Apc(Min) mutation upon cell-cell adhesion by examining the components of the adherens junction (AJ). We observed a reduced association between E-cadherin and beta-catenin in Apc(Min/+) enterocytes. Subcellular fractionation of proteins from Apc(+/+), Apc(Min/+), and Apc(Min/-) intestinal tissues revealed a cytoplasmic localization of intact E-cadherin only in Apc(Min/+), suggesting E-cadherin internalization in these enterocytes. beta-Catenin tyrosine phosphorylation was also increased in Apc(Min/+) enterocytes, consistent with its dissociation from E-cadherin. Furthermore, Apc(Min/+) enterocytes showed a decreased association between beta-catenin and receptor protein-tyrosine phosphatase beta/zeta (RPTPbeta/zeta), and Apc(Min/-) cells demonstrated an association between beta-catenin and receptor protein-tyrosine phosphatase gamma. In contrast to the Apc(Min/+) enterocytes, Apc(Min/-) adenomas displayed increased expression and association of E-cadherin, beta-catenin, and alpha-catenin relative to Apc(+/+) controls. These data show that Apc plays a role in regulating adherens junction structure and function in the intestine. In addition, discovery of these effects in initiated but histologically normal tissue (Apc(Min/+)) defines a pre-adenoma stage of tumorigenesis in the intestinal mucosa.
authors.affiliation: Department of Surgery, Weill College of Medicine, Cornell University, New York, the Strang Cancer Prevention Center, New York, New York 10021, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Carothers
authors.forename: K A
authors.initials: KA
authors.lastname: Melstrom
authors.forename: J D
authors.initials: JD
authors.lastname: Mueller
authors.forename: M J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: M M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D022005:Adherens Junctions / Q000737:chemistry*; D000483:Alleles; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant; D006579:Heterozygote; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D013347:Subcellular Fractions; D015534:Trans-Activators; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014443:Tyrosine