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J. Biol. Chem., Vol. 276, Issue 42, 39094-39102, October 19, 2001

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Progressive Changes in Adherens Junction Structure during Intestinal Adenoma Formation in Apc Mutant Mice^*

Adelaide M. Carothers, Kurt A. Melstrom Jr., James D. Mueller^§, Michael J. Weyant, and Monica M. Bertagnolli^¶

From the  Department of Surgery, Weill College of Medicine, Cornell University, New York, the Strang Cancer Prevention Center, New York, New York 10021, and the ^¶ Departments of Surgery and ^§ Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115

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 -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. -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 -catenin and receptor protein-tyrosine phosphatase / (RPTP/), and Apc^Min/ cells demonstrated an association between -catenin and receptor protein-tyrosine phosphatase . In contrast to the Apc^Min/+ enterocytes, Apc^Min/ adenomas displayed increased expression and association of E-cadherin, -catenin, and -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.

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