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J. Biol. Chem., Vol. 278, Issue 39, 38029-38039, September 26, 2003

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Nuclear Association of the Cytoplasmic Tail of MUC1 and -Catenin^*

Yunfei Wen  , Thomas C. Caffrey , Margaret J. Wheelock  ¶, Keith R. Johnson  ¶ and Michael A. Hollingsworth   ||

From the Eppley Institute for Research in Cancer and Allied Diseases, the Department of Biochemistry and Molecular Biology, and the ^¶Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805

MUC1, an integral membrane mucin associated with the metastatic phenotype, is overexpressed by most human carcinoma cells. The MUC1 cytoplasmic tail (CT) is postulated to function in morphogenetic signal transduction via interactions with Grb2/Sos, c-Src, and -catenin. We investigated intracellular trafficking of the MUC1 CT, using epitope-tagged constructs that were overexpressed in human pancreatic cancer cell lines S2-013 and Panc-1. The MUC1 CT was detected at the inner cell surface, in the cytosol, and in the nucleus of cells overexpressing MUC1. Fragments of the MUC1 CT were associated with -catenin in both cytoplasm and nuclei. Overexpression of MUC1 increased steady state levels of nuclear -catenin but decreased nuclear levels of plakoglobin (-catenin). There was no detectable association between plakoglobin and the MUC1 CT. Coimmunoprecipitation experiments revealed that the cytoplasmic and nuclear association of MUC1 CT and -catenin was not affected by disruption of Ca²⁺-dependent intercellular cadherin interactions. These results demonstrate nuclear localization of fragments of MUC1 CT in association with -catenin and raise the possibility that overexpression of the MUC1 CT stabilizes -catenin and enhances levels of nuclear -catenin during disruption of cadherin-mediated cell-cell adhesion.

Received for publication, April 25, 2003 , and in revised form, June 26, 2003.

^* This work was supported in part by National Institutes of Health Grants CA57362, CA72712, and CA36727 and by fellowship support (to Y. W.) from the Eppley Institute and the University of Nebraska Medical Center Program of Excellence. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Eppley Institute, University of Nebraska Medical Center, 986805 NE Medical Center, Omaha, NE 68198-6805. Tel.: 402-559-8343; Fax: 402-559-3339; E-mail: mahollin{at}unmc.edu.

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