Journal Article

Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of β-catenin from membrane bound E-cadherin and formation of nuclear β-catenin/LEF-1 complex

Jay M. Mei, Gregory L. Borchert, Steven P. Donald and James M. Phang

in Carcinogenesis

Volume 23, issue 12, pages 2119-2122
Published in print December 2002 | ISSN: 0143-3334
Published online December 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.12.2119
Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of β-catenin from membrane bound E-cadherin and formation of nuclear β-catenin/LEF-1 complex

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Modulation of the adenomatous polyposis coli (APC)-β-catenin pathway by inflammatory mediators and extracellular matrix may be important in colon carcinogenesis. We have recently shown that nitric oxide (NO) induces the accumulation of cytosolic β-catenin and subsequent formation of the nuclear β-catenin/lymphocyte enhancing factor (LEF)-1 complex in conditionally immortalized young mouse colonic epithelial (YAMC) cells. In the present study, we explored the mechanism(s) through which NO exerts its effect on cytosolic β-catenin accumulation and nuclear β-catenin/LEF-1 complex formation. We found that NO-induced degradation of the membrane bound E-cadherin at tight junctions. Using an anti-E-cadherin antibody specific for its extracellular domain, we detected a 50kDa degradation fragment of E-cadherin (120 kDa) from the culture medium conditioned by YAMC cells exposed to the NO-releasing drug, NOR-1, for 4 and 24 h. As β-catenin is normally bound to transmembrane E-cadherin and thus anchored to the cytoskeleton structure, the degradation of E-cadherin induced by NO may cause dissociation of β-catenin from membrane bound E-cadherin. This was demonstrated by the detection of β-catenin accumulation in the soluble cytosolic fractions in YAMC after exposure to NO-releasing drugs. Furthermore, the degradation of E-cadherin and the release of β-catenin to cytosol were accompanied by the formation of nuclear β-catenin/LEF-1 complex, demonstrating the dissociation of β-catenin from E-cadherin may be responsible for the activation of β-catenin/LEF-1 transcription complex. Co-treatment with NO donors and broad-spectrum matrix metalloproteinase (MMP) inhibitors TIMP-1 (100 ng/ml), GM6001 (10 μM) and GM1489 (10 μM) abolished the degradation of E-cadherin induced by NO as demonstrated by western blot analysis. These MMP inhibitors also blocked the cytosolic accumulation of β-catenin and nuclear formation of β-catenin/LEF-1 complex. The sum effect of MMP inhibitors demonstrated that NO-induced activation of MMP may cause the degradation of E-cadherin and the subsequent dissociation of β-catenin, thereby contributing to the cytosolic accumulation of β-catenin and nuclear formation of β-catenin/LEF-1 complex.

Keywords: APC, adenomatous polyposis coli; EMSAs, electrophoretic mobility shift assays; LEF, lymphocyte enhancing factor; NO, nitric oxide; MMP, matrix metalloproteinases; Tcf, T-cell factor; YAMC, young adult mouse colon.

Journal Article.  2854 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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