Sci. STKE, 26 August 2003
CELL ADHESION Bcl-2 Breaks Up Cell-Cell Junctions
Expression of Bcl-2 is stimulated by estrogen, and estrogen-responsive human tumors often have increased Bcl-2 levels. Li et al. examined the effect of overexpression of Bcl-2 on MCF-7 breast carcinoma cells and Madin-Darby canine kidney (MDCK) cells, a polarized epithelial cell line, and observed loss of cell-cell junctions and redistribution of proteins that were associated with E-cadherin-containing junctions in wild-type cells. E-cadherin, like Bcl-2, is regulated by estrogen; however, no consensus estrogen-responsive elements appear to exist in the promoter, so the regulation may be indirect. E-cadherin-containing junctions include tight junctions, gap junctions, and desmosomes. In MCF-7 cells overexpressing Bcl-2, proteins--which in wild-type cells were associated with the cell-cell junctions--were redistributed either to the cytosol or, for ZO-1, to the cytosol and the nucleus. ZO-1 is known to interact with ZONAB (ZO-1-associated nucleic acid binding protein), which stimulates expression of the epidermal growth factor receptor gene ErbB2, and indeed ErbB2 protein was increased in the Bcl-2-overexpressing cells. Upon estrogen withdrawal, wild-type MCF-7 cells dissociated from each other and became motile and also exhibited increased cell death. In contrast, the MCF-7 cells overexpressing Bcl-2 required prolonged withdrawal of estrogen in order to observe decreased Bcl-2 expression in subpopulations of cells that also formed cell-cell junctions and exhibited membrane association of the junctional proteins and cell surface expression of E-cadherin. In MDCK cells overexpressing Bcl-2, the junctional proteins were also redistributed to the cytosol; however, ZO-1 colocalized with Bcl-2 instead of appearing in the nucleus as in the MCF-7 cells. Disruption of tight junctions in the MDCK and MCF-7 cells overexpressing Bcl-2 was confirmed by a decrease in transepithelial cell resistance. Increased expression of Bcl-2 may contribute to cancer invasiveness through its role in regulating cell-cell contact, as well as contribute to the proliferation of cancer cells through its ability to inhibit apoptosis.
Citation: Bcl-2 Breaks Up Cell-Cell Junctions. Sci. STKE 2003, tw333 (2003).
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