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Cadmium (Cd 2+ ) induces nuclear translocation of β‐catenin and increases expression of c‐myc and Abcb1a in kidney proximal tubule (PT) cells
Author(s) -
Thevenod Frank,
Wolff Natascha A.,
Bork Ulrich,
Lee WingKee,
Abouhamed Marouan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a506-b
Subject(s) - adherens junction , apoptosis , microbiology and biotechnology , chromosomal translocation , catenin , cytosol , chemistry , programmed cell death , biology , signal transduction , cell , wnt signaling pathway , cadherin , biochemistry , gene , enzyme
Cd 2+ induces renal PT damage, including disruption of the E‐cadherin/β‐catenin complex of adherens junctions (AJs) and apoptosis. Yet, chronic Cd 2+ exposure causes malignant transformation of renal cells. Previously, we have demonstrated that Cd 2+ ‐mediated up‐regulation of the multidrug transporter Abcb1 causes apoptosis resistance in PT cells. We hypothesized that Cd 2+ activates adaptive signaling mechanisms mediated by β‐catenin to evade apoptosis and increase proliferation. Here we show that 50 μM Cd 2+ , which induces ~60% cell death of immmortalized rat renal PT cells, as measured by MTT assay, also decreases the trans‐epithelial resistance of a confluent monolayer, within 45 minutes of Cd 2+ exposure, as measured by electric cell‐substrate impedance sensing. Immunofluorescence microscopy demonstrates Cd 2+ ‐induced decrease of E‐cadherin at AJs and redistribution of β‐catenin from the E‐cadherin/β‐catenin complex of AJs to cytosol and nuclei after 3 hours. Immunoblotting confirms Cd 2+ ‐induced decrease of E‐cadherin expression and translocation of β‐catenin to cytosol and nuclei of PT cells. RT‐PCR shows Cd 2+ ‐induced increase of expression of c‐myc and of the isoform Abcb1a at 3 hours. We speculate that Cd 2+ activates β‐catenin/T‐cell factor signaling to transactivate proliferation and apoptosis resistance genes and promote carcinogenesis of PT cells. Funded by DFG TH 345/8‐1