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Activation of Wnt‐β‐catenin (β‐cat) signaling by cadmium (Cd) in kidney proximal tubule cells
Author(s) -
Thevenod Frank,
Chakraborty Prabir K.,
Horndasch Manuela,
Lee WingKee,
Wolff Natascha A.
Publication year - 2009
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.23.1_supplement.604.5
Subject(s) - wnt signaling pathway , mg132 , microbiology and biotechnology , cyclin d1 , apoptosis , chemistry , cell growth , transfection , catenin , biology , cell culture , proteasome inhibitor , signal transduction , proteasome , cell cycle , biochemistry , genetics
Cd causes apoptosis of the proximal tubule (PT), but is also a class 1 carcinogen. Using cultured PT cells, we have shown that Cd apoptosis peaks at 24 h, but then decreases over time, which is caused by overexpression of multidrug resistance P‐glycoprotein (Abcb1). One early event associated with Cd nephrotoxicity is disruption of cell‐cell adhesion. β‐cat participates in cell‐cell adhesion by bridging E‐cadherin to β‐cat and as part of the Wnt signaling co‐activates the LEF/TCF DNA‐binding protein. As such, β‐cat transactivates proliferation genes, e. g. c‐myc and cyclin D1, but also Abcb1 . The cytoplasmic level of β‐cat is controlled by the proteasome. We showed that Cd decreases transepithelial resistance of PT cells. This was associated with the degradation of E‐cadherin, release of β‐cat into the cytosol and nucleus, and increased expression of c‐myc and Abcb1 . Transfection with a β‐cat δN57 mutant, which is not degraded by the proteasome, also increased c‐myc and Abcb1 . To investigate whether Cd affects LEF/TCF activity, a luciferase reporter assay (TOPflash/FOPflash) containing LEF/TCF binding sites was used. Cd increased luciferase activity up to 5‐fold in PT cells These results suggest that β‐cat is involved in transcriptional regulation of genes for proliferation and cell survival triggered by Cd, which may induce apoptosis evasion and promote carcinogenesis. Supported by DFG TH 345/10‐1.