Premium
Cadmium (Cd)‐induced E‐cadherin (E‐cad)/β‐catenin (β‐cat) disruption triggers Wnt signaling and β‐catenin/TCF4‐dependent upregulation of proliferation and survival genes c‐Myc, cyclin‐D1 and ABCB1 in renal proximal tubule cells (PTC)
Author(s) -
Chakraborty Prabir Kumar,
Lee WingKee,
Molitor Malte,
Wolff Natascha A,
Thévenod Frank
Publication year - 2010
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.24.1_supplement.812.24
Subject(s) - wnt signaling pathway , cyclin d1 , catenin , cyclin d , cancer research , lrp6 , biology , lrp5 , downregulation and upregulation , tcf4 , carcinogenesis , microbiology and biotechnology , signal transduction , chemistry , transcription factor , apoptosis , cell cycle , biochemistry , cancer , genetics , gene , enhancer
The class 1 carcinogen Cd disrupts the E‐cad/β‐cat complex of epithelial adherence junctions (AJs). Deregulation of E‐cad adhesion and changes of Wnt/β‐cat signaling are known to contribute to carcinogenesis. We investigated Wnt signaling after Cd‐induced E‐cad disruption in cultured PTC. Cd (25μM, 3–9 h) caused nuclear translocation of β‐cat and triggered a Wnt response by TOPFLASH reporter assays. Cd reduced the interaction of β‐cat with AJ components and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c‐Myc, cyclin‐D1 and ABCB1) were upregulated by Cd, electromobility shift assays showed increased TCF4 binding to cyclin‐D1 and ABCB1 promoter sequences. Overexpression of wild‐type and mutant TCF4 confirmed Cd‐induced Wnt signaling. Wnt signaling triggered by Cd was more prominent in proliferating subconfluent than confluent cells, which showed increased E‐cad expression. Overexpression of E‐cad reduced Wnt signaling, PTC proliferation and Cd toxicity. Cd also induced ROS dependent expression of the pro‐apoptotic ER stress marker and Wnt suppressor CHOP which, however, did not abolish Wnt response and cell viability. Hence Cd may facilitate carcinogenesis of PTC by inducing the Wnt pathway to promote proliferation and survival of pre‐neoplastic cells. Funded by DFG TH 345/10‐1