Effects of cadmium on the sub-cellular localization of β-catenin and β-catenin-regulated gene expression in NRK-52E cells.
The E-cadherin/β-catenin complex is a structural component of adherens-type junctions in epithelial cells. Moreover, β-catenin acts as an intracellular signaling molecule that can influence the expression of a variety of genes that regulate apoptosis and cell cycle control. Cadmium (Cd) is an environmental toxicant that causes renal dysfunction and disrupts cadherin-dependent cell-cell adhesion in various types of epithelial cells. In this study, we examined the effects of Cd on the subcellular localization of β-catenin, the cadherin/β-catenin complex and β-catenin-mediated gene transcription in rat proximal tubule NRK-52E cells. Exposure to 5-10 μM Cd for 4 h caused the NRK cells to separate from each other without killing the cells or causing them to detach from the growing surface. This effect was associated with the loss of β-catenin and E-cadherin from the cell-cell contacts and apparent changes in the accumulation of β-catenin in the nuclear cell subfraction. The expression of the β-catenin-sensitive gene, c-jun was significantly increased in cells exposed to 5 μM Cd. However, there was no change in the expression of several other β-catenin-regulated genes including: c-myc, cyclin D1 and matrilysin. Additional studies utilizing the TOPFLASH β-catenin reporter gene construct showed that Cd caused a 2-3 fold increase in the expression of the luciferase reporter gene. Overall, these results indicate that Cd disrupts the cadherin/β-catenin complex in NRK-52E cells, but this effect leads to only partial activation of β-catenin-mediated gene transcription.
Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA. jedwar@midwestern.edu
Joshua R
JR
Edwards
Kevin
K
Kolman
Peter C
PC
Lamar
Nalini
N
Chandar
Michael J
MJ
Fay
Walter C
WC
Prozialeck
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019256:Cadmium Chloride / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D007668:Kidney / Q000166:cytology; D008094:Lithium / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D004785:Environmental Pollutants; D051176:beta Catenin; D008094:Lithium; D019256:Cadmium Chloride