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KMID : 1034820130090020159
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Molecular & Cellular Toxicology
2013 Volume.9 No. 2 p.159 ~ p.167
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In vitro nasal epithelial toxicity by cadmium accompanies up-regulation of RUNX3 protein with activation of PI3-kinase/Akt
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Seo Ji-Young
Lee Yoon-Jin
Oh Myung-Ho
Lee Sang-Han
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Abstract
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Nasal epithelium is the first cellular target for inhaled cadmium; however, the specific molecular events that mediate or accompany toxicity are not well studied. Using RPMI-2650 cells as an in vitro nasal epithelial model for the investigation of molecular events of cadmium toxicity, we found that treatment with cadmium acetate induced cell death with the typical morphological changes of apoptosis, such as chromatin condensation and nuclear fragmentation, as well as increased caspase-3/7 activity. This finding was accompanied with concentration-dependent increases of RUNX3, phospho-p53 (p-p53), and phospho-Akt (p-Akt) proteins with concomitant decrease in the Bcl-2 level. However, no significant changes were observed in the levels of Fas ligand and Fas-associated protein with death domain. Cadmium treatment increased the DNA binding activity of p53 toward a p53 consensus binding site. Blockage of RUNX3 expression with siRNA transfection did not affect a cadmium-induced increase in the p-p53 level but suppressed p53 binding activity to DNA. Nuclear co-localization of RUNX3 and p-p53 was enhanced by treatment with cadmium. The nuclear RUNX3 level was suppressed by the pretreatment with LY294002, a PI3-kinase inhibitor, while noticeable changes in the levels of p53 and p-p53 were not observed under the same condition. Cadmium-induced increase in the p53 binding to DNA was partly suppressed by LY294002, while it was enhanced by PD98059, a MEK inhibitor. Collectively, our findings suggest that cadmium induces up-regulation of RUNX3 protein through activation of PI3-kinase/Akt and leads to RPMI-2650 cell death, at least in part, through p53-dependent apoptosis pathway, in which RUNX3 may facilitate p53 binding to DNA.
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KEYWORD
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Cadmium, RUNX3, p53, Apoptosis, Gene silencing
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