Expression of metallothionein isoform 3 (MT-3) determines the choice between apoptotic or necrotic cell death in Cd+2-exposed human proximal tubule cells

This laboratory has shown that the third isoform of metallothionein (MT-3) is expressed in the human kidney in situ, including the cells of the proximal tubule. A subsequent analysis of MT-3 expression in cell cultures derived from the human proximal tubule (HPT) demonstrated that mortal HPT cells e...

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Published in:Toxicological sciences Vol. 80; no. 2; p. 358
Main Authors: Somji, Seema, Garrett, Scott H, Sens, Mary Ann, Gurel, Volkan, Sens, Donald A
Format: Journal Article
Language:English
Published: United States 01.08.2004
Subjects:
Apoptosis - drug effects
Cadmium - toxicity
Caspase 3
Caspases - metabolism
Cell Death - drug effects
Cell Line
Cell Survival - drug effects
DNA - genetics
Fluorescent Dyes
Humans
Indoles
Isomerism
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - pathology
L-Lactate Dehydrogenase - metabolism
Necrosis
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Reverse Transcriptase Polymerase Chain Reaction
Transfection
ISSN:1096-6080
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Summary:This laboratory has shown that the third isoform of metallothionein (MT-3) is expressed in the human kidney in situ, including the cells of the proximal tubule. A subsequent analysis of MT-3 expression in cell cultures derived from the human proximal tubule (HPT) demonstrated that mortal HPT cells expressed MT-3, while the HPV-immortalized HK-2 cells had no expression of MT-3. In the present study, the effect of MT-3 expression on Cd(+2)-induced cytotoxicity was determined by stable transfection of the MT-3 coding sequence into the HK-2 cell line. The results demonstrated that HK-2 cells stably transfected with MT-3 were more sensitive to the cytotoxic effects of Cd(+2). Furthermore, this increase in Cd(+2)-induced cytotoxicity was correlated to an alteration in the mechanism of cell death, being changed from an apoptotic mechanism in cells not expressing the MT-3 gene to a necrotic mechanism in cells expressing the MT-3 gene. The present study provides evidence that MT-3 could play a role in controlling the choice between apoptosis and necrosis in multiple epithelial cell types of the human kidney.
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ISSN:1096-6080
DOI:10.1093/toxsci/kfh158