The unique N-terminal sequence of metallothionein-3 is required to regulate the choice between apoptotic or necrotic cell death of human proximal tubule cells exposed to Cd+2

This laboratory has shown that MT-3 expression determines the choice between apoptotic or necrotic cell death in Cd(+2)-exposed human proximal tubule cells. Human proximal tubule cells that express MT-3 undergo necrosis when exposed to Cd(+2), while cells that have no basal expression of MT-3 underg...

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Vydáno v:Toxicological sciences Ročník 90; číslo 2; s. 369
Hlavní autoři: Somji, Seema, Garrett, Scott H, Sens, Mary Ann, Sens, Donald A
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.04.2006
Témata:
Alzheimer Disease - metabolism
Apoptosis
Cadmium - toxicity
Cell Death - drug effects
Cell Line
Cell Survival - drug effects
Humans
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - pathology
L-Lactate Dehydrogenase - metabolism
Mutagenesis, Site-Directed
Necrosis
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
RNA, Messenger - metabolism
ISSN:1096-6080
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Shrnutí:This laboratory has shown that MT-3 expression determines the choice between apoptotic or necrotic cell death in Cd(+2)-exposed human proximal tubule cells. Human proximal tubule cells that express MT-3 undergo necrosis when exposed to Cd(+2), while cells that have no basal expression of MT-3 undergo apoptotic cell death. It was also shown that cells which express MT-3 were more sensitive to Cd(+2)-induced cell death than those having no basal expression. In the present study, site directed mutagenesis was used to determine if the unique N-terminal sequence of MT-3 was required for these activities regarding toxicity and cell death. The results demonstrated that HK-2 cells stably transfected with MT-3 that had been modified by converting the 2 prolines at amino acid positions 7 and 9 to threonines was no longer active in promoting necrotic cell death at lower levels of Cd(+2) exposure. This was shown in comparison to cells containing the wild type MT-3 sequence and blank vector controls as regards the % of DAPI-stained fragmented nuclei, DNA laddering, LDH release, caspase-9, and caspase-3 activation. This study demonstrates that the unique N-terminal sequence of MT-3 is required to elicit an effect on the mechanism of Cd(+2)-induced death of the proximal tubule cell. This is the identical sequence that has been shown to be responsible for the growth inhibitory activity of MT-3 in the neural system.
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ISSN:1096-6080
DOI:10.1093/toxsci/kfj089