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ToxSci Advance Access originally published online on December 30, 2005
Toxicological Sciences 2006 90(2):369-376; doi:10.1093/toxsci/kfj089
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Seema Somji, Scott H. Garrett, Mary Ann Sens and Donald A. Sens1

Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Road, Grand Forks, North Dakota 58202

Received November 2, 2005; accepted December 27, 2005

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with MT-3 that had been modified by converting the 2 prolines at amino acid positions 7 and 9 to threonines was no longer active in promoting necrotic cell death at lower levels of Cd+2 exposure.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.

Key Words: cadmium; proximal tubule; nephrotoxicity; metallothionein; apoptosis; necrosis.


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C. S. Bathula, S. H. Garrett, X. D. Zhou, M. A. Sens, D. A. Sens, and S. Somji
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[Abstract] [Full Text] [PDF]


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