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ToxSci Advance Access published online on December 30, 2005
Toxicological Sciences, 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
Received November 2, 2005
Accepted December 27, 2005

Environmental Toxicology

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 1, Scott H. Garrett 1, Mary Ann Sens 1, and Donald A. Sens 1 *

1 Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202

* To whom correspondence should be addressed.
Donald A. Sens, E-mail: dsens{at}medicine.nodak.edu


  Abstract

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with MT-3 that had been modified by converting the 2 prolines at amino acid positions 7 and 9 to threonines was no longer active in promoting necrotic cell death at lower levels of Cd+2 exposure.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

Keywords: Cadmium; Proximal Tubule; Nephrotoxicity; Metallothionein; Apoptosis; Necrosis.
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[Abstract] [Full Text] [PDF]


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