METALLOTHIONEIN AND CELLULAR PROTECTION

  • Richardson, Arlan G (PI)

Project: Research project

Project Details

Description

The metallothioneins (MTs) are a group of small, ubiquitous, cysteine-
rich proteins that avidly bind heavy metal ions. Because MT binds to and
is induced by heavy metal ions, it is generally believed that MT evolved
to protect living organisms against the toxicity of heavy metals.
However, investigators have argued persuasively that it is unlikely that
the primary function of MT is to protect cells against heavy metals.
Thus the exact function of MT remains an enigma. Gene transfer studies
with mammalian cell lines demonstrate that the over-expression of MT
results in the cells becoming resistant to the toxicity of heavy metals
and alkylating agents. The latter observation is of interest because
alkylating agents are known to be carcinogenic in mammals. Although some
correlative data suggests that increased levels of MT also protect
tissues in vivo against the toxicity of heavy metals, this association
is not always observed. At the present time, there is not information
about the potential role MT might play in protecting tissues against the
toxic and carcinogenic action of alkylating agents. The objective of this project is to produce transgenic mice that over-
express MT and to use these mice to test the following hypothesis:
Increased expression of MT will protect an organism from the cytotoxic
and carcinogenic action of heavy metals and alkylating agents. The
specific aims of this project are as follows: 1. To produce and characterize transgenic mice that carry the human-
transferrin promoter fused to the human MT-II(Alpha) gene (phTF/hMT-
II(alpha). These transgenic mice will over-express the MT-II(Alpha) gene
in liver and brain. 2. To determine if the over-expression of MT protects an organism from
the toxicity of heavy metals. The hepatotoxicity of Cd will be compared
in phTF/hMT-II(Alpha) transgenic mice and mice without the transgene, and
the mechanism responsible for the reduced hepatotoxicity will be studied. 3. To determine if the over-expression of MT protects an organism from
carcinogenesis induced by alkylating agents. The ability of N-nitroso-N-
methylurea(NMU) to induce liver tumors in phTF/hMT-II(Alpha) transgenic
mice and mice without the transgene will be compared, and the mechanism
responsible for the reduced hepatocarcinogenesis will be studied.
StatusFinished
Effective start/end date1/1/9312/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Environmental Science(all)
  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.