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Nucleic Acids Research, 2002, Vol. 30, No. 14 3130-3140
© 2002 Oxford University Press

Mammalian metal response element-binding transcription factor-1 functions as a zinc sensor in yeast, but not as a sensor of cadmium or oxidative stress

Patrick J. Daniels, Doug Bittel, Irina V. Smirnova, Dennis R. Winge1 and Glen K. Andrews*

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7421, USA and 1 Department of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

*To whom correspondence should be addressed. Tel: +1 913 588 6935; Fax: +1 913 588 7035; Email: gandrews{at}kumc.edu
Present addresses:
Doug Bittel, Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, USA
Irina V. Smirnova, Department of Physical Therapy, University of Kansas Medical Center, Kansas City, KS 66160-7421, USA

The zinc finger protein, metal response element-binding transcription factor-1 (MTF-1) regulates the expression of genes in response to metal ions and oxidative stress. The precise mechanisms by which this occurs are not understood. To further examine this problem, mouse MTF-1 was expressed in Saccharomyces cerevisiae and tested for the ability to activate metal response element-driven reporter gene expression. Zinc was an effective inducer of reporter gene expression. In general, the magnitude of zinc induction was dependent on the concentration of zinc in the culture medium, but independent of the amount of MTF-1 expression. Zinc induction also occurred with either integrated or episomal reporter plasmids containing the native mouse metallothionein-I proximal promoter. Deletion of fingers 5 and 6 of MTF-1, which function in a zinc-dependent manner to stabilize the DNA-binding activity of the protein in vitro, did not diminish the zinc induction of either episomal or integrated promoters. However, a Gal4 DNA-binding domain– MTF-1 fusion protein, which binds constitutively to the Gal4-responsive promoter, was not zinc inducible but caused constitutive activation of reporter gene expression. This suggests that zinc activation of the DNA-binding activity of MTF-1 is the rate limiting step in its metalloregulatory function in yeast. In contrast, MTF-1 was not responsive to either cadmium or hydrogen peroxide, suggesting that distinct co-activators or signal transduction cascades not found in yeast are required to mediate MTF-1 activation of gene expression by this toxic metal and by oxidative stress.


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