The transcription factors described here have provided insight into the molecular mechanisms involved in the control of eukaryotic metal ion homeostasis. The regulation of these proteins at multiple levels is a recurring theme and may be characteristic of all eukaryotic metalloregulatory factors. There is also compelling evidence that these factors directly sense metal, although, to date, there is no direct in vivo evidence that their metal occupancy changes with cellular metal ion status. Therefore, alternative mechanisms of sensing, such as signal transduction pathways, that involve protein kinases cannot be discounted at present.
It is likely that other eukaryotic metal-responsive transcription factors exist. There are many fungal genes that are regulated in response to metal ions independent of the factors described in this review (19, 90, 102). In other eukaryotes, metal-regulated genes are continuously being identified, suggesting that other metalloregulators exist (for examples, see references 37, 58, 69, 86, 110, 111, 126, and 132). The influence of metals on human health has generated considerable interest in the understanding of the principles involved in metal homeostasis. As more metal-responsive transcription factors are discovered in both plants and mammals, it should become apparent whether or not there are general principles of metal ion sensing that are conserved throughout the eukaryotes. This will be indispensable to our understanding of intracellular metal homeostasis.
We thank Dennis Winge, Heather Carr, and Paul Cobine for helpful discussion and comments on the manuscript.
J.R. and A.B are both members of the Winge lab, whose work is supported by grant CA 61286 from the National Cancer Institute, National Institutes of Health.
* Corresponding author. Mailing address: University of Utah, Division of Hematology, 4C 416 SOM, 30 North 1900 East, Salt Lake City, UT 84132-2408. Phone: (801) 581-6713. Fax: (801) 585-5469. E-mail: [email protected]