Cellular zinc sensors: MTF-1 regulation of gene expression

Zinc metabolism in higher eukaryotes is complex, being controlled by uptake , efflux, and storage in individual cells, as well as in peripheral tissues and organs. Recently there have been advances in the understanding of the genes involved in these processes and their regulation. Metal-response elem ent-binding transcription factor-1 (MTF-1) functions as a cellular zinc sen sor which coordinates the expression of genes involved in zinc homeostasis, as well as protection against metal toxicity and oxidative stresses. In mi ce, these are known to include the metallothionein (MT), the zinc-transport er-1 (ZnT1) and the gamma -glutamylcysteine synthetase heavy chain (gamma G CS(hc)) genes. The cysteine-rich MTs function as an intracellular metal-che lators that bind zinc with high affinity, whereas the transmembrane protein ZnT1 exports zinc from the cell. gamma -Glutamylcysteine synthetase contro ls the rate limiting step in glutathione (GSH) biosynthesis. GSH, which is present in mM concentrations in cells, effectively chelates large amounts o f zinc in vitro. Both MT and GSH also function as antioxidants. The current model suggests that the zinc-finger domain of MTF-1 directly (and reversib ly) binds to zinc. This metalloregulatory protein then adopts a DNA-binding conformation and translocates to the nucleus, where it binds to metal-resp onse elements in these gene promoters leading to increased transcription. T he six zinc-finger domain of this factor is highly conserved from insects t o mammals, and biochemical studies confirm that the zinc-fingers are hetero geneous in function and in zinc-binding. Furthermore, the mouse MTF-1 gene is essential for development of the embryo, thus underscoring the importanc e of this transcription factor.