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 element-binding transcription factor-1 (MTF-1) functions as a cellular zinc sensor which coordinates the expression of genes involved in zinc homeostasis, as well as protection against metal toxicity and oxidative stresses. In mice, these are known to include the metallothionein (MT), the zinc-transporter-1 (ZnT1) and the gamma-glutamylcysteine synthetase heavy chain (gammaGCShc) genes. The cysteine-rich MTs function as an intracellular metal-chelators that bind zinc with high affinity, whereas the transmembrane protein ZnT1 exports zinc from the cell. Gamma-glutamylcysteine synthetase controls the rate limiting step in glutathione (GSH) biosynthesis. GSH, which is present in mM concentrations in cells, effectively chelates large amounts of 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 reversibly) binds to zinc. This metalloregulatory protein then adopts a DNA-binding conformation and translocates to the nucleus, where it binds to metal-response elements in these gene promoters leading to increased transcription. The six zinc-finger domain of this factor is highly conserved from insects to mammals, and biochemical studies confirm that the zinc-fingers are heterogeneous in function and in zinc-binding. Furthermore, the mouse MTF-1 gene is essential for development of the embryo, thus underscoring the importance of this transcription factor.
Andrews
G K
GK
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66160-7421, USA. gandrews@kumc.edu
D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015374:Biosensing Techniques; D002352:Carrier Proteins / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000032:analysis* / Q000378:metabolism / Q000494:pharmacology; D016335:Zinc Fingers; D000097809:Transcription Factor MTF-1
D000975:Antioxidants; D002352:Carrier Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D008668:Metallothionein; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C017800:zinc-binding protein