Metal response element binding transcription factor

Chu, W. A., Moehlenkamps, J. D., Bittel, D., Andrews, G. K., and Johnson, J. A. Cadmium-mediated activation of the metal response element in human neuroblastoma cells lacking functional metal response element-binding transcription factor-1. J. Bio. Chem. 274(9), 5279-5284,1999. 

Bittel, D., T. Dalton, S.L. Samson, L. Gedamu and G.K. Andrews. The DNA binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. J. Biol. Chem. 273 7127-7133, 1998. 

Dalton, T.P., D. Bittel and G.K. Andrews. Reversible activation of mouse metal response element-binding transcription factor 1 DNA binding involves zinc interaction with the zinc finger domain. Mol. Cell. Biol. 17 2781-2789, 1997. 

MTF-1= metal response element-binding transcription factor-1... 

The candidate metal responsive element-binding protein (MTF-1 for metal transcription factor-1) is a Zn-finger (Cys2His2) transcription factor [618]. 

Metallothionein expression is mainly regulated at the transcriptional level and is induced by various heavy metals, such as zinc. There are seven short sequence motifs located in a region within 200 base pairs upstream of the transcription start site. These cis-acting DNA elements are responsible for heavy metal induction and are thus termed metal responsive elements (MREs) (Stuart et al., 1984). Several regulatory proteins have been cloned which interact with these MREs. One of these, MRE-binding transcription factor-1 (MTF-1), is essential for the transcriptional activation of metallothionein genes by heavy metals like zinc and cadmium (Radtke et al., 1993 Palmiter, 1994 Heuchel et al., 1994 Koiszumi et al., 1999). 

The 5 end of MT-1 and MT-2 genes possess a TATA box, or core promoter element and numerous response elements that confer metal inducibility on the MT gene promoter (Figure 21.8). Some of these response elements such as API and AP2 in humans and in mouse, the antioxidant response element (ARE) and upstream stimulatory factor (USF) provide putative binding sites for MT transcription factors. The most common of these cis-acting proximal elements are the metal responsive elements (MREs), motifs that are conserved across vertebrate and invertebrate species. Multiple copies of MREs exist in the MT promoter region and act syner-gistically to enhance activity. 

Dalton TP, Li Q, Bittel D, Liang L, Andrews GK (1996) Oxidative stress activates metal-responsive transcription factor-1 binding activity. Occupancy in vivo of metal response elements in the metallothionein-I gene promoter. J Biol Chem 271 26233-26241 Danscher G, Howell G, Perez-Clausell J, Hertel N (1985) The dithizone, Timm s sulphide silver and the selenium methods demonstrate a chelatable pool of zinc in CNS. A proton activation (PIXE) analysis of carbon tetrachloride extracts from rat brains and spinal cords intravitally treated with dithizone. Histochemistry 83 419 22 Danscher G, Jensen KB, Frederickson CJ, Kemp K, Andreasen A, Juhl S, Stoltenberg M, Ravid R (1997) Increased amount of zinc in the hippocampus and amygdala of Alzheimer s diseased brains a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. J Neurosci Methods 76 53-59... 

Evidence suggests that the regulation of metallothionein levels by metal ions results from the binding of zinc (or other metal ions) to a special transcription factor (molecular weight = 105 kDa, with the subsequent binding of the zinc/transcription factor complex to d promoter that resides near the metallothionein gene. The zinc/transcription factor complex actually binds to the metal response element that resides in the promoter The sequence of the metal response element is ... 

The synthesis of MTs has been examined in several cell lines. Most studied have been two rainbow trout cell lines, RTH-149 and RTG-2, and the Chinook embryo cell line, CHSE-214151 160 229 231. Heavy metals induced MTs in RTH-149 and RTG-2 but not in CHSE-214. Methylation of the MT genes appeared to account for the failure of MTs to be induced in CHSE-214161. MTF-1, the metal response element (MRE)-binding transcription factor-1, has been demonstrated in RTH-149 and RTG-2 and in a zebrafish cell line, ZEM2S62. ZEM2S had a single isoform of MTF-1, whereas RTH-149 and RTG-2 contained two isoforms. Zn but not Cd activated MTF-1 binding to MRE in cells from both species. A cell line from at least one marine species has been studied for MT expression. In a turbot fibroblast cell line, Cd, Cu, Hg and Zn but not Pb induced MT mRNA and MT levels89. 

Dalton, T.P., Q. Li, D. Bittel, L. Liang and G.K. Andrews. Oxidative stress activates metal-responsive transcription factor-1 binding activity. Occupancy in vivo of metal response elements in the metallothionein-I gene promoter. J. Biol. Chem. 271 26233—26241, 1996. 

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