Metal-responsive transcription factors

Rutherford, J.C. and Bird, A.J. (2004) Metal-responsive transcription factors that regulate iron, zinc, and copper homeostasis in eukaryotic cells, Eukaryot. Cell, 3, 1-13. 

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... 

Maxwell P, Salnikow K. HIF-1 an oxygen and metal responsive transcription factor. Cancer Biol. Ther. 2004 3 29-35. Schlemminger I, Mole DR, McNeill LA, Dhanda A, Hewitson KS, Tian YM, Ratcliffe PJ, Pugh CW, Schofield CJ. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorg. Med. Chem. Lett. 2003 13 1451. 

Key words Stress response pathways, Transcription factor, p53, Nrf2, Unfolded protein response, ATF4, HIF-1 alpha, Metal-responsive transcription factor-1, Inflammation, FOXO, Energy stress response, Nuclear receptors... 

Egli, D., A. Selvaraj, H. Yepiskoposyan, B. Zhang, E. Hafen, O. Georgiev and W. Schaffner. Knockout of metal-responsive transcription factor MTF-1 in Drosophila by homologous recombination reveals its central role in heavy metal homeostasis. EMBO J. 22 100-108, 2003. 

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. 

Similar to metal-induced transcription in yeast, MREs mediate transcription through positively acting, metal-responsive transcription factors (MRTFs) (Seguin et al. 1984). Because de novo protein synthesis is not required for gene activation by metals, MRTFs must pre-exist (Karin et al. 1981). The characteristics of MRTFs in higher eukaryotes have been recently reviewed by Thiele (1992). Six mammalian MRTF activities in different species have been reported in the literature - whether they perform distinct metal-loregulatory functions is not known. They are ... 

Copper ion homeostasis in prokaryotes involves Cu ion efflux and sequestration. The proteins involved in these processes are regulated in their biosynthesis by the cellular Cu ion status. The best studied bacterial Cu metalloregulation system is found in the gram-positive bacterium Enterococcus hirae. Cellular Cu levels in this bacterium control the expression of two P-type ATPases critical for Cu homeostasis (Odermatt and Solioz, 1995). The CopA ATPase functions in Cu ion uptake, whereas the CopB ATPase is a Cu(I) efflux pump (Solioz and Odermatt, 1995). The biosynthesis of both ATPases is regulated by a Cu-responsive transcription factor, CopY (Harrison et al., 2000). In low ambient Cu levels Cop Y represses transcription of the two ATPase genes. On exposure to Cu(I), CopY dissociates from promoter/operator sites on DNA with a for Cu of 20 jlM (Strausak and Solioz, 1997). Transcription of copA and copB proceeds after dissociation of CuCopY. The only other metal ions that induce CopY dissociation from DNA in vitro are Ag(I) and Cd(II), although the in vivo activation of copA and copB is specihc to Cu salts. The CuCopY complex is dimeric with two Cu(I) ions binding per monomer (C. T. Dameron, personal communication). The structural basis for the Cu-induced dissociation of CopY is unknown. Curiously, CopY is also activated in Cu-dehcient cells, but the mechanism is distinct from the described Cu-induced dissociation from DNA (Wunderh-Ye and Solioz, 1999). 

Xu, C. (1993). cDNA cloning of a mouse factor that activates transcription from a metal response element of the mouse metallothionein-1 gene in yeast. DNA Cell Biol. 12, 517-525. 

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. 

Figure 21.9. Human MT promoter. (Adapted from Murphy, B. J., Andrews, G. K. Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Cancer Res. 59,1315-1322, 1999.)...

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. 

Cuajungco MP, Lees GJ (1996) Prevention of zinc neurotoxicity in vivo by N,N,N J< -tetrakis (2-pyridylmethyl) ethylene-diamine (TPEN). NeuroReport 7 1301-1304 Dalton TP, Bittel D, Andrews GK (1997) Reversible activation of mouse metal response elementbinding transcription factor 1 DNA binding involves zinc interaction with the zinc finger domain. Mol Cell Biol 17 2781-2789... 

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 ... 

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