Metallothionein gene regulation

Ren Y, Smith A. 1995. Mechansim of metallothionein gene regulation by heme-hemopexin. J. Biol. Chem. 270 23988-95... 

Skroch, P., Buchman, C., Karin, M. (1993). Regulation of human and yeast metallothionein gene transcription by heavy metal ions. Prog. Clin. Biol. Res. 380, 113-128. 

Imbra RJ. Karin M (1987) Metallothionein gene eiqjression is regulated by serum factors and activators of protein kinase C. Mol Cell Biol 7 1358-1363... 

Metal ions can serve as effector molecules as well as control the DNA-binding activity of regulatory proteins. An example is the regulation of the metallothionein gene in eucaryotes (Fig. 1.23). The metallothioneins are small, cysteine rich proteins which can specifically bind metal ions like Cu or Zn The complexation of metal ions functions to sequester the ions in a form that is not damaging to the cell. 

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). 

Andrews, G.K. (2000) Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem. Pharmacol., 59, 95-104. 

Heuchel, R., Radtke, F. and Schaffner, W. (1995) Transcriptional regulation by heavy metals, exemplified at the metallothionein genes. In P A.Baeuerle (ed.) Inducible Gene Expression, Vol. I, Birkhauser, Boston. 

Palmiter, R.D. (1994) Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1. Proc. Nat. Acad. Sci. USA, 91, 1219-1223. 

Stuart, G.W., Searl, P.F., Chen, H.Y., Brinster, R.L. and Palmiter, R.D. (1984) A 12-base-pair DNA motif that is repeated several times in metallothionein gene promoters confers metal regulation to a heterologous gene. Proc. Natl. Acad. Sci. USA, 81, 7318-7322. 

Trayhum P, Duncan JS, Wood AM, Beattie JH (2000) Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture. Horm Metab Res 32 542-547... 

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 ... 

Metallothionein, metal-binding proteins and phytochelatins (see Gagne and Blaise, Chapter 7 of this volume). Metallothioneins are low molecular weight, cysteine-rich proteins with a high affinity for transition metals. After they were first discovered in the kidney cortex of the horse they have been detected in a variety of animal species. It is widely accepted that metallothioneins are multifunctional proteins primarily involved in the homeostasis of essential trace metals, zinc-mediated gene regulation, and in the protection of cells against oxidative... 

Zafarullah, M., P.E. Olsson and L. Gedamu. Differential regulation of metallothionein genes in rainbow trout fibroblasts, RTG-2. Biochim. Biophys. Acta 1049 318-323, 1990. 

Karin, M., R.J. Imbra, A. Heguy and G. Wong. Interleukin 1 regulates human metallothionein gene expression. Mol. Cell. Biol. 5 2866-2869, 1985. 

Karin, M., G. Cathala and M.C. Nguyen-Huu. Expression and regulation of a human metallothionein gene carried on an autonomously replicating shuttle vector. Proc. Natl Acad. Sci. USA 80 4040-4044, 1983. 

Olsson, P.-E. and P. Kille. Functional comparison of the metal-regulated transcriptional control regions of metallothionein genes from cadmium-sensitive and tolerant fish species. Biochim. Biophys. Acta 1350 325-334, 1997. 

Carri MT, Galliazzo F, Ciriolo MR, Rotilio G. Evidence for co-regulation of Cu,Zn superoxide dismutases and metallothionein gene expression in yeast through transcriptional control by copper via the ACE1 factor. FEBS Lett 278 263-266, 1991. 

Schroeder, J. J., and Cousins, R. 1. lnterleukin-6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures. Proc. Natl. Acad. Sci. U.SA. 87,3137-3141 (1990). 

Karin M, Imbra RJ, Heguy A and Wong G (1985) Interleukin I regulates human metallothionein gene expression. Mol Cell Biol 5 2866-2869. 

Yeast Metallothionein Gene Function and Regulation by Metal Ions... 

Recently it has been shown that Cu(I), as well as its analog Ag(I), can activate metallothionein gene transcription in yeast by binding directly the ACEI trans-activator protein [8 Our experiments with the Ag(I) ion show that it does not appear to mimic the effect of Cu on the accumulation of qrt c-552 mRNA. This could indicate either that the active metalloregulator of the cyt c-552 gene is Cu(II) rather than Cu(I) or that the sensory molecule that responds to Cu is exquisitely specific for Cu (ys. other metals) as the regulator. This level of specificity combined with the extreme sensitivity of the response, < 100 nM total (chelated + free) Cu, suggest that the ( t c-552/Cu-response system could find practical application as a metal ion biosensor. 

Croston GE, Kadonaga JT (1993) Role of chromatin structure in the regulation of transcription by RNA polymerase II. Curr Opin Cell Biol 5 417-423 Culotta VC, Hamer DH (1989) Fine mapping of a mouse metallothionein gene metal response element. Mol Cell Biol 9 1376-1380 Danks DM (1989) Disorders of copper transport. In Scrives C, Beaudet A, Sly W, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 1411-1432... 

Sato M, Sasaki M, Hojo H (1993) Induction of metallothionein synthesis by oxidative stress and possible role in acute phase response. In Suzuki KT, Imura N, Kimura M (eds) Metallothionein III. Birkhauser, Basel, pp 125-140 Satoh M, Tsuchiya T, Kumada Y, Naganuma A, Imura N (1993) Protection against lethal toxicity of various anticancer drugs by preinduction of metallothionein synthesis in mice. J Trace Element Exp Med 6 41-44 Schroeder JJ, Cousins RJ (1990) Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures. Proc Natl Acad Sci USA 87 3137-3141... 

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