Metallothionein gene

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. 

Mehra RK, JR Garey, DR Winge (1990) Selective and tandem amplification of a member of the metallothionein gene family in Candida glabrata. J Biol Chem 265 6369-6375. 

Gardea-Torresdey JL, Arenas NMC, Francisco KJ et al (1998) Ability of immobilized cyanobacteria to remove metal ions from solution and demonstration of the presence of metallothionein genes in various strains. J Hazard Subst Res 1 1-8... 

When animals are fed experimental diets lacking copper or zinc, their copper or zinc status rapidly declines, suggesting that there is not a storage pool of these metals. Thus, while the small, cysteine-rich protein metallothionein (see below) can avidly bind zinc and copper, this may reflect its role in detoxification rather than as a specific storage form. This is reflected by the fact that metallothionein genes are typically expressed at a basal level, but their transcription is strongly induced by heavy metal load. 

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... 

Yu CW, Chen JH, Lin LY (1997) Metal-induced metallothionein gene expression can be inactivated by protein kinase C inhinbitor. FEBS Lett 420 69-73... 

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. 

Evans, I.M., Gatehouse, L.N., Gatehouse, J.A., Robinson, N.J. Cray, R.R.D. (1990). A gene from pea (Pisum sativum) with homology to metallothionein genes. FEBS Letters 262, 29-32. 

Furst, F.S., Hu, S., Hackett, R. Hamer, R. (1988). Copper activates metallothionein gene transcription by altering the conformation of a specific DNA-binding protein. Cell 55, 705-17. 

Munger, K., Germann, U.A. Lerch, K. (1987). The Neurospora crassa metallothionein gene. Journal of Biological Chemistry 262, 7363-7. 

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., Georgiev, O., Stark, G., Aguet, M. and Schaffner, W. (1994) The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression. EMBO J., 13, 2870-2875. 

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. 

West, A.K., Hildebrand, C.E., Karin, M. and Richards, R.L (1990) Human metallothionein genes Structure of the functional locus at 16ql3. Genomics, 8, 513-518. 

Alcedo JA, Misra M, Hamilton JW, et al. 1994. The genotoxic carcinogen chromium(VI) alters the metal-inducible expression but not the basal expression of the metallothionein gene in vivo. Carcinogenesis 15(5) 1089-1092. 

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.)...

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... 

Figure 6.30. Rat Growth Hormone-Metallothionein Gene Construct. The gene for rat growth hormone (shown in yellow) was inserted into a plasmid next to the metallothionein promoter, which is activated by the addition of heavy metals, such as cadmium ion.

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 ... 

Karin M, Richards RJ.The human metallothionein gene family. Structure and expression. Environ Elealth Perspect 1984 54 111-115. 

Lu J, JinT, Nordberg GF, Nordberg M. Metallothionein gene expression in peripheral lymphocytes from cadmium exposed workers. Cell Stress Chaperones 2001 6 97-104. 

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