Metallothionein regulation

Zn shows a variety of effects within the nervous system, thereby requiring that levels of zinc are regulated to a very precise level. A fine balance between ion sequestration, intracellular buffering, and extrusion exists in order to maintain cellular zinc homeostasis. A family of proteins known as metallothioneins regulates zinc sequestration and buffering, while zinc uptake and extrusion is mediated by membrane-associated zinc transporters. Mitochondria may serve as the pool of histochemically reactive zinc in neurons and glial cells. 

Koropatnick J, Leibbrandt M, Cherian MG (1989) Organ-specific metallothionein induction in mice by x-irradiation. Radiat Res 119 356-365 Lehman-McKeeman LD, Kershaw WC, Klaassen CD (1991) Species differences in metallothionein regulation a comparison of the induction of isometallothioneins in rats and mice. In Klaassen CD, Suzuki KT (eds) Metallothionein in biology and medicine, CRC, Boca Raton, pp 121-132 Lui EMK (1987) Metabolism of copper and zinc in the liver and bone of perinatal guinea pig. Comp Biochem Physiol 86 173-183 Maitani T, Cuppage FE, Klaassen CD (1988) Nephrotoxicity of intravenously injected cadmium-metallothionein critical concentration and tolerance. Fund Appl Toxicol 10 98-108... 

As more is learned about the chromosomal effects on HS gene expression, it is important to point out that these genes are actually a subset of inducible responses to cellular stress. Not all of these inducible responses involve HSF, and this indicates that cells have diversified transcriptional responses to cope with different types of stress. This diversification is manifested by glucose regulated genes (grp), as well as the metallothionein and oxidant-injury genes (Watswich, 1988 Storz et al., 1990 Devary et al., 1992 Skroch et al., 1993 Xu, 1993). 

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. 

The Tissue Levels of Copper of Certain Other Metals Are Regulated in Part by Metallothioneins... 

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

Hogstrand, C. 1991. Regulation of metallothionein in teleost fish during exposure. Ph.D. dissertation. Univ. Goteborg, Goteborg, Sweden. 176 pp. 

Engel, D.W. 1987. Metal regulation and molting in the blue crab, Callinectes sapidus copper, zinc, and metallothionein. Biol. Bull. 172 69-82. 

Olsson, P.E., M. Zafarullah, and L. Gedamu. 1989. A role of metallothionein in zinc regulation after oestradiol induction of vitellogenin synthesis in rainbow trout, Salmo gairdneri. Biochem. Jour. 257 555-559. 

Pillet, S. et al., Presence and regulation of metallothioneins in peripheral blood leukocytes of grey seals, Toxicol. Appl. Pharmacol., 185, 207, 2002. 

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

To detoxify heavy metals, the liver contains metallothioneins, a group of cysteine-rich proteins with a high af nity for divalent metal ions such as Cd Cu Hg, and Zn T These metal ions also induce the formation of metallothioneins via a special metal-regulating element (MRE) in the gene s promoter (see p. 244). 

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. 

The gene for metallothionein is induced by metal ions. The goal of the regulation is to provide enough metallothionein for the complexation of metal ions and thus to maintain the concentration of free metal ions at a tolerable level for the cell. 

The transcription of genes for metallothionein is imder positive regulation by the DNA-binding protein ACE, which binds an ACE-specific DNA element in the metal-... 

Fig. 1.23. Regulation of the transcription of metallothionein by Cu. The transcription of metallothionein is controlled by the transcription activator ACE, whose specific DNA-binding capacity is regulated by Cu which functions as an effector of the ACE protein by binding to the protein and regulating its DNA-binding abihty.

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