Induction, Regulation, Degradation, and Biological Significance of Mammalian Metallothioneins

Abstract

MTs are small cysteine-rich metal-binding proteins found in many species and, although there are differences between them, it is of note that they have a great deal of sequence and structural homology. Mammalian MTs are 61 or 62 amino acid polypeptides containing 20 conserved cysteine residues that underpin the binding of metals. The existence of MT across species is indicative of its biological demand, while the conservation of cysteines indicates that these are undoubtedly central to the function of this protein. Four MT isoforms have been found so far, MT-1, MT-2, MT-3, and MT-4, but these also have subtypes with 17 MT genes identified in man, of which 10 are known to be functional. Different cells express different MT isoforms with varying levels of expression perhaps as a result of the different function of each isoform. Even different metals induce and bind to MTs to different extents. Over 40 years of research into MT have yielded much information on this protein, but have failed to assign to it a definitive biological role. The fact that multiple MT isoforms exist, and the great variety of substances and agents that act as inducers, further complicates the search for the biological role of MTs. This article reviews the current knowledge on the biochemistry, induction, regulation, and degradation of this protein in mammals, with a particular emphasis on human MTs. It also considers the possible biological roles of this protein, which include participation in cell proliferation and apoptosis, homeostasis of essential metals, cellular free radical scavenging, and metal detoxification.

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

“…As a variety of endogenous factors (e.g. glucocorticosteroids, ILs, IFNg, TNF-a) are involved in the induction of the synthesis of intracellular MT, one may suggest that this may lead to an overprotection of tumour cells against apoptosis, and, on the other hand, supporting the metastatic behaviour of the tumour (Karin et al, 1985;Karasawa et al, 1987;Nath et al, 1988;Schroeder and Cousins, 1990;Sato and Sasaki, 1992;Tsangaris and TzortzatouStathopoulou, 1998;Miles et al, 2000;Nishimura et al, 2000).…”

“…They have a specific binding capacity for heavy metal ions of group II such as zinc, copper or cadmium (Nath et al, 1988;Miles et al, 2000;Nordberg and Nordberg, 2000). To date, four major isoforms have been identified in mammals; the specific functional roles of MT isoforms or molecular interaction are still not precisely known.…”

“…To date, four major isoforms have been identified in mammals; the specific functional roles of MT isoforms or molecular interaction are still not precisely known. As far as we know, MT are involved in many physiological and pathophysiological processes such as the intracellular storage, transport and metabolism of heavy metal ions; they regulate essential trace metal homeostasis and play a protective role in heavy metal detoxification reactions (Miles et al, 2000;Simpkins, 2000). They can protect cells against UV-/ionic radiation (Hansen et al, 1997;Hanada et al, 1998;Reeve et al, 2000) as well as cytotoxic alkylating agents including chemotherapeutics (Chin et al, 1993;Hishikawa et al, 1997;Okazaki et al, 1998;Sunada et al, 2005), modulate oxygen free radicals and nitric oxide and inhibit apoptosis (Tsangaris and Tzortzatou-Stathopoulou, 1998).…”

A robust inducible-repressible promoter greatly facilitates gene knockouts, conditional expression, and overexpression of homologous and heterologous genes in Tetrahymena thermophila

“…Metallothioneins (MTTs) are highly conserved, low molecular weight, cysteine-rich metal-binding proteins whose primary function is unknown, but who are generally considered to play a role in the homeostasis of metals such as zinc and copper and in the detoxification of cadmium (20). The synthesis of many metallothioneins, including those of Tetrahymena pyriformis and T. thermophila, can be induced by heavy metals, such as zinc, copper, and cadmium (21).…”

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

“…31 Metallothionein is expressed in mouse and human skin. [32][33][34] In MT-ret transgenic animals, the c-Ret protein is expressed in the skin, mainly in the inner and outer root sheaths of hair follicles. 35 Highest expression levels are found soon after birth.…”