Metallothioneins in Normal and Cancer Cells

Piotr Dziegiel, Bartosz Pula, Christopher Kobierzycki, Mariusz Stasiolek, Marzenna Podhorska-Okolow

Numerous studies on the MT-1 and MT-2 proteins are currently under way, but the MT-3 isoform, first described about 20 years ago by Uchida et al. as a neuronal growth-inhibitory factor (GIF), still raises many questions (Uchida et al. 1991). The original name was derived from the initially discovered functions of this protein, i.e., its strong ability to impair neurite overgrowth and neural survival of cultured neurons. Further studies on the structure and function of GIF showed a 70 % amino acid similarity to proteins of the MT family, which allowed it to be given its final name of MT-3 (Palmiter et al. 1992). MT-3 consists of 68 amino acids containing 20 cysteine residues in conserved positions with two inserts: an acidic hexapeptide in the C-terminal region and a threonin at position 5. Moreover, the conserved Cys-Pro-Cys-Pro motif between positions 6 and 9 is unique to MT-3 (Uchida et al. 1991; Romero-Isart and Vasak 2002; West et al. 2008). Primarily in physiological conditions, abundant MT-3 expression has been observed in fibrous and protoplasmic cortical astrocytes (Aschner 1996a, b). Subsequently, its expression on the mRNA and protein levels was disclosed in peripheral organs outside the brain, suggesting functions other than neurite-growth inhibition (Hozumi et al. 2008). Nevertheless, studies on the functions of the MT-3 in the nervous system dominate in the literature. Its mRNA and protein upregulation have often been observed following brain injury caused by various factors, whereas its downregulation has been observed in neurodegenerative conditions, such as Alzheimer's disease (AD). These findings directly suggest the strong involvement of MT-3 in central nervous system (CNS) repair (Chung et al. 2002; Lee et al. 2011; Manso et al. 2012; Luo et al. 2013). MT-3 shares several biological and chemical properties with other MT isoforms, mainly associated with their structure, e.g., the sequestration, distribution, and detoxification of metal ions. However, there are also very distinct chemical features that might be relevant to the particular biological functions of MT-3, such as its neuromodulation of catecholaminergic, glutamatergic, and GABAergic transmission in the nervous system (Frederickson and Moncrieff 1994).