Metallothioneins in Normal and Cancer Cells

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

Early studies analyzing the expression of MTs in particular organs had already suggested the existence of a tissue-specific repertoire of MT proteins (Chakrabarty and Maiti 1985). MTs were also detected in immune organs, including the spleen, the bone marrow, and the thymus (Savino et al. 1984; Huber and Cousins 1993). In the human thymus, MTs were found to colocalize with thymulin on the cellular level (Savino et al. 1984). The biological activity of thymulin-a metallopeptide known to be one of the main regulators of immune cell development and function (Safieh-Garabedian et al. 2012)-strongly depends on zinc ion binding (Dardenne et al. 1982), which suggests a potential role of MTs as zinc donors in the control of active thymulin secretion. The expression of both the thymic and the bone marrow MT-1 and MT-2 genes has been shown to respond positively to inflammatory stimuli, such as IL-1, and to correlate with increased zinc uptake in these immune organs (Cousins and Leinart 1988). Multiple factors, including metal ions and proinflammatory substances, such as bacterial products (lipopolysaccharide, LPS) and mitogens (concanavalin A, Con A), have been demonstrated to stimulate MT expression in human peripheral blood immune cells, both directly and by inducing the secretion of other inflammatory mediators (Oberbarnscheidt et al. 1988; Vandeghinste et al. 2000). The basal and induced expression of MTs in immune cells has been shown to be dependent on the cell type, with monocytes expressing more MTs than lymphocytes and granulocytes (Harley et al. 1989; Yurkow and DeCoste 1999). In the lymphocytic population, cadmium-induced MT levels determined by a specific antibody and flow cytometry were shown to be higher in CD4+ and CD8+ T cells than in B cells and natural killer (NK) cells (Yurkow and Makhijani 1998). More detailed analyses performed on human peripheral blood lymphocytes have shown the expression of genes of various MT-isoforms, including MT-1A, MT-1E, MT-1F, MT-1G, MT-1H, MT-1X, MT-2A, and MT-3. The presence of MT-1A, MT-1E, MT-1F, MT-1G, MT-1H, MT-1X, MT-1K, and MT-2A has also been confirmed on the protein level (Vandeghinste et al. 2000).