Modulation of Glucocorticoid Signaling and Leukocyte Activation by Transition Metals

Abstract

Metallothioneins (MTs) are low molecular weight (typically less than 10, 000 daltons), cysteine-rich, metal-binding proteins that are found in all eukaryotes, and transcriptionally regulated by a variety of metals, hormones, and developmental signals. They most certainly play a role in resistance to heavy metal toxicity, and have been postulated to mediate several roles important in metal homeostasis in eukaryotes (Kagi and Schaffer, 1988). They are encoded by a family of genes in mammals. Humans possess 16 MT genes linked on chromosome 16 (including MT-1A, MT IB, MT-IE, MT-IF, MT-1G, MT-2A, MT-3, and MT-4)(West et al., 1990). Rodents have only four functional genes (MT-1, MT-2, MT-3 and MT-4) on chromosome 8 (Quaife et al., 1994). Gene sequences are similar among isoforms, and even between species. This allows cross-hybridization of specific probes among species (Hamer, 1986; Koropatnick et al., 1988). MTs are classically induced by a variety of transition metals, but MTs are expressed without metal induction in many different tissues and cell types. Intriguingly, some isoforms are restricted to specific tissues. MT-3 is expressed predominantly in brain and is not metal-inducible (Uchida et al., 1991). MT-4 is restricted to coraified, stratified, squamous epithelium (which provides a protective surface on skin, tongue, the upper part of the alimentary tract, and the vagina) without metal induction (Quaife et al., 1994). MTs are also expressed during retinoic acidinduced differentiation of teratocarcinoma cells in vitro (Hamer, 1986, and Fraser and Koropatnick, manuscript submitted)), during growth and proliferation in a human prostate stem cell line (Koropatnick et al., 1995), in rat kidney undergoing compensatory hypertrophy (Zalups et al., 1995), in proliferating human colonie cancer cells (Nagel and Vallee, 1995), in cells on the proliferative edge of epithelial tumours in situ(Kontozoglou et al., 1989), the proliferating cell compartment of human breast and colon tumours (Meskel et al., 1993), and in human monocytes undergoing a respiratory burst (Leibbrandt and Koropatnick, 1994; Leibbrandt et al., 1994). In rodents and humans, MT expression in visceral yolk sac and liver is developmentally-regulated (Hamer, 1986; Ouellette, 1982; Koropatnick and Duerksen, 1987; Slotkin and Cherian, 1989). Subpopulations of mouse ova and preimplantation embryo cells express high MT levels (Andrews et al., 1991). The intracellular location of MT is dependent upon the stage of tissue development: MT is located in the nuclei of parenchymal cells in fetal and newborn liver, and is primarily cytoplasmic in adult liver (Panemangalore et al., 1983; Nartey et al., 1987; Cherian, 1994). MT isoforms change during differentiation in mice. As inner layer keratinocytes in stratified epithelium differentiate into the outer stratum spinosum, and switch keratin isoform production, they also switch from MT-1 to MT-4 production (Quaife et al., 1994). Cultured embryocarcinoma cells, induced to differentiate by retinoic acid, express MT-1 mRNA and MT protein at increasing levels during differentiation to visceral endoderm (Andrews et al., 1984). Overall, MT is clearly associated with proliferation and hypertrophy, and differentiation and cell activation.