Metallothionein Expression in Animals: A Physiological Perspective on Function

Abstract

An integration of knowledge concerning regulation of metallothionein expression with research on metallothionein's proposed functions is necessary to delineate how this metalloprotein affects cellular processes, especially zinc metabolism. Metallothionein expression is driven by a number of physiological mediators through several response elements in the metallothionein gene promoter. Cellular accumulation of metallothionein depends on both gene expression and protein degradation. Both depend largely on availability of cellular zinc derived from the dietary zinc supply. Metallothionein expression is related to zinc accumulation in certain organs. Evidence has been produced, which suggests that metallothionein could act in a number of biochemical processes. It may act in zinc trafficking and/or zinc donation to apoproteins, including zinc finger proteins that act in cellular signaling and transcriptional regulation. As a result, metallothionein expression may affect a number of cellular processes including gene expression, apoptosis, proliferation and differentiation. The ability of metallothionein to exchange other metals with zinc in these proteins may explain a role in metal toxicity. Similarly, mobilization of zinc from metallothionein by oxidative stresses may explain its proposed antioxidant function. Apparent good health of metallothionein-deficient mice argues against a critical biological role for metallothionein; however, expression may be critical in times of stress.

Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells

“…Another explanation is that zinc may be mobilized from endogenous intracellular zinc-metallothionein by gallium-generated ROS. It is likely that the latter process is at play since others have shown that zinc can be released from metallothionein under conditions of cellular oxidative stress [22,37,38]. Regardless of the process involved, our present study suggests that an increase in the intracellular zinc pool contributes to the upregulation of MT2A expression in cells exposed to gallium nitrate.…”

“…It is known that changes in the cellular zinc pool and oxidative stress may increase MTF-1 activity [22,23] and we therefore hypothesized that gallium might act through these pathways. In the present investigation, we show that the increase in cellular MT2A in cells exposed to gallium nitrate results from a gallium-induced production of reactive oxygen species (ROS) and is associated with a shift in intracellular zinc pools that are accessible to chelation.…”

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

“…[12][13][14][15] MT is distinctive in having numerous cysteines that participate in metal binding. [12][13][14][15] Part of the normal functioning of MT likely involves zinc homeostasis. 13 MT is also a critical part of the biological response to toxicological stress induced by a variety of metals.…”

“…4,5,10,11 Metallothionein (MT) is a multi-functional, ubiquitously expressed, low-molecular-weight, metal-binding protein. [12][13][14][15] MT is distinctive in having numerous cysteines that participate in metal binding. [12][13][14][15] Part of the normal functioning of MT likely involves zinc homeostasis.…”

“…[12][13][14][15] Part of the normal functioning of MT likely involves zinc homeostasis. 13 MT is also a critical part of the biological response to toxicological stress induced by a variety of metals. 12,14,15 MT synthesis is highly inducible and is markedly elevated in response to exposure to many toxic metals.…”