Abstract
A study of factors proposed to affect metallothionein-3 (MT3) function was carried out to elucidate the opaque role MT3 plays in human metalloneurochemistry. Gene expression of Mt2 and Mt3 was examined in tissues extracted from the dentate gyrus of mouse brains and in human neuronal cell cultures. The whole-genome gene expression analysis identified significant variations in the mRNA levels of genes associated with zinc homeostasis, including Mt2 and Mt3. Mt3 was found to be the most differentially expressed gene in the identified groups, pointing to the existence of a factor, not yet identified, that differentially controls Mt3 expression. To examine the expression of the human metallothioneins in neurons, mRNA levels of MT3 and MT2 were compared in BE(2)C and SH-SY5Y cell cultures treated with lead, zinc, cobalt, and lithium. MT2 was highly upregulated by Zn2+ in both cell cultures, while MT3 was not affected, and no other metal had an effect on either MT2 or MT3.
Highlights
Mammalian metallothionein-3 isoform (MT3) is an unusual protein with a puzzling role in neurochemistry [1]
This study focused on gaining a better understanding of MT3 metalloneurochemistry by examining relationships between Mt3/Mt2 and known zinc homeostasis gene expression in mice brains and by comparing how MT3 and MT2 levels in neuronal cell cultures respond to metal ion treatments
The dataset was generated by microarray analysis of the mouse gene complement represented by 60,000 probes on Agilent gene expression arrays and consisted of 21,000 genes that were identified as present based on their hybridization signals above the background
Summary
Mammalian metallothionein-3 isoform (MT3) is an unusual protein with a puzzling role in neurochemistry [1]. It has the hallmarks of a typical mammalian metallothionein and is comprised of 68 amino acids, 20 of which are cysteines. Most mammalian metallothioneins are induced by high levels of zinc by a mechanism initiated by Zn2+ binding to a metal-responsive transcription factor [3]. Because toxic metals such as Cd2+ and Ag+ displace zinc bound to metallothionein, their presence indirectly leads to elevated MT levels. MT3 has been shown to bind to β-actin and facilitate actin polymerization [7]. β-Actin polymerization is involved in cytoskeletal growth, fueling speculation that the neuronal growth inhibitor effects of MT3 could occur via an interaction with β-actin [8]
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