Mechanism of Metallothionein Gene Activation Mediated by Heavy-metal Dependent Transcription Factor MTF-1

Abstract

Transcriptional activation of metallothionein (MT) genes by heavy metals is a valuable system for understanding the functions of MT as well as the cellular response against heavy metals. Although it is now known that heavy metal signals culminating in MT induction converge upon a transcription factor MTF-1, the mechanism underlying the MTF-1 response to heavy metals has not been elucidated. To address this issue, we investigated various aspects of the in vivo response of MTF-1 against heavy metals. Chromatin immunoprecipitation assay showed that heavy metal-dependent DNA binding of MTF-1 is the critical step in vivo. MTF-1 is primarily localized in the nucleus so that heavy metal-dependent nuclear translocation demonstrated by other groups does not seem to be universal and hence may not be critical for activation of MTF-1. In the six Znˆnger motifs, the hallmark of MTF-1, the third and the fourthˆngers are essential for the nuclear localization of MTF-1. Furthermore, allˆngers except the last are important for transcriptional activation function of MTF-1, suggesting their key role for MTF-1 function. Also, a cysteine cluster structure located in the C-terminal region of MTF-1 is critical for transactivating function of MTF-1. These results suggest a central role of the Znnger domain and intramolecular cooperation through a structural change of MTF-1 for its response to heavy metal challenge.

Induction of metallothionein isoforms in cultured bovine aortic endothelial cells exposed to cadmium

“…MTF-1 requires zinc ions to bind to the MRE in the promoter region of MT genes (Radtke et al, 1993;Zhang et al, 2001). As cadmium does not have the ability to bind to MTF-1 (Koizumi et al, 1992;Heuchel et al, 1994), it is considered that free zinc ions released from zinc-binding proteins by cadmium activate MTF-1 (Otsuka et al, 2007). For these reasons, heavy metals such as cadmium and zinc are typical inducers of MT.…”

Transcription Factor MTF-1 Involved in the Cellular Response to Zinc

“…Domain Architecture of Human MTF-1,29) and the Cys Residues Involved in Its Function Numerals indicate amino acid residue numbers starting from the MTF-1 N-terminus. Vertical lines with closed circles indicate Cys residues involved in MTF-1 functions, which are summarized based on previousˆndings 4,32,33).…”