The taste of heavy metals: Gene regulation by MTF-1

Abstract

The metal-responsive transcription factor-1 (MTF-1, also termed MRE-binding transcription factor-1 or metal regulatory transcription factor-1) is a pluripotent transcriptional regulator involved in cellular adaptation to various stress conditions, primarily exposure to heavy metals but also to hypoxia or oxidative stress. MTF-1 is evolutionarily conserved from insects to humans and is the main activator of metallothionein genes, which encode small cysteine-rich proteins that can scavenge toxic heavy metals and free radicals. MTF-1 has been suggested to act as an intracellular metal sensor but evidence for direct metal sensing was scarce. Here we review recent advances in our understanding of MTF-1 regulation with a focus on the mechanism underlying heavy metal responsiveness and transcriptional activation mediated by mammalian or Drosophila MTF-1. This article is part of a Special Issue entitled: Cell Biology of Metals.

The Double Zinc Finger Domain and Adjacent Accessory Domain from the Transcription Factor Loss of Zinc Sensing 1 (Loz1) Are Necessary for DNA Binding and Zinc Sensing

“…Zinc also inhibits Zap1 DNA binding activity (11). In mammals, zinc regulates MTF-1 DNA binding activity, cellular localization, and transactivation domain function (8). The presence of these multiple zinc-responsive domains ensures that the activity of each factor can be precisely controlled by changes in cellular zinc status.…”

“…In eukaryotes, zinc-responsive transcription factors play a primary role in maintaining zinc homeostasis by controlling the expression of genes necessary for zinc transport and/or zinc storage (4). Transcription factors that regulate gene expression in response to zinc levels include Zap1 from Saccharomyces cerevisiae, MTF-1 in mammals and fish, Loz1 in Schizosaccharomyces pombe, and bZip19 and bZip23 in Arabidopsis thaliana (5)(6)(7)(8).…”

Enhanced Oxidative Stress Resistance through Activation of a Zinc Deficiency Transcription Factor inBrachypodium distachyon

“…In yeast, Drosophila spp., and mammals, the zinc deficiency response is controlled by zinc finger transcription factors ZINC-RESPONSIVE ACTIVATOR PROTEIN1 (ZAP; Eide, 2009), Drosophila homolog of METAL-RESPONSIVE TRANSCRIPTION FACTOR1 (dMTF-1; Zhang et al, 2001), and METAL-REGULATORY TRANSCRIPTION FACTOR1 (MTF-1; Günther et al, 2012), respectively. MTF-1 is autoregulated and activated during multiple stresses, including hypoxia and oxidative stress, in addition to zinc deficiency.…”

“…results in decreased resistance to oxidative stress (Higgins et al, 2002;Swindell, 2011). Reciprocally, dietary supplementation of zinc to oxidative stressed cells reverses oxidative stress sensitivity (Ha et al, 2006;Günther et al, 2012). Zinc deficiency increases the level of cellular ROS, resulting in the activation of zinc transporters for increased influx of intracellular zinc (Günther et al, 2012).…”

“…Reciprocally, dietary supplementation of zinc to oxidative stressed cells reverses oxidative stress sensitivity (Ha et al, 2006;Günther et al, 2012). Zinc deficiency increases the level of cellular ROS, resulting in the activation of zinc transporters for increased influx of intracellular zinc (Günther et al, 2012). Though this response also activates glutathione synthesis in animals and plants for detoxification of ROS (Cakmak, 2000;Günther et al, 2012), the precise mechanism for how cells respond to zinc deficiency-mediated oxidative stress is not fully understood.…”