Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1)

doi:10.1016/j.abb.2007.03.019

Archives of Biochemistry and Biophysics

Volume 463, Issue 2, 15 July 2007, Pages 201-210

https://doi.org/10.1016/j.abb.2007.03.019 Get rights and content

Abstract

The regulation of divalent zinc has been observed in a wide range of organisms. Since this metal is an essential nutrient, but also toxic in excess, zinc homeostasis is crucial for normal cellular functioning. The metal-responsive-element-binding transcription factor-1 (MTF-1) is a key regulator of zinc in higher eukaryotes ranging from insects to mammals. MTF-1 controls the expression of metallothioneins (MTs) and a number of other genes directly involved in the intracellular sequestration and transport of zinc. Although the diverse functions of MTF-1 extend well beyond zinc homeostasis to include stress-responses to heavy metal toxicity, oxidative stress, and selected chemical agents, in this review we focus on the recent advances in understanding the mechanisms whereby MTF-1 regulates MT gene expression to protect the cell from fluctuations in environmental zinc. Particular emphasis is devoted to recent studies involving the Cys₂His₂ zinc finger DNA-binding domain of MTF-1, which is an important contributor to the zinc-sensing and metal-dependent transcriptional activation functions of this protein.

Section snippets

Overview of zinc homeostasis

As the second most abundant essential transition metal ion, zinc provides a structural scaffold for many proteins such as zinc fingers, zinc clusters, and nuclear hormone receptors [26], [27], [28]. An equally diverse group of functions are mediated through these metalloproteins, many of which are essential for cellular development and differentiation [29]. Zinc also acts as an activator or co-activator in over 300 human proteins from all six enzyme classes [30].

Dietary zinc deficiency has been

Function of MTs and regulation by MTF-1

The functions of MT proteins in higher eukaryotes include metal homeostasis, heavy metal detoxification, and protection from oxidative stresses [8], [9], [79]. Expression of the mouse MT-I and MT-II genes, for example, is regulated in response to these cellular stresses at the transcriptional level [4], [8], [9], [48]. Evidence for limited stress response regulation of MT-IV, which is expressed in squamous epithelia and reproductive organs [80], has also been reported. In contrast, mouse MT-III

Molecular mechanisms of zinc-sensing and MT zinc-induction by MTF-1

Experimental evidence described above and elsewhere demonstrates that the zinc-sensing mechanism of MTF-1 at least partially involves the six-zinc finger DNA-binding domain (hereafter referred to as F1–F6, Fig. 1b). Elucidating the molecular details of this mechanism, and more precisely, defining the distinct sensing and other finger-specific functions potentially relegated to individual MTF-1 zinc fingers within the DNA-binding domain, has been the focus of a number of research groups since

Co-activators and other MTF-1 domains in cellular stress responses

The above observations do not rule out other regions of MTF-1, or additional factors as contributors to the zinc-sensing and metal-dependent transcriptional activation mechanisms conferred by MTF-1. Moreover, given that other regions of MTF-1 are less conserved than the metalloregulatory DNA-binding domain, some orthologous MTF-1 proteins may be more dependent on other as yet uncharacterized domains for full control of zinc metalloregulation (most of the studies described in the previous

Acknowledgments

We acknowledge support from the National Institutes of Health (R01 ES05704 to G.K.A.) and the University of Missouri Research Board (J.H.L.) for funding of selected studies described in this review. We thank L.S. Feng for assistance in manuscript preparation.

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MinireviewUnderstanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1)

Abstract

Section snippets

Overview of zinc homeostasis

Function of MTs and regulation by MTF-1

Molecular mechanisms of zinc-sensing and MT zinc-induction by MTF-1

Co-activators and other MTF-1 domains in cellular stress responses

Acknowledgments

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Minireview
Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1)