Activation of Gene Expression by Metal-Responsive Signal Transduction Pathways

Metallothioneins are small, cysteine-rich, metal-binding proteins that play important roles in maintaining intracellular metal homeostasis and in transition metal detoxification. MTF-1 (metal transcription factor-1) plays a central role in regulating the metal-inducible, transcriptional activation o...

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Bibliographic Details
Published in:Environmental health perspectives 2002-10, Vol.110 (suppl 5), p.813-817
Main Authors: Adams, Timothy K., Saydam, Nurten, Steiner, Florian, Schaffner, Walter, Freedman, Jonathan H.
Format: Article
Language:English
Subjects:
Animals
Cadmium
COS Cells
Cyclic AMP-Dependent Protein Kinases - pharmacology
DNA Adducts
DNA-Binding Proteins
Gene expression
HEK293 cells
HeLa Cells
Homeostasis
Humans
Metallothionein - metabolism
Metals, Heavy - adverse effects
Metals, Heavy - pharmacology
Oxidative stress
Phosphorylation
Plasmids
Protein Kinases
Signal Transduction
Signal Transduction and Effects on Gene Expression
Transcription Factor MTF-1
Transcription factors
Transcription Factors - pharmacology
Transcription, Genetic - drug effects
Zinc
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Summary:Metallothioneins are small, cysteine-rich, metal-binding proteins that play important roles in maintaining intracellular metal homeostasis and in transition metal detoxification. MTF-1 (metal transcription factor-1) plays a central role in regulating the metal-inducible, transcriptional activation of metallothionein. Here we report that the phosphorylation of MTF-1 plays a critical role in the activation of MTF-1/metal-responsive element-mediated transcription. Inhibitor studies indicate that signal transduction cascades, including those mediated by protein kinase C, tyrosine kinase, and casein kinase II, are essential for zinc- and cadmium-inducible transcription. In addition, calcium signaling is also involved in regulating transcription. In contrast, cAMP-dependent protein kinase may not be directly involved in the metal response. Contrary to what has been reported for other transcription factors, the inhibition of transcriptional activation does not impair the binding of MTF-1 to DNA, suggesting that phosphorylation is not regulating DNA binding. Elevated phosphorylation of MTF-1 is observed under conditions of protein kinase C inhibition, suggesting that dephosphorylation of this transcription factor mediates its activation.
ISSN:0091-6765
1552-9924
DOI:10.1289/ehp.02110s5813