Activation of gene expression by metal-responsive signal transduction pathways

Timothy K. Adams, Nurten Saydam, Florian Steiner, Walter Schaffner, Jonathan H. Freedman

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Metallothioneins are small, cysteine-rich, metal-binding proteins that play important roles in maintaining intracelluar 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 signalling 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.

Original languageEnglish (US)
Pages (from-to)813-817
Number of pages5
JournalEnvironmental health perspectives
Volume110
Issue numberSUPPL. 5
DOIs
StatePublished - Oct 2002

Keywords

  • Cadmium
  • Casein kinase II
  • MTF-1
  • Metallothionein
  • Metals
  • Phosphorylation
  • Protein kinase C
  • Signal transduction
  • Transcription
  • Zinc

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