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 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.
Adams
Timothy K
TK
Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC 27708-0328, USA.
Saydam
Nurten
N
Steiner
Florian
F
Schaffner
Walter
W
Freedman
Jonathan H
JH
D000818:Animals; D019556:COS Cells; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008668:Metallothionein / Q000378:metabolism*; D019216:Metals, Heavy / Q000009:adverse effects / Q000494:pharmacology*; D010766:Phosphorylation; D010957:Plasmids; D011494:Protein Kinases; D015398:Signal Transduction; D014157:Transcription Factors / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000097809:Transcription Factor MTF-1
D017868:Cyclic AMP-Dependent Protein Kinases; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D008668:Metallothionein; D019216:Metals, Heavy; D011494:Protein Kinases; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1