Induction of transcription by occupational heavy metals through the metal-activated transcription factor 1 is regulated by a labile repressor. Superinduction of metallothionein 1 by cyclohexmide.
Bi-Y; Lin-GX; Millecchia-L; Ma-Q
FASEB J 2006 Mar; 20(5):A1341
Induction of metallothioneins (MTs) through the metal-activated transcripton factor-1 (MTF-1) provides a model response for analyzing transcriptional gene regulation by heavy metals. We report inhibition of protein synthesis by cycloheximide (CHX) increases induction of Mtl by approximately 5 fold. Characterization of superinduction reveals it is time and conncentration-dependent of CHX, requires the presence of an Mt1 inducer, and occurs at a transcriptional level, suggesting a labile repressor in the control of Mt1 induction. Genetic analyses show that superinduction of Mt1 is mediated through MTF-1 and MRE-dependent transcription. Analyses by inductively coupled plasma emission spectroscopy and fluorescence imaging demonstrate that treatment with CHX alone or CHX plus an inducer does not increase the total zinc accumulation or the concentration of free zinc in cells. Moreover, superinduction is observed in cells cultured in a zinc-depleted medium, suggesting that superinduction does not involve elevation of intracellular zinc concentration. Finally, inhibition of the ubiquitin-26S proteasome mediated protein turnover by MGl32 superinduces Mtl similarly to CHX, implicating the 26S proteasome pathway in the superinduction of Mt1. We propose that a labile repressor negatively controls Mtl induction through a 26S proteasome-dependent pathway.
Metals; Heavy-metals; Protein-synthesis; Genetic-factors; Zinc-compounds; Metal-compounds
Abstract; Conference/Symposia Proceedings
The FASEB Journal