Cadmium‐induced gene expression is regulated by MTF‐1, a key metal‐responsive transcription factor

Abstract

The transition metal cadmium is a serious occupational and environmental toxin. To inhibit cadmium‐induced damage, cells respond by increasing the expression of genes that encode stress‐responsive proteins. The metal‐regulatory transcription factor 1 (MTF‐1) is a key regulator of heavy‐metal induced transcription of metallothionein‐I and II and other genes in mammals and other metazoans. Transcriptional activation of genes by MTF‐1 is mediated through binding to metal‐responsive elements in the target gene promoters. Phosphorylation of MTF‐1 plays a critical role in the cadmium‐inducible transcriptional activation of metallothionein and other responses. Studies using inhibitors indicate that multiple kinases and signal transduction cascades, including those mediated by protein kinase C, tyrosine kinase and casein kinase II, are essential for cadmium‐mediated transcriptional activation. In addition, calcium signaling is also involved in regulating metal‐activated transcription. In several species, cadmium induces heat shock genes. Recently much progress has been made in elucidating the cellular machinery that regulates this metal‐inducible gene expression. This review summarizes these recent advances in understanding the role of some known cadmium‐responsive genes and the molecular mechanisms that activate metal‐responsive transcription factor, MTF‐1.