New insights into the mechanisms of cadmium regulation of mouse metallothionein-I gene expression

Abstract

Mouse MT-I and MT-II gene transcription is induced rapidly by heavy metals (especially Zn & Cd) [1]. Metal response elements (MRE) are essential for this induction, and these elements are present in multiple copies in the proximal promoters of these MT genes. MREs were initially shown to mediate transcriptional response of MT genes to Zn and Cd [2–4], and more recently to oxidative stress (5, 6). The Zn-finger transcription factor MTF-1 (MRE-binding transcription factor-1) binds specifically to MREs and transactivates MT gene expression [7, 8]. The Zn-fingers of MTF-1 are of the Cys2His2 family and we have shown that the DNA-binding activity of MTF-1 is reversibly regulated by Zn interactions with the Zn-finger domain [9]. In contrast with some Zn-finger proteins, including Zn-finger transcription factors, which can bind Zn with pM to nM disassociation constants [10, 11], MTF-1 is regulated by μM concentrations of this metal. Thus, MTF-1 may serve as a sensor for “free” Zn within the cell.