Individual Metal Responsive Elements of the Human Metallothionein-IIA Gene Independently Mediate Responses to Various Heavy Metal Signals

Metallothioneins (MTs) are small metal-binding proteins that have a role in the defense against heavy metals. Mammalian MT genes are transcriptionally activated by metals such as Cd and Zn through multiple copies of the metal responsive element (MRE) present in the 5'-flanking region. To examine whether each MRE in a single promoter has a distinct role, we characterized seven MREs located upstream of the human MT-IIA gene. By transient transfection experiments using MRE-driven reporter gene constructs, individual MREs were assayed for the activity to mediate transcription in response to several heavy metal species. Four MREs including MREs a, b, e and g independently mediated reporter gene expression in response to Zn, Cd and Hg, while other MREs were not responsive to any of these metals. These results suggest that the multiplicity of MRE contributes to enhancing its activity, rather than providing functional diversity.