The Difference in Zinc Concentrations Required for Induction among Metallothionein Isoforms Can Be Explained by the Different MTF1 Affinities to MREs in Its Promoter

Metallothioneins (MTs) are cysteine-rich low-molecular-weight proteins that protect cells from heavy metal toxicity. MT1 and MT2 are considered ubiquitously expressed among the MT isoforms ranging from 1 to 4. These MT1 and MT2 transcriptions are regulated by metal regulatory transcription factor 1 (MTF1) binding to the metal response element (MRE) of the promoter, which is upregulated in response to zinc. The functional MT isoforms are MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, MT1X, and MT2A in humans, but these expressions were differently regulated. Here, MT1A was shown to be significantly less upregulated by zinc than MT1E, MT1G, MT1X, and MT2A. The poor responsiveness of the MT1A zinc was suggested to be due to the MRE sequence in the MT1A promoter region having a lower MTF1 binding affinity compared to the other isoforms. MT1A may be induced via pathways other than the MTF1-MRE binding pathway. These findings may help elucidate the differential regulation of MT isoform expression.