HGNC Approved Gene Symbol: MTF1
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:37,809,574-37,859,592 (from NCBI)
The metallothioneins are small cysteine-rich proteins that bind heavy metal ions such as zinc, cadmium, and copper with high affinity, and have been functionally implicated in heavy metal detoxification and radical scavenging. Transcription of metallothionein genes is induced by exposure of cells to heavy metals. This induction is mediated by metal-responsive promoter elements (MREs). Westin and Schaffner (1988) and Radtke et al. (1993) cloned a mouse transcription factor, designated Mtf-1, that binds to these metal-responsive promoter elements. Brugnera et al. (1994) cloned the human counterpart of the mouse gene. The human protein has 753 amino acids with 93% amino acid sequence identity to the mouse protein and has an extension of 78 amino acids at the C terminus without counterpart in the mouse. In the 2 species the factor has the same overall structure, including 6 zinc fingers in the DNA binding domain.
Brugnera et al. (1994) found that, in transfected cells, the human MTF1 gene mediated a more pronounced metal response of a reporter gene than did the mouse factor, indicating that it is critically involved in zinc induction of metallothionein genes.
Selvaraj et al. (2005) found that copper depletion in Drosophila resulted in Mtf1-mediated activation of Ctr1b, which encodes a copper importer. Activation depended on the same type of upstream MRE motifs as are normally required for metal induction during copper toxicity.
By knockout analysis in HEK293A cells, Han et al. (2022) showed that the Hippo pathway played a negative role in protecting cells from heavy metal toxicity. The Hippo pathway controlled heavy metal response gene transcription, but the process was independent of its classic downstream effectors YAP (YAP1; 606608) and TAZ (WWTR1; 607392). Instead, the Hippo pathway regulated the heavy metal response via the transcription factor MTF1, and MTF1 regulated a Hippo pathway downstream transcription program distinct from the YAP/TAZ-TEAD complex-regulated transcription program. MTF1 transcriptional activity was inhibited by LATS1 and LATS2, which inhibited association of MTF1 with the promoters of heavy metal response genes. LATS1 kinase activity was required to inhibit MTF1, because LATS1 bound and phosphorylated MTF1 at ser152, leading to inhibition of MTF1-mediated transcriptional activity and heavy metal response. Analysis with Hippo signaling inhibitors revealed heavy metal detoxification in mice in vivo and confirmed the negative role of LATS in regulating heavy metal response in vitro. Hippo signaling was also found to control heavy metal response in Drosophila, indicating evolutionarily conserved regulation of MTF1 and heavy metal response by the Hippo pathway. Cd and Zn treatment inhibited the Hippo pathway by specifically inhibiting LATS. Cd and Zn interacted directly with LATS1 and LATS2, and truncation analysis showed that Zn bound directly to the LATS1 C3 region containing a hydrophobic motif. Zn binding had dual-inhibitory effects on LATS, as it inhibited LATS intrinsic kinase activity and hydrophobic motif phosphorylation. Further analysis indicated that the Hippo-MTF1 axis also acted in response to other heavy metals.
By fluorescence in situ hybridization, Brugnera et al. (1994) mapped the MTF1 gene to 1p34-p32, with 1p33 as the most likely location.
Gunes et al. (1998) generated mice deficient in MTF1 by targeted disruption. Embryos lacking MTF1 died in utero at approximately day 14 of gestation. They showed impaired development of hepatocytes and, at later stages, liver decay and generalized edema. Mtf1 -/- embryos failed to transcribe metallothionein I and II genes, and also showed diminished transcripts of the gene which encodes the heavy-chain subunit of the gamma-glutamylcysteine synthetase, a key enzyme for glutathione biosynthesis. Metallothionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermediates. Accordingly, primary mouse embryo fibroblasts lacking MTF1 show increased susceptibility to the cytotoxic effects of cadmium or hydrogen peroxide. Thus, Gunes et al. (1998) concluded that MTF1 may help to control metal homeostasis and probably cellular redox state, especially during liver development. They also noted that the Mtf1-null mutant phenotype bears some similarity to those of 2 other regulators of cellular stress response, namely c-jun and NF-kappa-B (NFKB3; 164014).
Brugnera, E., Georgiev, O., Radtke, F., Heuchel, R., Baker, E., Sutherland, G. R., Schaffner, W. Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1. Nucleic Acids Res. 22: 3167-3173, 1994. [PubMed: 8065932] [Full Text: https://doi.org/10.1093/nar/22.15.3167]
Gunes, C., Heuchel, R., Georgiev, O., Muller, K.-H., Lichtlen, P., Bluthmann, H., Marino, S., Aguzzi, A., Schaffner, W. Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J. 17: 2846-2854, 1998. [PubMed: 9582278] [Full Text: https://doi.org/10.1093/emboj/17.10.2846]
Han, H., Nakaoka, H. J., Hofmann, L., Zhou, J. J., Yu, C., Zeng, L., Nan, J., Seo, G., Vargas, R. E., Yang, B., Qi, R., Bardwell, L., Fishman, D. A., Cho, K. W. Y., Huang, L., Luo, R., Warrior, R., Wang, W. The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1. Nature Cell Biol. 24: 74-87, 2022. [PubMed: 35027733] [Full Text: https://doi.org/10.1038/s41556-021-00813-8]
Radtke, F., Heuchel, R., Georgiev, O., Hergersberg, M., Gariglio, M., Dembic, Z., Schaffner, W. Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter. EMBO J. 12: 1355-1362, 1993. [PubMed: 8467794] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05780.x]
Selvaraj, A., Balamurugan, K., Yepiskoposyan, H., Zhou, H., Egli, D., Georgiev, O., Thiele, D. J., Schaffner, W. Metal-responsive transcription factor (MTF-1) handles both extremes, copper load and copper starvation, by activating different genes. Genes Dev. 19: 891-896, 2005. [PubMed: 15833915] [Full Text: https://doi.org/10.1101/gad.1301805]
Westin, W., Schaffner, W. A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J. 7: 3763-3770, 1988. [PubMed: 3208749] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03260.x]