Metal‐responsive transcription factor‐1 (MTF‐1) is essential for embryonic liver development and heavy metal detoxification in the adult liver

Abstract

Metal-responsive transcription factor-1 (MTF-1) activates the transcription of metallothionein genes and other target genes in response to heavy metal load and other stresses such as hypoxia and oxidative stress. It also has an essential function during embryogenesis: targeted disruption of Mtf1 in the mouse results in lethal liver degeneration on day 14 of gestation. Here we studied Mtf1 knockout mice at embryonic and adult stages, the latter by means of conditional knockout. Hepatocytes from Mtf1 null mutant and wild-type embryos were taken into culture on day 12.5 of gestation. Both initially appeared normal, but mutant cells were lost within a few days. Furthermore, Mtf1 null hepatocytes were poorly, if at all, rescued by cocultivation with wild-type rat embryo hepatocytes, indicating a cell-autonomous defect. When the Mtf1 gene was excised by Cre recombinase after birth in liver and bone marrow and to a lesser extent in other organs, mice were viable under non-stress conditions but highly susceptible to cadmium toxicity, in support of a role of MTF-1 in coping with heavy metal stress. An additional MTF-1 function was revealed upon analysis of the hematopoietic system in conditional knockout mice where leukocytes, especially lymphocytes, were found to be severely underrepresented. Together, these findings point to a critical role of MTF-1 in embryonic liver formation, heavy metal toxicity, and hematopoiesis.

Effects of non-toxic zinc exposure on human epidermal keratinocytes

“…Although the effects of zinc on intracellular signalling events are not completely known, a positive impact of Zn (II) on cell proliferation might be attributed, at least in part, to the inhibition of phosphatases, leading to augmented protein tyrosine phosphorylation 30 . The proliferation advantage by Zn (II) treatment can also be a consequence of increased calcium uptake 31 or up-regulated gene expression (e.g., NOTCH1, see Table 1) 32,33 . Interestingly, in aged skin, which is characterised by decreased epidermal renewal, the expression of MT is lower 34 .…”

Metal-responsive transcription factor (MTF-1) and heavy metal stress response in Drosophila and mammalian cells: a functional comparison

“…Secondly, it is essential for embryonic liver development; disruption of MTF-1 results in liver degeneration and death in utero at E14 (Gü nes et al, 1998). This requirement is strictly stage-specific, because removal of MTF-1 in the liver of adult mice does not cause lethality; such mice are healthy under standard laboratory conditions but more sensitive to cadmium than wild-type mice (Wang et al, 2004). Finally, MTF-1 contributes to the hypoxic/anoxic induction of the gene encoding placental growth factor (PlGF), an angiogenic protein of the vascular endothelial (A) Structural features of human and Drosophila MTF-1.…”

Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1)

“…Inpp5b encodes a ubiquitously expressed type-II inositol polyphosphate 5-phosphatase (Hellsten et al, 2001), and Mtf-1 encodes a zinc-finger transcription factor that responds to heavy metal exposure and oxidative stress and plays a role in cellular stress responses ). Gene-knockout mice of Inpp5b do not show any prominent phenotype except for infertility in male mice (Hellsten et al, 2001), whereas Mtf-1 -/-mice die in utero due to acute degeneration of hepatocytes (Gunes et al, 1998;Wang et al, 2004). This embryonic lethality suggests Mtf-1 as a plausible candidate because a polymorphism reducing gene function is likely to affect the phenotype.…”