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Target gene search for the metal-responsive transcription factor MTF-1.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Lichtlen, Peter Wang, Ying Belser, Thomas Georgiev, Oleg Certa, Ulrich Sack, Ragna Schaffner, Walter |
| Copyright Year | 2001 |
| Abstract | Activation of genes by heavy metals, notably zinc, cadmium and copper, depends on MTF-1, a unique zinc finger transcription factor conserved from insects to human. Knockout of MTF-1 in the mouse results in embryonic lethality due to liver decay, while knockout of its best characterized target genes, the stress-inducible metallothionein genes I and II, is viable, suggesting additional target genes of MTF-1. Here we report on a multi-pronged search for potential target genes of MTF-1, including microarray screening, SABRE selective amplification, a computer search for MREs (DNA-binding sites of MTF-1) and transfection of reporter genes driven by candidate gene promoters. Some new candidate target genes emerged, including those encoding alpha-fetoprotein, the liver-enriched transcription factor C/EBPalpha and tear lipocalin/von Ebner's gland protein, all of which have a role in toxicity/the cell stress response. In contrast, expression of other cell stress-associated genes, such as those for superoxide dismutases, thioredoxin and heat shock proteins, do not appear to be affected by loss of MTF-1. Our experiments have also exposed some problems with target gene searches. First, finding the optimal time window for detecting MTF-1 target genes in a lethal phenotype of rapid liver decay proved problematical: 12.5-day-old mouse embryos (stage E12.5) yielded hardly any differentially expressed genes, whereas at stage 13.0 reduced expression of secretory liver proteins probably reflected the onset of liver decay, i.e. a secondary effect. Likewise, up-regulation of some proliferation-associated genes may also just reflect responses to the concomitant loss of hepatocytes. Another sobering finding concerns gamma-glutamylcysteine synthetase(hc) (gamma-GCS(hc)), which controls synthesis of the antioxidant glutathione and which was previously suggested to be a target gene contributing to the lethal phenotype in MTF-1 knockout mice. gamma-GCS(hc) mRNA is reduced at the onset of liver decay but MTF-1 null mutant embryos manage to maintain a very high glutathione level until shortly before that stage, perhaps in an attempt to compensate for low expression of metallothioneins, which also have a role as antioxidants. |
| File Format | PDF HTM / HTML |
| DOI | 10.1093/nar/29.7.1514 |
| PubMed reference number | 11266553 |
| Journal | Medline |
| Volume Number | 29 |
| Issue Number | 7 |
| Alternate Webpage(s) | https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/nar/29/7/10.1093_nar_29.7.1514/1/291514.pdf?Expires=1491284102&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q&Signature=BNejxU8J3qOcw-ZNrCHrjKJjPgv8DRTYOQqwhlLhbqiRmkjC120ui9-2XSsMjevXvFcxjbT64prNRsdnxD6UFaubF28h0joPGPrn6hSEiS37r2uLZ7iVadGs2mj-Rn41bA1slLS~W317XEvqDkfi4SVv0K4cpAUgiTyX6eU6N8PM65KociSdNl7qkXgEPv~H1uWL~soBYkgkokOsW2B-oLGuTuwiIcz1W0YeF6EqdrnxYY3netIyuajc~RWh3HM9mdBVkRmpL5-ADjKtuR1vuAL7-BsjLWY9Wznujy0~w~QZ2igZFgrf4SAytJLdV8tGO7hdYQpvyr1p9DLop1F7EQ__ |
| Alternate Webpage(s) | https://doi.org/10.1093/nar%2F29.7.1514 |
| Journal | Nucleic acids research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
