Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1994 Aug 11;22(15):3167–3173. doi: 10.1093/nar/22.15.3167

Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1.

E Brugnera 1, O Georgiev 1, F Radtke 1, R Heuchel 1, E Baker 1, G R Sutherland 1, W Schaffner 1
PMCID: PMC310292  PMID: 8065932

Abstract

Metallothioneins (MTs) 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 metallothioneins genes is induced by exposure of cells to heavy metals. This induction is mediated by metal-responsive promoter elements (MREs). We have previously cloned the cDNA of an MRE-binding transcription factor (MTF-1) from the mouse. Here we present the human cDNA equivalent of this metal-regulatory factor. Human MTF-1 is a protein of 753 amino acids with 93% amino acid sequence identity to mouse MTF-1 and has an extension of 78 amino acids at the C-terminus without counterpart in the mouse. The factors of both species have the same overall structure including six zinc fingers in the DNA binding domain. We have physically mapped the human MTF-1 gene to human chromosome 1 where it localizes to the short arm in the region 1p32-34, most likely 1p33. Both human and mouse MTF-1 when produced in transfected mammalian cells strongly bind to a consensus MRE of metallothionein promoters. However, human MTF-1 is more effective than the mouse MTF-1 clone in mediating zinc-induced transcription.

Full text

PDF
3173

Images in this article

3170Image
on p.3170
3170Image
on p.3170
3171Image
on p.3171

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Böck A., Forchhammer K., Heider J., Baron C. Selenoprotein synthesis: an expansion of the genetic code. Trends Biochem Sci. 1991 Dec;16(12):463–467. doi: 10.1016/0968-0004(91)90180-4. [DOI] [PubMed] [Google Scholar]
  2. Callen D. F., Baker E., Eyre H. J., Chernos J. E., Bell J. A., Sutherland G. R. Reassessment of two apparent deletions of chromosome 16p to an ins(11;16) and a t(1;16) by chromosome painting. Ann Genet. 1990;33(4):219–221. [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Fried M., Crothers D. M. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis. Nucleic Acids Res. 1981 Dec 11;9(23):6505–6525. doi: 10.1093/nar/9.23.6505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Garner M. M., Revzin A. A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system. Nucleic Acids Res. 1981 Jul 10;9(13):3047–3060. doi: 10.1093/nar/9.13.3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  7. Hamer D. H. Metallothionein. Annu Rev Biochem. 1986;55:913–951. doi: 10.1146/annurev.bi.55.070186.004405. [DOI] [PubMed] [Google Scholar]
  8. Karin M. Metallothioneins: proteins in search of function. Cell. 1985 May;41(1):9–10. doi: 10.1016/0092-8674(85)90051-0. [DOI] [PubMed] [Google Scholar]
  9. Kägi J. H., Kojima Y. Chemistry and biochemistry of metallothionein. Experientia Suppl. 1987;52:25–61. doi: 10.1007/978-3-0348-6784-9_3. [DOI] [PubMed] [Google Scholar]
  10. Lee W., Haslinger A., Karin M., Tjian R. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40. Nature. 1987 Jan 22;325(6102):368–372. doi: 10.1038/325368a0. [DOI] [PubMed] [Google Scholar]
  11. Masters B. A., Kelly E. J., Quaife C. J., Brinster R. L., Palmiter R. D. Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):584–588. doi: 10.1073/pnas.91.2.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. McGinnis W., Levine M. S., Hafen E., Kuroiwa A., Gehring W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. 1984 Mar 29-Apr 4Nature. 308(5958):428–433. doi: 10.1038/308428a0. [DOI] [PubMed] [Google Scholar]
  13. Michalska A. E., Choo K. H. Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8088–8092. doi: 10.1073/pnas.90.17.8088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Palmiter R. D. Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1219–1223. doi: 10.1073/pnas.91.4.1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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. 1993 Apr;12(4):1355–1362. doi: 10.1002/j.1460-2075.1993.tb05780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rastinejad F., Conboy M. J., Rando T. A., Blau H. M. Tumor suppression by RNA from the 3' untranslated region of alpha-tropomyosin. Cell. 1993 Dec 17;75(6):1107–1117. doi: 10.1016/0092-8674(93)90320-p. [DOI] [PubMed] [Google Scholar]
  17. Sailer A., MacDonald N. J., Weissmann C. Cloning and sequencing of the murine homologue of the human splicing factor U2AF65. Nucleic Acids Res. 1992 May 11;20(9):2374–2374. doi: 10.1093/nar/20.9.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Serfling E., Lübbe A., Dorsch-Häsler K., Schaffner W. Metal-dependent SV40 viruses containing inducible enhancers from the upstream region of metallothionein genes. EMBO J. 1985 Dec 30;4(13B):3851–3859. doi: 10.1002/j.1460-2075.1985.tb04157.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Severne Y., Wieland S., Schaffner W., Rusconi S. Metal binding 'finger' structures in the glucocorticoid receptor defined by site-directed mutagenesis. EMBO J. 1988 Aug;7(8):2503–2508. doi: 10.1002/j.1460-2075.1988.tb03097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Uchida Y., Takio K., Titani K., Ihara Y., Tomonaga M. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron. 1991 Aug;7(2):337–347. doi: 10.1016/0896-6273(91)90272-2. [DOI] [PubMed] [Google Scholar]
  23. Westin G., Gerster T., Müller M. M., Schaffner G., Schaffner W. OVEC, a versatile system to study transcription in mammalian cells and cell-free extracts. Nucleic Acids Res. 1987 Sep 11;15(17):6787–6798. doi: 10.1093/nar/15.17.6787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Westin G., Schaffner W. A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J. 1988 Dec 1;7(12):3763–3770. doi: 10.1002/j.1460-2075.1988.tb03260.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Xu L., Rungger D., Georgiev O., Seipel K., Schaffner W. Different potential of cellular and viral activators of transcription revealed in oocytes and early embryos of Xenopus laevis. Biol Chem Hoppe Seyler. 1994 Feb;375(2):105–112. doi: 10.1515/bchm3.1994.375.2.105. [DOI] [PubMed] [Google Scholar]
  26. van der Schroeff J. G., van Leeuwen-Cornelisse I., van Haeringen A., Went L. N. Further evidence for localization of the gene of erythrokeratodermia variabilis. Hum Genet. 1988 Sep;80(1):97–98. doi: 10.1007/BF00451466. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES