Skip to main content
SpringerLink
Log in
Book cover

Metals and Genetics pp 375–390Cite as

Transcriptional Regulation of the Gene Encoding Mouse Metallothionein-3

  • Chapter

  • 288 Accesses

Abstract

Metallothioneins (MTs) are small cysteine-rich proteins that bind transition metal ions such as Cd2+, Zn2+, and Cu+ (metals) (Andrews, 1990; Suzuki et al., 1993; Moffatt and Denizeau, 1997). All vertebrates examined contain two or more distinct MT isoforms which are grouped into four classes, MT-1 through MT-4. MTs have been identified in a wide range of species and are present in various tissues and cell types from yeast to humans. The genes encoding MTs are inducible at the transcriptional level by a wide variety of agents, including metals, hormones, cytokines and reactive oxygen species. Metals are the most general and potent of these inducers. Metal activation of MT gene transcription is dependent on the presence of cfc-acting metal regulatory elements (MREs) which are present in six non-identical copies (MREa through MREf) in the 5′ flanking region of the mouse MT-1gene. The highly conserved MRE core sequence, 5′-TGCRCNC-3′ (R, purine; N, any nucleotide), is necessary and sufficient for induction by metals (Imbert et al., 1990). At least two MREs are required for efficient metal induction and they can be present either in tandem or opposite orientations. In addition, in the mouse MT-1promoter, MREs have different transcriptional efficiencies. MREd is the strongest, MREa and MREc are 50 to 80% weaker, MREb is very weak and MREe and MREf are apparently nonfunctional (Stuart et al., 1985). In addition to MREs, MTgene promoters contain binding sites for the transcription factors Spl, USF/MLTF, AP-1, and AP-2 which contribute to their basal transcriptional efficiency (Imbert et al., 1990).

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Amoureux, M.C., Van Gool, D., Herrero, M.T., Dom, R., Colpaert, EC, and Pauwels, P.J. (1997). Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired. Mol. Chem. Neuropathol. 32, 101–121.

    Article  PubMed  CAS  Google Scholar 

  • Amoureux, M.C., Wurch, T., and Pauwels, P.J. (1995). Expression of human metailothionein-III confers protection against serum-free exposure of stably transfected Chinese hamster ovary CHO-K1 cells. Neurosci. Lett. 201, 61–64.

    Article  PubMed  CAS  Google Scholar 

  • Amoureux, M.C., Wurch, T., and Pauwels, P.J. (1995). Modulation of metallothionein-III mRNA content and growth rate of rat C6-glial cells by transfection with human 5-HT1D receptor genes. Biochem. Biophys. Res. Commun. 214, 639–645.

    Article  PubMed  CAS  Google Scholar 

  • Andrews, G.K. (1990). Regulation of metallothionein gene expression. Prog. Food Nutrition Science 14, 193–258.

    CAS  Google Scholar 

  • Aschner, M., Cherian, M.G., Klaassen, C.D., Palmiter, R.D., Erickson, J.C, and Bush, A.I. (1997). Metallothioneins in brain — The role in physiology and pathology. Toxicol. Appl. Pharmacol. 142, 229–242.

    Article  PubMed  CAS  Google Scholar 

  • Bain, G., Ray, W.J., Yao, M., and Gottlieb, D.I. (1994). From embryonal carcinoma to neurons: the PI9 pathway. Bioessays 16, 343–348.

    Article  PubMed  CAS  Google Scholar 

  • Baskin, F., Li, Y.P., Hersh, L.B., Davis, R.M., and Rosenberg, R.N. (1997). An AP-2 binding sequence within exon 1 of human and porcine choline acetyltransferase genes enhances transcription in neural cells. Neuroscience 76, 821–827.

    Article  PubMed  CAS  Google Scholar 

  • Belloso, E., Hernandez, J., Giralt, M., Kille, R, and Hidalgo, J. (1996). Effect of stress on mouse and rat brain metallothionein I and III mRNA levels. Neuroendocrinology. 64, 430–439.

    Article  PubMed  CAS  Google Scholar 

  • Choudhuri, S., Kramer, K.K., Berman, N.E.J., Dalton, T.P., Andrews, G.K., and Klaassen, C.D. (1995). Constitutive expression of metallothionein genes in mouse brain. Toxicol. Appl. Pharmacol. 131, 144–154.

    Article  PubMed  CAS  Google Scholar 

  • Dalton, T., Pazdernik, T.L., Wagner, J., Samson, F., and Andrews, G.K. (1995). Temporalspatial patterns of expression of metallothionein-I and III and other stress related genes in rat brain after kainic acid-induced seizures. Neurochem. Int. 27, 59–71.

    Article  PubMed  CAS  Google Scholar 

  • Erickson, J.C, Hollopeter, G., Thomas, S.A., Froelick, G.J., and Palmiter, R.D. (1997). Disruption of the metallothionein-III gene in mice: Analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures. J. Neurosci. 17, 1271–1281.

    PubMed  CAS  Google Scholar 

  • Erickson, J.C, Sewell, A.K., Jensen, L.T., Winge, D.R., and Palmiter, R.D. (1994). Enhanced neurotrophic activity in Alzheimer’ disease cortex is not associated with down-regulation of metallothionein-III (GIF). Brain Res. 649, 297–304.

    Article  PubMed  CAS  Google Scholar 

  • Faraonio, R., Moffatt, P., Larochelle, O., St-Arnaud, R., Schipper, H.M., and Séguin, C (1998). Transcriptional activation of the gene encoding metallothionein-3 during neuroectodermal differentiation of P19 mouse embryonal carcinoma cells. Submitted for publication

    Google Scholar 

  • Garcia, M.A., Vazquez, J., Gimenez, C., Valdivieso, F., and Zafra, F. (1996). Transcription factor AP-2 regulates human apolipoprotein E gene expression in astrocytoma cells. J. Neurosci. 16, 7550–7556.

    PubMed  CAS  Google Scholar 

  • Greco, D., Zelimer, E., Zhang, Z., and Lewis, E. (1995). Transcription factor AP-2 regulates expression of the dopamine beta-hydroxylase gene. J. Neurochem. 65, 510–516.

    Article  PubMed  CAS  Google Scholar 

  • Gunes, C., Heuchel, R., Georgiev, O., Muller, K.H., Lichtlen, P., Bluthmann, H., Marino, S., Aguzzi, A., and Schaffiier, W. (1998). Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J. 17, 2846–2854.

    Article  PubMed  CAS  Google Scholar 

  • Hernandez, J., Molinero, A., Campbell, I.L., and Hidalgo, J. (1997). Transgenic expression of interleukin 6 in the central nervous system regulates brain metallothionein-I and-III expression in mice. Mol. Brain Res. 48, 125–131.

    Article  PubMed  CAS  Google Scholar 

  • Heuchel, R., Radtke, E, Georgiev, O., Stark, G., Aguet, M., and Schaffner, W. (1994). The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression. EMBO J. 13, 2870–2875.

    PubMed  CAS  Google Scholar 

  • Hozumi, I., Inuzuka, T., Hiraiwa, M., Uchida, Y., Anezaki, T., Ishiguro, H., Kobayashi, H., Uda, Y., Miyatake, T., and Tsuji, S. (1995). Changes of growth inhibitory factor after stab wounds in rat brain. Brain Res. 688, 143–148.

    Article  PubMed  CAS  Google Scholar 

  • Hozumi, I., Inuzuka, T., Ishiguro, H., Riiraiwa, M., Uchida, Y, and Tsuji, S. (1996). Immunoreactivity of growth inhibitory factor in normal rat brain and after stab wounds-An immunocytochemical study using confocal laser scan microscope. Brain Res. 741, 197–204.

    Article  PubMed  CAS  Google Scholar 

  • Hozumi, I., Inuzuka, T., and Tsuji, S. (1998). Brain injury and growth inhibitory factor (GIF)-a minireview. Neurochem. Res. 23, 319–328.

    Article  PubMed  CAS  Google Scholar 

  • Imagawa, M., Ishikawa, Y, Shimano, H., Osada, S., and Nishihara, T. (1995). CTG triplet repeat in mouse growth inhibitory factor/metallothionein III gene promoter represses the transcriptional activity of the heterologous promoters. J. Biol. Chem. 270, 20898–20900.

    Article  PubMed  CAS  Google Scholar 

  • Imbert, J., Culotta, V.C., Fürst, P., Gedamu, L., and Hamer, D.H. (1990). Regulation of metallothionein gene transcription by metals. Adv. Inorg. Biochem. 8, 139–164.

    PubMed  CAS  Google Scholar 

  • Inuzuka, T., Hozumi, L., Tamura, A., Hiraiwa, M., and Tsuji, S. (1996). Patterns of growth inhibitory factor (GIF) and glial fibrillary acidic protein relative level changes differ following left middle cerebral artery occlusion in rats. Brain Res. 709, 151–153.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi, H., Uchida, Y, Ihara, Y, Nakajima, K., Kohsaka, S., Miyatake, T., and Tsuji, S. (1993). Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system. Mol. Brain Res. 19, 188–194.

    Article  PubMed  CAS  Google Scholar 

  • Kramer, K.K., Liu, J., Choudhuri, S., and Klaassen, C.D. (1996). Induction of metallothionein mRNA and protein in murine astrocyte cultures. Toxicol. Appl. Pharmacol. 136, 94–100.

    Article  PubMed  CAS  Google Scholar 

  • Kramer, K.K., Zoelle, J.T., and Klaassen, C.D. (1996). Induction of metallothionein mRNA and protein in primary murine neuron cultures. Toxicol. Appl. Pharmacol. 141, 1–7.

    PubMed  CAS  Google Scholar 

  • Liang, L., Fu, K., Lee, D.K., Sobieski, R.J., Dalton, T., and Andrews, G.K. (1996). Activation of the complete mouse metallothionein gene locus in the maternal deciduum. Mol. Reprod. Dev. 43, 25–37.

    Article  PubMed  CAS  Google Scholar 

  • Masters, B.A., Quaife, C.J., Erickson, J.C., Kelly, E.J., Froelick, G.J., Zambrowicz, B.P., Brinster, R.L., and Palmiter, R.D. (1994). Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J. Neurosci. 14, 5844–5857.

    PubMed  CAS  Google Scholar 

  • Meier, P., Koedood, M., Philipp, J., Fontana, A., and Mitchell, P.J. (1995). Alternative mRNAs encode multiple isoforms of transcription factor AP-2 during murine embryogenesis. Dev. Biol. 169, 1–14.

    Article  PubMed  CAS  Google Scholar 

  • Moffatt, P. and Denizeau, F. (1997). Metallothionein in physiological and physiopathological processes. Drug Metab. Rev. 29, 261–307.

    Article  PubMed  CAS  Google Scholar 

  • Moffatt, P. and Séguin, C (1998). Expression of the gene encoding metallothionein-3 in the organs of the reproductive system. DNA Cell Biol. 17, 501–510.

    Article  PubMed  CAS  Google Scholar 

  • Palmiter, R.D., Findley, S.D., Whitmore, T.E., and Durnam, D.M. (1992). MT-III, a brain-specific member of the metallothionein gene family. Proc. Natl. Acad. Sci. USA 89, 6333–6337.

    Article  PubMed  CAS  Google Scholar 

  • Philipp, J., Mitchell, P.J., Malipiero, U., and Fontana, A. (1994). Cell type-specific regulation of expression of transcription factor AP-2 in neuroectodermal cells. Dev. Biol. 165, 602–614.

    Article  PubMed  CAS  Google Scholar 

  • Quaife, C.J., Kelly, E.J., Masters, B.A., Brinster, R.L., and Palmiter, R.D. (1998). Ectopic expression of metallothionein-III causes pancreatic acinar cell necrosis in transgenic mice. Toxicol. Appl. Pharmacol. 148, 148–157.

    Article  PubMed  CAS  Google Scholar 

  • Quinn, J.P., Mcallister, J., and Mendelson, S. (1995). Multiple protein complexes, including AP2 and Spl, interact with a specific site within the rat preprotachykinin-A promoter. Bba-Gene. Struct. Express. 1263, 25–34.

    Article  Google Scholar 

  • Radany, E.H., Brenner, M., Besnard, F., Bigornia, V., Bishop, J.M., and Deschepper, CF. (1992). Directed establishment of rat brain cell lines with the phenotypic characteristics of type 1 astrocytes. Proc. Natl. Acad. Sci. USA 89, 6467–6471.

    Article  PubMed  CAS  Google Scholar 

  • Radtke, F., Georgiev, O., Muller, H.P., Brugnera, E., and Schaffner, W. (1995). Functional domains of the heavy metal-responsive transcription regulator MTF-1. Nucleic Acids Res. 23, 2277–2286.

    Article  PubMed  CAS  Google Scholar 

  • Radtke, F., Heuchel, R., Georgiev, O., Hergersberg, M., Gariglio, M., Dembic, Z., and Schaffner, W. (1993). Cloned transcription factor MTF-1 activates the mouse metallothionein-I promoter. EMBO J. 12, 1355–1362.

    PubMed  CAS  Google Scholar 

  • Rudnicki, M.A. and McBumey, M.W. (1987). Cell culture methods and induction of differentiation of embryonal carcinoma cell lines. In: Robertson, EJ. (Ed.) “Teratocarcinomas and embryonic stem cells: a practical approach.” IRL Press, Oxford, pp 19–49.

    Google Scholar 

  • Russo, T., Mogavero, A.R., Ammendola, R., Mesuraca, M., Fiore, F., Fatatis, A., Salvatore, G., and Cimino, F. (1993). Immortalization of a cell line showing some characteristics of the oligodendrocyte phenotype. Neurosci. Lett. 159, 159–162.

    Article  PubMed  CAS  Google Scholar 

  • Sewell, A.K., Jensen, L.T., Erickson, J.C., Palmiter, R.D., and Winge, D.R. (1995). Bioactivity of metallothionein-3 correlates with its novel beta domain sequence rather than metal binding properties. Biochemistry 34, 4740–4747.

    Article  PubMed  CAS  Google Scholar 

  • Smith, C.L. and Hager, G.L. (1997). Trsnscriptional regulation of mammalian genes in vivo. A tale of two templates. J. Biol. Chem. 272, 27493–27496.

    CAS  Google Scholar 

  • Stuart, G.W., Searle, P.F., and Palmiter, R.D. (1985). Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences. Nature 317, 828–831.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki, K.T., Imura, N., and Kimura, M. (Eds.) (1993). “Metallothionein III: Biological roles and medical implications.” Birkauser, Basel.

    Google Scholar 

  • Tang, C.M., Tomkinson, A.E., Lane, W.S., Wold, M.S., and Seto, E. (1996). Replication protein A is a component of a complex that binds the human metallothionein IIA gene transcription start site. J. Biol. Chem. 271, 21637–21644.

    Article  PubMed  CAS  Google Scholar 

  • Tsuji, S., Kobayashi, H., Uchida, Y., Ihara, Y., and Miyatake, T. (1992). Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer’ disease. EMBO J. 11, 4843–4850.

    PubMed  CAS  Google Scholar 

  • Uchida, Y. and Ihara, Y. (1995). The N-terminal portion of growth inhibitory factor is sufficient for biological activity. J. Biol. Chem. 270, 3365–3369.

    Article  PubMed  CAS  Google Scholar 

  • Uchida, Y, Takio, K., Titani, K., Ihara, Y., and Tomonaga, M. (1991). The growth inhibitory factor that is deficient in the Alzheimer’ disease brain is a 68 amino acid metallothionein-like protein. Neuron 7, 337–347.

    Article  PubMed  CAS  Google Scholar 

  • Watabe, M., Gross, S., Lawyer, C., Brewer, G.J., Mashimo, T., and Watabe, K. (1997). Sequence and functional analysis of the 5’-flanking region of the mouse growth inhibitory factor gene. Cell Mol. Neurobiol. 17, 235–243.

    Article  PubMed  CAS  Google Scholar 

  • Westin, G. and Schaffner, W. (1988). A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J. 7, 3763–3770.

    PubMed  CAS  Google Scholar 

  • Yamada, M., Hayashi, S., Hozumi, I., Inuzuka, T., Tsuji, S., and Takahashi, H. (1996). Subcellular localization of growth inhibitory factor in rat brain: Light and electron microscopic immunohistochemical studies. Brain Res. 735, 257–264.

    Article  PubMed  CAS  Google Scholar 

  • Yuguchi, T., Kohmura, E., Sakaki, T., Nonaka, M., Yamada, K., Yamashita, T., Kishiguchi, T., Sakaguchi, T., and Hayakawa, T. (1997). Expression of growth inhibitory factor mRNA after focal ischemia in rat brain. J. Cereb. Blood Flow Metab. 17, 745–752.

    Article  PubMed  CAS  Google Scholar 

  • Yuguchi, T., Kohmura, E., Yamada, K., Sakaki, T., Yamashita, T., Otsuki, H., Wanaka, A., Tohyama, M., Tsuji, S., and Hayakawa, T. (1995). Changes in growth inhibitory factor mRNA expression compared with those in c-jun mRNA expression following facial nerve transection. Mol. Brain Res. 28, 181–185.

    Article  PubMed  CAS  Google Scholar 

  • Zheng, H., Berman, N.E.J., and Klaassen, C.D. (1995). Chemical modulation of metallothionein I and III mRNA in mouse brain. Neurochem. Int. 27, 43–58.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre de Recherche en Cancérologie de l’Université Laval, CHUQ, l’Hôtel-Dieu de Québec, Québec, Canada, G1R 2J6

    R. Faraonio, P. Moffatt, O. LaRochelle & C. Séguin

  2. Shriners Hospital for Children, Genetics Unit Montréal, Québec, Canada, H3G 1A6

    R. Saint-Arnaud

Authors
  1. R. Faraonio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Moffatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. LaRochelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Saint-Arnaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Séguin
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada

    Bibudhendra Sarkar

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Faraonio, R., Moffatt, P., LaRochelle, O., Saint-Arnaud, R., Séguin, C. (1999). Transcriptional Regulation of the Gene Encoding Mouse Metallothionein-3. In: Sarkar, B. (eds) Metals and Genetics. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4723-5_29

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4723-5_29

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7140-3

  • Online ISBN: 978-1-4615-4723-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation