Influence of metallothionein-1 localisation on its function

M. Levadoux-Martin, J. E. Hesketh, J. H. Beattie, Heather Mann Wallace

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Metallothioneins (MTs) have a major role to play in metal metabolism, and may also protect DNA against oxidative damage. MT protein has been found localized in the nucleus during S-phase. The mRNA encoding the MT-1 isoform has a perinuclear localization, and is associated with the cytoskeleton; this targeting, due to signals within the 3'-untranslated region (3'-UTR), facilitates nuclear localization of MT-I during S-phase [Levadoux, Mahon, Beattie, Wallace and Hesketh (1999) J. Biol. Chem. 274, 34961-34966]. Using cells transfected with MT gene constructs differing in their 3'-UTRs, the role of MT protein in the nucleus has been studied. Chinese hamster ovary cells were transfected with either the full MT gene (MTMT cells) or with the MT 5'-UTR and coding region linked to the 3'-UTR of glutathione peroxidase (MTGSH cells). Cell survival following exposure to oxidative stress and chemical agents was higher in cells expressing the native MT gene than in cells where MT localization was disrupted, or in untransfected cells. Also, MTMT cells showed less DNA damage than MTGSH cells in response to either hydrogen peroxide or mutagen. After exposure to UV light or mutagen, MTMT cells showed less apoptosis than MTCSH cells, as assessed by DNA fragmentation and flow cytometry. The data indicate that the perinuclear localization of MT mRNA is important for the function of MT in a protective role against DNA damage and apoptosis induced by external stress.

Original languageEnglish
Pages (from-to)473-479
Number of pages6
JournalBiochemical Journal
Volume355
DOIs
Publication statusPublished - 2001

Keywords

  • apoptosis
  • DNA damage
  • mRNA localization
  • nuclear localization
  • oxidative stress
  • CYTOSKELETAL-BOUND POLYSOMES
  • MESSENGER-RNAS
  • 3'-UNTRANSLATED REGION
  • C-MYC
  • PERINUCLEAR CYTOPLASM
  • THYMOCYTE APOPTOSIS
  • STRAND BREAKS
  • PROTEINS
  • SIGNAL
  • CELLS

Cite this

Influence of metallothionein-1 localisation on its function. / Levadoux-Martin, M.; Hesketh, J. E.; Beattie, J. H.; Wallace, Heather Mann.

In: Biochemical Journal, Vol. 355, 2001, p. 473-479.

Research output: Contribution to journalArticle

Levadoux-Martin, M. ; Hesketh, J. E. ; Beattie, J. H. ; Wallace, Heather Mann. / Influence of metallothionein-1 localisation on its function. In: Biochemical Journal. 2001 ; Vol. 355. pp. 473-479.
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AB - Metallothioneins (MTs) have a major role to play in metal metabolism, and may also protect DNA against oxidative damage. MT protein has been found localized in the nucleus during S-phase. The mRNA encoding the MT-1 isoform has a perinuclear localization, and is associated with the cytoskeleton; this targeting, due to signals within the 3'-untranslated region (3'-UTR), facilitates nuclear localization of MT-I during S-phase [Levadoux, Mahon, Beattie, Wallace and Hesketh (1999) J. Biol. Chem. 274, 34961-34966]. Using cells transfected with MT gene constructs differing in their 3'-UTRs, the role of MT protein in the nucleus has been studied. Chinese hamster ovary cells were transfected with either the full MT gene (MTMT cells) or with the MT 5'-UTR and coding region linked to the 3'-UTR of glutathione peroxidase (MTGSH cells). Cell survival following exposure to oxidative stress and chemical agents was higher in cells expressing the native MT gene than in cells where MT localization was disrupted, or in untransfected cells. Also, MTMT cells showed less DNA damage than MTGSH cells in response to either hydrogen peroxide or mutagen. After exposure to UV light or mutagen, MTMT cells showed less apoptosis than MTCSH cells, as assessed by DNA fragmentation and flow cytometry. The data indicate that the perinuclear localization of MT mRNA is important for the function of MT in a protective role against DNA damage and apoptosis induced by external stress.

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