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Dissection of Drosophila MTF-1 reveals a domain for differential target gene activation upon copper overload vs. copper starvation


Günther, V; Waldvogel, D; Nosswitz, M; Georgiev, O; Schaffner, W (2012). Dissection of Drosophila MTF-1 reveals a domain for differential target gene activation upon copper overload vs. copper starvation. International Journal of Biochemistry & Cell Biology, 44(2):404-411.

Abstract

Metal-responsive transcription factor-1 (MTF-1) is a zinc finger protein conserved from mammals to insects. It mediates protection against heavy metal load by activating the expression of metallothionein and other genes. In Drosophila, MTF-1 serves a dual function in that it not only helps to protect against heavy metal load but also induces the expression of Ctr1B, the gene for an intestinal copper importer, upon copper starvation. By dissecting Drosophila MTF-1 function, we have identified determinants for nuclear import and export, and characterized a phosphorylation site mutant (T127A) that differentially affects MTF-1 target genes. Further, by generating a series of fusion proteins with the heterologous DNA binding domain of Gal4 we identified a strong, constitutive activation domain in the central region of MTF-1 (aa 352-540). By contrast, an extended fusion protein that includes MTF-1's C-terminus (aa 352-791) is not active in standard conditions but induced by copper load. The paramount regulatory importance of the C-terminal part, that harbors a cysteine-rich "metallothionein-like" domain, was corroborated by different experiments. Transgenic flies expressing C-terminally truncated MTF-1 variants displayed high constitutive transcription of both, the genes for metallothioneins and the copper importer Ctr1B. The indiscriminate activation of these genes that are normally induced under opposite conditions of copper load and copper starvation manifested itself in a shortened life span, crippled wings, and female sterility.

Metal-responsive transcription factor-1 (MTF-1) is a zinc finger protein conserved from mammals to insects. It mediates protection against heavy metal load by activating the expression of metallothionein and other genes. In Drosophila, MTF-1 serves a dual function in that it not only helps to protect against heavy metal load but also induces the expression of Ctr1B, the gene for an intestinal copper importer, upon copper starvation. By dissecting Drosophila MTF-1 function, we have identified determinants for nuclear import and export, and characterized a phosphorylation site mutant (T127A) that differentially affects MTF-1 target genes. Further, by generating a series of fusion proteins with the heterologous DNA binding domain of Gal4 we identified a strong, constitutive activation domain in the central region of MTF-1 (aa 352-540). By contrast, an extended fusion protein that includes MTF-1's C-terminus (aa 352-791) is not active in standard conditions but induced by copper load. The paramount regulatory importance of the C-terminal part, that harbors a cysteine-rich "metallothionein-like" domain, was corroborated by different experiments. Transgenic flies expressing C-terminally truncated MTF-1 variants displayed high constitutive transcription of both, the genes for metallothioneins and the copper importer Ctr1B. The indiscriminate activation of these genes that are normally induced under opposite conditions of copper load and copper starvation manifested itself in a shortened life span, crippled wings, and female sterility.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2012
Deposited On:09 Jan 2012 14:10
Last Modified:05 Apr 2016 15:15
Publisher:Elsevier
ISSN:1357-2725
Publisher DOI:10.1016/j.biocel.2011.11.016
PubMed ID:22138226
Permanent URL: http://doi.org/10.5167/uzh-53025

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