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Molecular and Cellular Biology, December 2009, p. 6283-6293, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00847-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Metal-Responsive Transcription Factor 1 (MTF-1) Activity Is Regulated by a Nonconventional Nuclear Localization Signal and a Metal-Responsive Transactivation Domain{triangledown} ,{dagger}

Uschi Lindert,1,2 Mirjam Cramer,1 Michael Meuli,1 Oleg Georgiev,1 and Walter Schaffner1*

Institute of Molecular Biology, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland,1 Zurich Ph.D. Program in Molecular Life Sciences, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland2

Received 29 June 2009/ Returned for modification 25 July 2009/ Accepted 12 September 2009

Metal-responsive transcription factor 1 (MTF-1) mediates both basal and heavy metal-induced transcription of metallothionein genes and also regulates other genes involved in the cell stress response and in metal homeostasis. In resting cells, MTF-1 localizes to both the cytoplasm and the nucleus but quantitatively accumulates in the nucleus upon metal load and under other stress conditions. Here we show that within the DNA-binding domain, a region spanning zinc fingers 1 to 3 (amino acids [aa] 137 to 228 in human MTF-1) harbors a nonconventional nuclear localization signal. This protein segment confers constitutive nuclear localization to a cytoplasmic marker protein. The deletion of the three zinc fingers impairs nuclear localization. The export of MTF-1 to the cytoplasm is controlled by a classical nuclear export signal (NES) embedded in the acidic activation domain. We show that this activation domain confers metal inducibility in distinct cell types when fused to a heterologous DNA-binding domain. Furthermore, the cause of a previously described stronger inducibility of human versus mouse MTF-1 could be narrowed down to a 3-aa difference in the NES; "humanizing" mouse MTF-1 at these three positions enhanced its metal inducibility to the level of human MTF-1.

* Corresponding author. Mailing address: Institute of Molecular Biology, University of Zürich, Winterthurer Str. 190, CH-8057 Zürich, Switzerland. Phone: 41 44 635 31 50. Fax: 41 44 635 68 11. E-mail: walter.schaffner{at}molbio.uzh.ch

{triangledown} Published ahead of print on 21 September 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2009, p. 6283-6293, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00847-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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