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J. Biol. Chem., Vol. 283, Issue 13, 8190-8201, March 28, 2008

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Nuclear Factor-1 and Metal Transcription Factor-1 Synergistically Activate the Mouse Metallothionein-1 Gene in Response to Metal Ions^*

From the Centre de recherche en cancérologie de l'Université Laval, CHUQ, Hôtel-Dieu de Québec, Québec G1R 2J6 and the Département d'anatomie et de physiologie, Facultédemédecine, Université Laval, Québec G1K 7P4, Canada

Metal activation of metallothionein (MT) gene transcription is dependent on the presence of metal regulatory elements (MREs), which are present in five non-identical copies (MREa through MREe) in the promoter of the mouse MT-1 gene and on the capacity of metal transcription factor-1 (MTF-1) to bind to the MREs in the presence of zinc. We detected a protein, distinct from MTF-1, specifically binding to the MREc region. DNA binding competition experiments using synthetic oligonucleotides and specific anti-NF1 antibodies showed that this protein binds to an NF1 site overlapping the MREc element as well as to a second site upstream of the Sp1a site and corresponds to NF1 or a related protein. Transfection experiments showed that loss of the two NF1 sites decreased metal-induced MT promoter activity by 55–70% in transiently transfected cells and almost completely abrogated metal and tert-butylhydroquinone (tBHQ) induction in stably transfected cells. Similarly, expression of an inactive NF1 protein strongly inhibited MT-1 promoter activity. Using synthetic promoters containing NF1 and MRE sites fused to a minimal MT promoter, we showed that these NF1 sites did not confer metal induction but enhanced metal-induced promoter activity. Chromatin immunoprecipitation assays confirmed that NF1 binds to the mouse MT-1 promoter in vivo and showed that NF1 binding is zinc-inducible. In addition, zinc-induced NF1 DNA binding was MTF-1-dependent. Taken together, these studies show that NF1 acts synergistically with MTF-1 to activate the mouse MT-1 promoter in response to metal ions and tert-butylhydroquinone and contributes to maximal activation of the gene.

Received for publication, January 24, 2008

^* This work was supported by a grant from the Conseil de recherches en sciences naturelles et en génie du Canada (to C. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Département de Biochimie, Facultédemédecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.

² To whom correspondence should be addressed: Centre de recherche en cancérologie, Hôtel-Dieu de Québec, 11 côte du Palais, Québec G1R 2J6, Canada. Tel.: 418-525-4444 (ext. 15544); Fax: 418-691-5439; E-mail: carl.seguin{at}crhdq.ulaval.ca.

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