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Molecular and Cellular Biology, July 2008, p. 4275-4284, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00369-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Zinc-Induced Formation of a Coactivator Complex Containing the Zinc-Sensing Transcription Factor MTF-1, p300/CBP, and Sp1 {triangledown}

Yong Li,1 Tomoki Kimura,1,{ddagger} Ryan W. Huyck,2 John H. Laity,2 and Glen K. Andrews1*

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421,1 Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri—Kansas City, Kansas City, Missouri 64110-24992

Received 4 March 2008/ Returned for modification 1 April 2008/ Accepted 24 April 2008

Herein, the mechanisms of transactivation of gene expression by mouse metal response element-binding transcription factor 1 (MTF-1) were investigated. Evidence obtained from coimmunoprecipitation assays revealed that exposure of the cells to zinc resulted in the rapid formation of a multiprotein complex containing MTF-1, the histone acetyltransferase p300/CBP, and the transcription factor Sp1. Down-regulation of endogenous p300 expression by small interfering RNA transfection significantly decreased zinc-dependent metallothionein I (MT-I) gene transcription without altering induction of zinc transporter 1 (ZnT1). MTF-1 independently facilitated the recruitment of Sp1 and p300 to the protein complex in response to zinc. Mutagenesis demonstrated that the acidic domain, one of three transactivation domains of MTF-1, is required for recruitment of p300 but not Sp1 as well as for zinc-dependent activation of MT-I gene transcription. Furthermore, mutation of leucine residues (L->A) within a nuclear exclusion signal in the MTF-1 acidic domain impaired recruitment of p300 and zinc-dependent activation of the MT-I gene. Nuclear magnetic resonance characterization of an isolated protein fragment corresponding to the MTF-1 acidic region demonstrated that this region is largely unstructured in the presence and absence of excess stoichiometric amounts of zinc. This suggests that the mechanism by which MTF-1 recruits p300 to this complex involves extrinsic-zinc-dependent steps. These studies reveal a novel zinc-responsive mechanism requiring an acidic region of MTF-1 that functions as a nuclear exclusion signal as well as participating in formation of a coactivator complex essential for transactivation of MT-I gene expression.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Mail Stop 3030, University of Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, KS 66160-7421. Phone: (913) 588-6935. Fax: (913) 588-3920. E-mail: gandrews{at}kumc.edu

{triangledown} Published ahead of print on 5 May 2008.

{ddagger} Present address: Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.

Molecular and Cellular Biology, July 2008, p. 4275-4284, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00369-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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