Zinc-induced formation of a co-activator complex containing the zinc-sensing transcription factor MTF-1, p300/CBP and Sp1.

Authors:	Yong Li, Tomoki Kimura, Ryan W Huyck, John H Laity, Glen K Andrews
Language:	ENG.
Date:	6-5-2008
Journal:	Molecular and cellular biology (1098-5549)
Release:	Mol Cell Biol. 5 May 2008
Abstract:	Herein, the mechanisms of transactivation of gene expression by mouse metal-response element binding transcription factor-1 (MTF-1) were investigated. Evidence obtained from co-immunoprecipitation 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 siRNA 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. NMR structural characterization of an isolated protein fragment corresponding to the MTF-1 acidic region demonstrated that it is largely unstructured in the presence and absence of excess stoichiometric amounts of zinc. This suggests that the mechanism of MTF-1 recruiting 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 co-activator complex essential for transactivation MT-I gene expression.
Copyright:	Molecular and cellular biology Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421; and Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110-2499.
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