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Induction of metallothionein I by arsenic via metal-activated transcription factor 1. Critical role of c-terminal cysteine residues in arsenic sensing.

Authors
He-X; Ma-Q
Source
J Biol Chem 2009 May; 285(19):12609-12621
NIOSHTIC No.
20035352
Abstract
Metal-activated transcription factor 1 (MTF1) mediates the induction of metallothioneins I and II by zinc and stress signals. The mechanism of MTF1 activation has not been well understood. We analyzed the interaction between arsenic (As(3+)) and MTF1 for Mt1 induction. As(3+) potently induces Mt1 mRNA expression in mouse hepa1c1c7 cells. Induction is dependent upon functional MTF1 as induction is lost in Mtf1 knockout cells but is restored upon reconstitution with Mtf1; moreover, As(3+) induces the binding of MTF1 to the metal response elements of endogenous Mt1. Induction is not affected by modulating zinc concentrations but is markedly enhanced by cycloheximide. Phenylarsine oxide (PAO), which covalently binds to vicinal protein cysteine thiol groups, induces Mt1 with a magnitude of higher potency than that of As(3+). PAO affinity beads effectively pulls down the carboxyl half of MTF1 (MTF1(321-675)) by binding to a cluster of five cysteine residues near the terminus. Preincubation with As(3+), Cd(2+), Co(2+), Ni(2+), Ag(+), Hg(2+), and Bi(3+) blocks pulldown of MTF1(321-675) by PAO beads in vitro and in vivo, indicating that binding of the metal inducers to the same C-terminal cysteine cluster as PAO occurs. Deletion of the C-terminal cysteine cluster or mutation of the cysteine residues abolishes or markedly reduces the transcription activation activity of MTF1 and the ability of MTF1 to restore Mt1 induction in Mtf1 knockout cells. The findings demonstrate a critical role of the C-terminal cysteine cluster of MTF1 in arsenic sensing and gene transcription via arsenic-cysteine thiol interaction.
Keywords
Protein-synthesis; Heavy-metals; Metals; Genes; Cell-cultures; Proteins; Arsenic-compounds; Zinc-compounds
Contact
Qiang Ma, Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Rd., Morgantown, WV 265
CODEN
JBCHA3
CAS No.
7440-38-2; 7440-66-6
Publication Date
20090508
Document Type
Journal Article
Email Address
qam1@cdc.gov
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Issue of Publication
19
ISSN
0021-9258
NIOSH Division
HELD
Source Name
Journal of Biological Chemistry
State
WV
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