PMID- 14998373
OWN - NLM
STAT- MEDLINE
DCOM- 20041104
LR  - 20231213
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 380
IP  - Pt 3
DP  - 2004 Jun 15
TI  - Induction of metallothionein I by phenolic antioxidants requires metal-activated 
      transcription factor 1 (MTF-1) and zinc.
PG  - 695-703
AB  - Phenolic antioxidants, such as tBHQ [2,5-di-(t-butyl)-1,4-hydroquinone], induce 
      Mt1 (metallothionein 1) gene expression and accumulation of MT protein. Induction 
      of Mt1 mRNA does not depend on protein synthesis, and correlates with 
      oxidation-reduction functions of the antioxidants. In the present study, we 
      analysed the biochemical pathway of the induction. Induction depends on the 
      presence of MTF-1 (metal-activated transcription factor 1), a transcription 
      factor that is required for metal-induced transcription of Mt1, but does not 
      require nuclear factor erythroid 2-related factor 2, a tBHQ-activated CNC bZip 
      (cap 'n' collar basic leucine zipper) protein, that is responsible for regulating 
      genes encoding phase II drug-metabolizing enzymes. Moreover, tBHQ induces the 
      expression of MRE-beta Geo, a reporter gene driven by five metal response 
      elements that constitute an optimal MTF-1 binding site. Reconstitution of Mtf1 
      -null cells with MTF-1 restores induction by both zinc and tBHQ. Unlike 
      activation of phase II genes by tBHQ, induction of Mt1 expression does not occur 
      in the presence of EDTA, when cells are cultured in zinc-depleted medium, or in 
      cells with reduced intracellular 'free' zinc due to overexpression of ZnT1, a 
      zinc-efflux transporter, indicating that induction requires zinc. In addition, 
      fluorescence imaging reveals that tBHQ increases cytoplasmic free zinc 
      concentration by mobilizing intracellular zinc pools. These findings establish 
      that phenolic antioxidants activate Mt1 transcription by a zinc-dependent 
      mechanism, which involves MTF-1 binding to metal regulator elements in the Mt1 
      gene promoter.
FAU - Bi, Yongyi
AU  - Bi Y
AD  - 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, Morgantown, WV 26505, USA.
FAU - Palmiter, Richard D
AU  - Palmiter RD
FAU - Wood, Kristi M
AU  - Wood KM
FAU - Ma, Qiang
AU  - Ma Q
LA  - eng
PT  - Journal Article
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Antioxidants)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Hydroquinones)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 9038-94-2 (Metallothionein)
RN  - C12674942B (2-tert-butylhydroquinone)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Carcinoma, Hepatocellular/chemistry/pathology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cricetinae
MH  - DNA-Binding Proteins/deficiency/physiology
MH  - Embryo, Mammalian/cytology
MH  - Fibroblasts/chemistry
MH  - Hydroquinones/*metabolism
MH  - Kidney/cytology
MH  - Liver Neoplasms, Experimental/chemistry/pathology
MH  - Metallothionein/*biosynthesis/metabolism
MH  - Mice
MH  - NF-E2-Related Factor 2
MH  - Oxidation-Reduction
MH  - RNA, Messenger/biosynthesis
MH  - Trans-Activators/deficiency/physiology
MH  - Transcription Factors/deficiency/*physiology
MH  - Transcription, Genetic/*physiology
MH  - Zinc/metabolism/*physiology
MH  - Transcription Factor MTF-1
PMC - PMC1224208
EDAT- 2004/03/05 05:00
MHDA- 2004/11/05 09:00
PMCR- 2004/12/15
CRDT- 2004/03/05 05:00
PHST- 2004/03/03 00:00 [accepted]
PHST- 2004/03/02 00:00 [revised]
PHST- 2003/11/04 00:00 [received]
PHST- 2004/03/05 05:00 [pubmed]
PHST- 2004/11/05 09:00 [medline]
PHST- 2004/03/05 05:00 [entrez]
PHST- 2004/12/15 00:00 [pmc-release]
AID - BJ20031677 [pii]
AID - 10.1042/BJ20031677 [doi]
PST - ppublish
SO  - Biochem J. 2004 Jun 15;380(Pt 3):695-703. doi: 10.1042/BJ20031677.