Induction of Metallothionein I by Arsenic via Metal-Activated Transcription Factor 1. Critical Role of C-Terminal Cysteine Residues in Arsenic Sensing

Details

• Personal Author:
  He X ; Ma Q
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Arsenic Cells, Cultured Genetics Inorganic Chemicals Metals Metals, Heavy Occupational Health Safety Zinc Compounds
• Keywords:
  Arsenic-compounds Cell-cultures Genes Heavy-metals Protein-synthesis Proteins Zinc-compounds
• ISSN:
  0021-9258
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  284
• Issue:
  19
• NIOSHTIC Number:
  nn:20035352
• Citation:
  J Biol Chem 2009 May; 285(19):12609-12621
• Contact Point Address:
  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
• Email:
  qam1@cdc.gov
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2) ; Zinc (CAS RN 7440-66-6)
• Federal Fiscal Year:
  2009
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Biological Chemistry
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:40b630f3682f182d3408081eb9432b462b33788947d56f66ce17352aa085208a052a0d2f049bef636af32792f97c7d88561836bca90192a959e7fb3a591e4ddb
• Download URL:
  https://stacks.cdc.gov/view/cdc/187240/cdc_187240_DS1.pdf
• File Type:
  [PDF - 900.88 KB ]