Transcriptional activation of metalloid tolerance genes in Saccharomyces cerevisiae requires the AP-1-like proteins Yap1p and Yap8p

Mol Biol Cell. 2004 May;15(5):2049-60. doi: 10.1091/mbc.e03-04-0236. Epub 2004 Feb 20.

Abstract

All organisms are equipped with systems for detoxification of the metalloids arsenic and antimony. Here, we show that two parallel pathways involving the AP-1-like proteins Yap1p and Yap8p are required for acquisition of metalloid tolerance in the budding yeast S. cerevisiae. Yap8p is demonstrated to reside in the nucleus where it mediates enhanced expression of the arsenic detoxification genes ACR2 and ACR3. Using chromatin immunoprecipitation assays, we show that Yap8p is associated with the ACR3 promoter in untreated as well as arsenic-exposed cells. Like for Yap1p, specific cysteine residues are critical for Yap8p function. We further show that metalloid exposure triggers nuclear accumulation of Yap1p and stimulates expression of antioxidant genes. Yap1p mutants that are unable to accumulate in the nucleus during H(2)O(2) treatment showed nearly normal nuclear retention in response to metalloid exposure. Thus, our data are the first to demonstrate that Yap1p is being regulated by metalloid stress and to indicate that this activation of Yap1p operates in a manner distinct from stress caused by chemical oxidants. We conclude that Yap1p and Yap8p mediate tolerance by controlling separate subsets of detoxification genes and propose that the two AP-1-like proteins respond to metalloids through distinct mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimony / pharmacology*
  • Arsenate Reductases
  • Arsenic / pharmacology*
  • Arsenite Transporting ATPases
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors
  • Binding Sites
  • Cell Nucleus / ultrastructure
  • Cysteine / genetics
  • Cysteine / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Fungal
  • Gene Expression Regulation, Fungal
  • Hydrogen Peroxide / pharmacology
  • Ion Pumps / genetics
  • Ion Pumps / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins
  • Models, Genetic
  • Molecular Sequence Data
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Oxidative Stress / drug effects
  • Response Elements / genetics
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology*
  • Thioredoxin-Disulfide Reductase / genetics
  • Thioredoxin-Disulfide Reductase / metabolism
  • Thioredoxins / genetics
  • Thioredoxins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation*

Substances

  • ACR3 protein, S cerevisiae
  • ARR1 protein, S cerevisiae
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Ion Pumps
  • Membrane Proteins
  • Membrane Transport Proteins
  • Multienzyme Complexes
  • Saccharomyces cerevisiae Proteins
  • TRX2 protein, S cerevisiae
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • YAP1 protein, S cerevisiae
  • Thioredoxins
  • Antimony
  • Hydrogen Peroxide
  • ARR2 protein, S cerevisiae
  • Arsenate Reductases
  • Thioredoxin-Disulfide Reductase
  • Arsenite Transporting ATPases
  • Cysteine
  • Arsenic