Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341

Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1461-6. doi: 10.1073/pnas.032516399.


Although the biochemical targets of most drugs are known, the biological consequences of their actions are typically less well understood. In this study, we have used two whole-genome technologies in Saccharomyces cerevisiae to determine the cellular impact of the proteasome inhibitor PS-341. By combining population genomics, the screening of a comprehensive panel of bar-coded mutant strains, and transcript profiling, we have identified the genes and pathways most affected by proteasome inhibition. Many of these function in regulated protein degradation or a subset of mitotic activities. In addition, we identified Rpn4p as the transcription factor most responsible for the cell's ability to compensate for proteasome inhibition. Used together, these complementary technologies provide a general and powerful means to elucidate the cellular ramifications of drug treatment.

MeSH terms

  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Nucleus / genetics
  • Cell Nucleus / ultrastructure
  • Cysteine Endopeptidases / metabolism*
  • DNA Repair
  • DNA, Fungal / genetics
  • Fungal Proteins / metabolism
  • Gene Deletion
  • Gene Expression Profiling
  • Genome, Fungal*
  • Genomics / methods*
  • Microbial Sensitivity Tests
  • Multienzyme Complexes / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex
  • Pyrazines / pharmacology*
  • RNA, Fungal / genetics
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Transcription, Genetic


  • Boronic Acids
  • DNA, Fungal
  • Fungal Proteins
  • Multienzyme Complexes
  • Protease Inhibitors
  • Pyrazines
  • RNA, Fungal
  • Bortezomib
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex