title: Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341.
abstract: 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.
authors.affiliation: Millennium Pharmaceuticals, Incorporated, 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Fleming
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lightcap
authors.forename: Seth
authors.initials: S
authors.lastname: Sadis
authors.forename: Vala
authors.initials: V
authors.lastname: Thoroddsen
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bulawa
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Blackman
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002467:Cell Nucleus / Q000235:genetics / Q000648:ultrastructure; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D016681:Genome, Fungal; D023281:Genomics / Q000379:methods*; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D012331:RNA, Fungal / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D001897:Boronic Acids; D004271:DNA, Fungal; D005656:Fungal Proteins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D012331:RNA, Fungal; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex