Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341.
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.
Fleming
James A
JA
Millennium Pharmaceuticals, Incorporated, 75 Sidney Street, Cambridge, MA 02139, USA.
Lightcap
Eric S
ES
Sadis
Seth
S
Thoroddsen
Vala
V
Bulawa
Christine E
CE
Blackman
Ronald K
RK
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
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