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PMID: 11830665 Published · ppublish English Journal Article

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 3 ·2002-02-05 ·Pages 1461-6

Fleming JA, Lightcap ES, Sadis S, Thoroddsen V, Bulawa CE, Blackman RK

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.

MeSH Terms
Boronic Acids/pharmacology Bortezomib Cell Nucleus/genetics,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,enzymology,genetics Transcription, Genetic
Chemicals
Boronic Acids DNA, Fungal Fungal Proteins Multienzyme Complexes Protease Inhibitors Pyrazines RNA, Fungal Bortezomib Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Fleming James A
Millennium Pharmaceuticals, Incorporated, 75 Sidney Street, Cambridge, MA 02139, USA.
Lightcap Eric S
Sadis Seth
Thoroddsen Vala
Bulawa Christine E
Blackman Ronald K
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.032516399
Published
2002-02-05
Pages
1461-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC122213
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.032516399 PMC Full Text View journal details
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