Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 3, 1461-1466, February 5, 2002
James A. Fleming, Eric S. Lightcap, Seth Sadis, Vala Thoroddsen, Christine E. Bulawa, and Ronald K. Blackman*
Millennium Pharmaceuticals, Incorporated, 75 Sidney Street, Cambridge, MA 02139
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.
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www.pnas.org/cgi/doi/10.1073/pnas.032516399 |
