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Washburn Lab Generates Insight into the Mechanism of Action of Rapamycin Kansas City, Mo. (Nov. 24, 2009) – The Stowers Institute’s Washburn Lab has identified new proteins involved in the target of rapamycin (TOR) pathway, a protein network which is inhibited by the drug rapamycin and which plays an important role in regulating cell-cycle progression. The mammalian TOR pathway underlies conditions such as cancer, the rejection of transplanted organs, and the narrowing of coronary arteries treated with stents. The work was published by Molecular and Cellular Proteomics. Rapamycin is currently used as an anti-rejection drug in kidney transplants. It may also have potential for the treatment of cancer. The Washburn Lab applied quantitative shotgun proteomic, transcriptomic, and functional analyses in an effort to better understand the cellular response to rapamycin. This knowledge may ultimately help researchers identify proteins that represent promising targets for new drugs. “We found a significant delay in the correlation of mRNA and protein expression,” said Marjorie Fournier, Ph.D., formerly a Senior Research Associate and lead author on the work. “Early mRNA expression correlated best with protein expression changes late in rapamycin treatment. This suggested that rapamycin effects mediated through protein expression might not be immediate.” Some proteins whose abundance increased, which were not correlated with increased mRNA expression, were shown to impact the sensitivity of rapamycin. These proteins —involved in mitochondrial genome maintenance, endocytosis, or drug export — potentially represent new candidates in the mechanism of action of rapamycin. “The delayed correlation of mRNA and protein expression in cells treated with rapamycin provides new insights into the regulation of gene expression and protein abundance changes in response to rapamycin,” said Mike Washburn, Ph.D., Director of Proteomics and senior author on the work. “Some proteins whose function was required to promote rapamycin sensitivity were post-translationally regulated. This is intriguing because rapamycin strongly inhibited gene transcription and mRNA translation. The more we know about the mechanism of action of rapamycin, the better we understand its cellular effect and therapeutic potential.” Additional contributing authors from the Stowers Institute include Ariel Paulson, Programmer Analyst II; Norman Pavelka, Ph.D., Postdoctoral Research Associate; Amber Mosley, Ph.D., Senior Research Associate; Karin Zueckert-Gaudenz, Laboratory Manager II; William Bradford, Research Specialist I; Earl Glynn, formerly a Scientific Programmer; Hua Li, Biostatistician; Mihaela Sardiu, Ph.D., Senior Research Associate; Brian Fleharty, Research Technician II; Christopher Seidel, Ph.D., Research Advisor; and Laurence Florens, Ph.D., Managing Director of Proteomics. Dr. Washburn also holds a faculty appointment as an Associate Professor in the Department of Pathology & Laboratory Medicine at The University of Kansas School of Medicine. Learn more about his work at www.stowers.org/labs/WashburnLab.asp. About the Stowers Institute for Medical Research
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