Reference: Fournier ML, et al. (2010) Delayed Correlation of mRNA and Protein Expression in Rapamycin-treated Cells and a Role for Ggc1 in Cellular Sensitivity to Rapamycin. Mol Cell Proteomics 9(2):271-84

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Abstract


To identify new molecular targets of rapamycin, an anticancer and immunosupressive drug, we analyzed temporal changes in yeast over six hours in response to rapamycin at the transcriptome and proteome levels and integrated the expression patterns with functional profiling. We show that the integration of transcriptomic, proteomic, and functional datasets provide novel insights into the molecular mechanisms of rapamycin action. We first observed a temporal delay in the correlation of mRNA and protein expression where mRNA expression at one and two hours correlated best with protein expression changes after six hours of rapamycin treatment. This was especially the case for the inhibition of ribosome biogenesis and induction of heat shock and autophagy, essential to promote rapamycin's cellular sensitivity. However, increased levels of vacuolar protease could enhance resistance to rapamycin. Of the 85 proteins identified as statistically significantly changing in abundance, most of the proteins that decreased in abundance were correlated with a decrease in mRNA expression. However, of the 56 proteins increasing in abundance 26 were not correlated with an increase in mRNA expression. These protein changes were correlated with unchanged or down-regulated mRNA expression. These proteins, involved in mitochondrial genome maintenance, endocytosis or drug export, represent new candidates effecting rapamycin action, whose expression might be post-transcriptionally or post-translationary regulated. We identified Ggc1, a mitochondrial GTP / GDP carrier, as a new component of the rapamycin / TOR signaling pathway. We determined that the protein product of Ggc1 was stabilized in the presence of rapamycin, and the deletion of the Ggc1 gene enhanced growth fitness in the presence of rapamycin. A dynamic mRNA expression analysis of ggc1 and wild type cells treated with rapamycin revealed a key role for Ggc1 in the regulation of ribosome biogenesis and cell cycle progression under TOR control.

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Journal Article
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Fournier ML, Paulson A, Pavelka N, Mosley AL, Zueckert-Gaudenz K, Bradford WD, Glynn E, Li H, Sardiu ME, Fleharty B, ... Show all
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