Recovery from rapamycin: Drug-insensitive activity of yeast TORC1 supports residual proliferation that dilutes rapamycin among progeny cells

Stephanie K Evans, Karl EV Burgess, Joseph V Gray

Research output: Contribution to journalArticlepeer-review

Abstract

The Target of Rapamycin Complex 1 (TORC1) is a key and conserved regulator of eukaryotic cell growth. The xenobiotic rapamycin is a potent inhibitor of the yeast complex. Surprisingly, the EGO complex, a non-essential in vivo activator of TORC1, is somehow required for yeast cells to recover efficiently from a period of treatment with rapamycin. Why? Here, we find that rapamycin is only a partial inhibitor of TORC1: we confirm that saturating amounts of rapamycin do not fully inhibit proliferation of wild-type cells; we find that the residual proliferation in the presence of the drug is dependent on the EGO complex and on activity of TORC1. We find that this residual, TORC1-dependent proliferation is key to recovery from rapamycin treatment. First, the residual proliferation rate correlates with the ability of cells to recover from treatment. Second, the residual proliferation rate persists long after washout of the drug and until cells recover. Third, the total observable pool of cell-associated rapamycin is extremely stable and decreases only with increasing cell number after washout of the drug. Finally, consideration of the residual proliferation rate alone accurately and quantitatively accounts for the kinetics of recovery of wild-type cells and for the nature and severity of the ego- mutant defect. Overall, our results reveal that rapamycin is a partial inhibitor of yeast TORC1, that persistence of the drug limits recovery, and that rapamycin is not detoxified by yeast but is passively diluted among progeny cells because of residual proliferation.
Original languageEnglish
Pages (from-to)26554-26565
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number38
Publication statusPublished - 7 Aug 2014

Keywords

  • cell signaling
  • drug metabolism
  • enzyme inhibitor
  • TOR complex (TORC)
  • yeast
  • EGO complex
  • proliferation-dependent dilution
  • rapamycin
  • rapamycin-insensitive function

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