Rapamycin conditionally inhibits Hsp90 but not Hsp70 mRNA translation in Drosophila: implications for the mechanisms of Hsp mRNA translation.
Rapamycin inhibits the activity of the target of rapamycin (TOR)-dependent signaling pathway, which has been characterized as one dedicated to translational regulation through modulating cap-dependent translation, involving eIF4E binding protein (eIF4E-BP) or 4E-BP. Results show that rapamycin strongly inhibits global translation in Drosophila cells. However, Hsp70 mRNA translation is virtually unaffected by rapamycin treatment, whereas Hsp90 mRNA translation is strongly inhibited, at normal growth temperature. Intriguingly, during heat shock Hsp90 mRNA becomes significantly less sensitive to rapamycin-mediated inhibition, suggesting the pathway for Hsp90 mRNA translation is altered during heat shock. Reporter mRNAs containing the Hsp90 or Hsp70 mRNAs' 5' untranslated region recapitulate these rapamycin-dependent translational characteristics, indicating this region regulates rapamycin-dependent translational sensitivity as well as heat shock preferential translation. Surprisingly, rapamycin-mediated inhibition of Hsp90 mRNA translation at normal growth temperature is not caused by 4E-BP-mediated inhibition of cap-dependent translation. Indeed, no evidence for rapamycin-mediated impaired eIF4E function is observed. These results support the proposal that preferential translation of different Hsp mRNA utilizes distinct translation mechanisms, even within a single species.
Duncan
Roger F
RF
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA. rduncan@usc.edu
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006358:Hot Temperature; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012315:RNA Caps / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D014162:Transfection
D020121:5' Untranslated Regions; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011500:Protein Synthesis Inhibitors; D012315:RNA Caps; D012333:RNA, Messenger; C105238:cup protein, Drosophila; C523051:eIF4G2 protein, Drosophila; D020123:Sirolimus