Staurosporine inhibits phosphorylation of translational regulators linked to mTOR.
Treatment of Swiss 3T3 cells with staurosporine resulted in dephosphorylation of two proteins which play key roles in regulating mRNA translation. This occurred before the execution of apoptosis, assessed by caspase-3 activity. These translation regulators are p70 S6 kinase, which phosphorylates ribosomal protein S6, and eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), which both lie downstream of the mammalian target of rapamycin (mTOR). This resulted in decreased p70 S6 kinase activity, dephosphorylation of ribosomal protein S6, increased binding of 4E-BP1 to eIF4E and a concomitant decrease in eIF4F complexes. Our data show that staurosporine impairs mTOR signalling in vivo but that this not due to direct inhibition of mTOR or to inhibition of protein kinase C. It is becoming clear that agents which cause apoptosis inactivate mTOR signalling as a common early response prior to the execution of apoptosis, i.e., before caspase activation.
Tee
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School of Life Sciences, Medical Sciences Institute/Wellcome Trust Building Complex, University of Dundee, Dow Street, Dundee, DD1 5EH, UK. a.r.tee@dundee.ac.uk
Proud
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D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D039642:Eukaryotic Initiation Factors; D007328:Insulin; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D020169:Caspases; D019311:Staurosporine; D020123:Sirolimus