Proteasomes play an essential role in thymocyte apoptosis.
Cell death in many different organisms requires the activation of proteolytic cascades involving cytosolic proteases. Here we describe a novel requirement in thymocyte cell death for the 20S proteasome, a highly conserved multicatalytic protease found in all eukaryotes. Specific inhibitors of proteasome function blocked cell death induced by ionizing radiation, glucocorticoids or phorbol ester. In addition to inhibiting apoptosis, these signals prevented the cleavage of poly(ADP-ribose) polymerase that accompanies many cell deaths. Since overall rates of protein degradation were not altered significantly during cell death in thymocytes, these results suggest that the proteasome may either degrade regulatory protein(s) that normally inhibit the apoptotic pathway or may proteolytically activate protein(s) than promote cell death.
Grimm
L M
LM
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Goldberg
A L
AL
Poirier
G G
GG
Schwartz
L M
LM
Osborne
B A
BA
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D011506:Proteins; C089487:acetyl-leucinyl-leucinyl-methional; C063261:acetylleucyl-leucyl-norleucinal; C067713:lactacystin; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D011088:DNA Ligases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine