Proteasome inhibitors induce cerebellar granule cell death: inhibition of nuclear factor-kB activation.
Many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity, are regulated by the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). In resting cells, NF-kappaB activity is present both in the cytoplasm, as an inducible-inactive complex, and in the nucleus as a constitutive form. The activation of its inducible form is related to processing of IkappaB(s), which occurs through the proteasome. To understand whether NF-kappaB is involved in the survival of cerebellar granule cells (CGCs) maintained under conditions of mild depolarization (25 mM KCl), these cells were treated with different proteasome inhibitors. The results presented show that these pharmacological tools reduce CGC survival with changes in nuclear morphology and induction of apoptosis. Furthermore, we demonstrate that PSI-induced apoptosis is reverted by inhibitors of transcription and translation, as well as by specific caspase inhibitors. These issues are also associated with a redistribution of NF-kappaB, in that a reduced amount of nuclear NF-kappaB and an increased p65 cytoplasmic level have been observed. Finally, we propose that, at least in part, p65 metabolism could also be regulated by the ubiquitin-proteasome complex. Altogether, the results presented define an important role for NF-kappaB in maintainig CGC survival.
Porcile
Carola
C
Section of Pharmacology and Neuroscience, National Institute for Cancer Research (IST), c/o CBA Largo Rosanna Benzi 10, 16132 Genova, Italy.
Piccioli
Patrizia
P
Stanzione
Sabrina
S
Bajetto
Adrianna
A
Bonavia
Rudy
R
Barbero
Simone
S
Florio
Tullio
T
Schettinia
Gennaro
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology*; D007700:Kinetics; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley
D061945:Caspase Inhibitors; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009842:Oligopeptides; D011480:Protease Inhibitors; C118632:tyrosyl-valyl-alanyl-aspartal; D003561:Cytarabine; D003609:Dactinomycin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex