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Proteasome Inhibitors Induce Cerebellar Granule Cell Death
Author(s) -
PORCILE CAROLA,
PICCIOLI PATRIZIA,
STANZIONE SABRINA,
BAJETTO ADRIANA,
BONAVIA RUDY,
BARBERO SIMONE,
FLORIO TULLIO,
SCHETTINIA GENNARO
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04673.x
Subject(s) - proteasome , programmed cell death , microbiology and biotechnology , chemistry , granule (geology) , cerebellum , neuroscience , biology , biochemistry , apoptosis , paleontology
A bstract : Many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity, are regulated by the activity of the transcription factor nuclear factor‐κB (NF‐κB). In resting cells, NF‐κB 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 IκB(s), which occurs through the proteasome. To understand whether NF‐κB 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‐κB, in that a reduced amount of nuclear NF‐κB 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‐κB in maintainig CGC survival.