 | CELL SIGNALING, TRANSCRIPTION, AND TRANSLATION AS THERAPEUTIC TARGETS
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 973:402-413 (2002)
© 2002 New York Academy of Sciences
Proteasome Inhibitors Induce Cerebellar Granule Cell Death
Inhibition of Nuclear Factor-kB Activation
CAROLA PORCILEa,b,
PATRIZIA PICCIOLIa,b,
SABRINA STANZIONEa,
ADRIANA BAJETTOa,c,
RUDY BONAVIAa,c,
SIMONE BARBEROa,c,
TULLIO FLORIOa,d AND
GENNARO SCHETTINIAc
aSection of Pharmacology and Neuroscience, National Institute for Cancer Research (IST), c/o CBA Largo Rosanna Benzi 10, 16132 Genova, Italy
cSection of Pharmacology, Department of Oncology, Biology and Genetics, School of Medicine, University of Genova, Genova, Italy
dDepartment of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy
Address for correspondence: Gennaro Schettini, Section of Pharmacology and Neuroscience, National Institute for Cancer Research, c/o CBA Largo Rosanna Benzi 10, 16132 Genova, Italy. Voice: 0039-10-5737256; fax 0039-10-5737257.
schettini{at}sirio.cba.unige.it
bThese authors contributed equally to this work.
Ann. N.Y. Acad. Sci. 973: 402-413 (2002).
Many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity, are regulated by the activity of the transcription factor nuclear factor-  B (NF- B). In resting cells, NF- B 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 I B(s), which occurs through the proteasome. To understand whether NF- B 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- B, in that a reduced amount of nuclear NF- B 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- B in maintainig CGC survival.
Key Words: apoptosis • cerebellar granule cells • nuclear factor-kB • p65 • ubiquitin-proteasome complex
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