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Inhibition of nuclear factor‐κB activation induces apoptosis in cerebellar granule cells
Author(s) -
Piccioli Patrizia,
Porcile Carola,
Stanzione Sabrina,
Bisaglia Michela,
Bajetto Adriana,
Bonavia Rudy,
Florio Tullio,
Schettini Gennaro
Publication year - 2001
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.1251
Subject(s) - microbiology and biotechnology , neuroprotection , proteasome , apoptosis , transcription factor , cytoplasm , nucleus , nf κb , neurodegeneration , biology , depolarization , neurotoxicity , chemistry , biochemistry , medicine , neuroscience , endocrinology , toxicity , gene , disease , organic chemistry
The nuclear factor (NF)‐κB family of transcription factors plays important roles in the regulation of many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity. 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. Regulation of its inducible activity relies on processing of IκB(s), which occurs through the proteasome. Here we show that in cerebellar granule cells (CGC) the induction of apoptosis, by potassium withdrawal (5 mM KCl), decreases the amount of nuclear NF‐κB. To understand whether NF‐κB was required for CGC survival, these cells, maintained under depolarizing conditions (25 mM KCl and serum), were treated with proteasome inhibitors. The results show that these treatments reduce the nuclear amount of NF‐κB and increase p65 cytoplasmic levels, a process partially regulated via IκBα degradation. These events are also associated with an impairment in CGC survival, with changes in nuclear morphology, induction of DNA laddering, and oligonucleosome formation, consistent with apoptosis. According to the K + deprivation model, PSI‐induced apoptosis is reversed by inhibitors of transcription and translation as well as by specific caspase inhibitors. Together our results show an important role for NF‐κB in maintaining CGC survival. Indeed, under conditions of mild depolarization (K25) necessary for CGC survival, NF‐κB is distributed between cytosol and nucleus, whereas, under apoptotic conditions (K5), it is depleted from the nucleus, such as after proteasome inhibitor treatment. Therefore, NF‐κB nuclear deprivation is involved in the induction of CGC apoptosis. J Neurosci. Res. 66:1064–1073, 2001. © 2001 Wiley‐Liss, Inc.