NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons.
نویسندگان
چکیده
Pigment epithelium-derived factor (PEDF) protects immature cerebellar granule cells (1-3 days in vitro) against induced apoptosis and mature cells (5+ days in vitro) against glutamate toxicity, but its precise mechanism is still unknown. Because the transcription factor NFkappaB blocks cell death, including neuronal apoptosis, we have investigated the ability of PEDF to exert its effects via NFkappaB activation. PEDF induced an increased phosphorylation of IkappaBalpha, decreased levels of IkappaB proteins, and translocation of p65 (RelA) to the nucleus followed by a time-dependent increase of NFkappaB-DNA binding activity in both immature and mature neurons. The protective effects of PEDF against both induced apoptosis and glutamate toxicity were blocked by the addition of either the IkappaB kinase inhibitor BAY 11-7082, which inhibits the phosphorylation of IkappaB, or N-acetyl-Leu-Leu-norleucinal, which blocks proteosome degradation of IkappaB, demonstrating that NFkappaB is required for the neuroprotective effects of PEDF. Reverse transcription-polymerase chain reaction analysis revealed that up-regulation of the anti-apoptotic genes for Bcl-2, Bcl-x, and manganese superoxide dismutase was observed in PEDF-treated immature but not mature neurons. Up-regulation of nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor mRNA was long-lasting in mature neurons. These results suggest that PEDF promotes neuronal survival through activation of NFkappaB, which in turn induces expression of anti-apoptotic and/or neurotrophic factor genes.
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bstract—Pigment epithelium-derived factor (PEDF) protects mmature cerebellar granule cell neurons (CGCs) against apotosis induced by K and serum deprivation. However, the recise mechanism of this protection remains unknown. We ecently reported that the transcription factor nuclear factor appa B (NFB) is activated in PEDF-treated CGCs. Although it s well known that NFB blocks apoptotic cell deat...
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ورودعنوان ژورنال:
- The Journal of biological chemistry
دوره 276 46 شماره
صفحات -
تاریخ انتشار 2001