Mechanism of NF-kappaB inactivation induced by survival signal withdrawal in cerebellar granule neurons.
Activity of the transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to be necessary for maintaining neuronal viability. In cultured rat cerebellar granule neurons, trophic factor withdrawal induces NF-kappaB inactivation, resulting in cell death. The exact mechanism of this inactivation, however, has not been revealed. Here we report that trophic factor deprivation in cultured cerebellar granule neurons leads to a rapid and sustained increase in the level of IkappaBalpha and IkappaBbeta, the inhibitory proteins of NF-kappaB, causing prolonged NF-kappaB inactivation. Transient NF-kappaB activation resulting in new IkappaBalpha mRNA and protein synthesis gives rise to the rapid increase of IkappaBalpha level. The importance of elevated IkappaB level in neuronal apoptosis was confirmed in transfection experiments. Ectopic expression of a stabilized form of IkappaBalpha protein promoted neuronal death. Our findings suggest a novel mode of initiation of neuronal apoptosis wherein survival signal withdrawal induces NF-kappaB to lethally turn itself off.
Kovács
Attila D
AD
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Chakraborty-Sett
Shikha
S
Ramirez
Servio H
SH
Sniderhan
Lynn F
LF
Williamson
Andrea L
AL
Maggirwar
Sanjay B
SB
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods; D007976:Leupeptins / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D011233:Precipitin Tests / Q000379:methods; D020543:Proteome; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D044967:Serum / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods
D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D007976:Leupeptins; D008164:Luminescent Proteins; D016328:NF-kappa B; D020543:Proteome; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D011188:Potassium