title: Functional interplay between nuclear factor-kappaB and c-Jun integrated by coactivator p300 determines the survival of nerve growth factor-dependent PC12 cells.
abstract: Nerve growth factor (NGF) activates the transcription factors nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) in sympathetic neurons. Whereas NGF-inducible NF-kappaB is required for the survival of neurons, c-Jun has the ability to promote neuronal death. In this report, we have examined the effect of NGF withdrawal on c-Jun and NF-kappaB transcription factors in PC12 cells differentiated to a neuronal phenotype. We show that the withdrawal of NGF from these cultures results in de novo synthesis of c-Jun, increase in AP-1 activity, and down-regulation of NF-kappaB activity. To investigate how the signal transduction pathways activating c-Jun and NF-kappaB are differentially regulated by NGF, we performed transcriptional analyses. Expression of ReIA (NF-kappaB) suppressed the c-Jun-dependent transcription of c-jun, and this effect was reversed by overexpression of the coactivator p300. RelA's effects on c-Jun transcription were mediated by competitive binding of the carboxy-terminal region of RelA to the CH1 domain of p300, which also binds to c-Jun; deletion of this region abrogated the ability of RelA to inhibit c-Jun activity. Furthermore, the inhibition of endogenous NF-kappaB in NGF-maintained neuronal PC12 cells led to the induction of c-Jun synthesis and a marked increase in cell death. Together, these studies demonstrate a functional interaction between NF-kappaB and c-Jun and suggest a novel mechanism of NF-kappaB-mediated neuroprotection.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, New York 14642, USA. sanjay_maggirwar@urmc.rochester.edu
authors.forename: S B
authors.initials: SB
authors.lastname: Maggirwar
authors.forename: S
authors.initials: S
authors.lastname: Ramirez
authors.forename: N
authors.initials: N
authors.lastname: Tong
authors.forename: H A
authors.initials: HA
authors.lastname: Gelbard
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D050881:E1A-Associated p300 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D020932:Nerve Growth Factor / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D016716:PC12 Cells; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D015534:Trans-Activators / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D020932:Nerve Growth Factor; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat