Functional Interplay Between Nuclear Factor-κB and c-Jun Integrated by Coactivator p300 Determines the Survival of Nerve Growth Factor-Dependent PC12 Cells

Authors

  • Sanjay B. Maggirwar,

    1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, U.S.A.*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Cancer Center, University of Rochester Medical Center, Rochester, New York, U.S.A.
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  • Servio Ramirez,

    1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, U.S.A.*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Cancer Center, University of Rochester Medical Center, Rochester, New York, U.S.A.
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  • Ning Tong,

    1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, U.S.A.*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Cancer Center, University of Rochester Medical Center, Rochester, New York, U.S.A.
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  • * Harris A. Gelbard,

    1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, U.S.A.*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Cancer Center, University of Rochester Medical Center, Rochester, New York, U.S.A.
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  • and * Stephen Dewhurst

    1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, U.S.A.*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, U.S.A.Department of Cancer Center, University of Rochester Medical Center, Rochester, New York, U.S.A.
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  • International Society for Neurochemistry

  • Abbreviations used: AP-1, activator protein-1; CBP, cyclic AMP response element-binding protein (CREB)-binding protein; EMSA, electrophoretic mobility shift assay; FITC, fluorescein isothiocyanate; GST, glutathione S-transferase; IVTT, in vitro transcription-translation; JNK, c-Jun NH2-terminal protein kinase; MAP, mitogen-activated protein; NF-κB, nuclear factor κB; NFAT, nuclear factor of activated T cells; NGF, nerve growth factor; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; TUNEL, terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end-labeling.

Address correspondence and reprint requests to Dr. S. B. Maggirwar at Department of Microbiology and Immunology, University of Rochester Medical Center, 575 Elmwood Avenue, Box 672, Rochester, NY 14642, U.S.A. E-mail: sanjay_maggirwar@urmc.rochester.edu

Abstract

Abstract: Nerve growth factor (NGF) activates the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in sympathetic neurons. Whereas NGF-inducible NF-κB 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-κB 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-κB activity. To investigate how the signal transduction pathways activating c-Jun and NF-κB are differentially regulated by NGF, we performed transcriptional analyses. Expression of RelA (NF-κB) 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-κB 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-κB and c-Jun and suggest a novel mechanism of NF-κB-mediated neuroprotection.

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