title: Pituitary adenylate cyclase-activating polypeptide (PACAP) promotes both survival and neuritogenesis in PC12 cells through activation of nuclear factor κB (NF-κB) pathway: involvement of extracellular signal-regulated kinase (ERK), calcium, and c-REL.
abstract: The pituitary adenylate cyclase-activating polypeptide (PACAP) is a trophic factor that promotes neuronal survival and neurite outgrowth. However, the signaling pathways and the transcriptional mechanisms involved are not completely elucidated. Our previous studies aimed at characterizing the transcriptome of PACAP-differentiated PC12 cells revealed an increase in the expression of nuclear factor κB2 (NF-κB2) gene coding for p100/p52 subunit of NF-κB transcription factor. Here, we examined the role of the NF-κB pathway in neuronal differentiation promoted by PACAP. We first showed that PACAP-driven survival and neuritic extension in PC12 cells are inhibited following NF-κB pathway blockade. PACAP stimulated both c-Rel and p52 NF-κB subunit gene expression and nuclear translocation, whereas c-Rel down-regulation inhibited cell survival and neuritogenesis elicited by the neuropeptide. PACAP-induced c-Rel nuclear translocation was inhibited by ERK1/2 and Ca(2+) blockers. Furthermore, the neuropeptide stimulated NF-κB p100 subunit processing into p52, indicative of activation of the NF-κB alternative pathway. Taken together, our data show that PACAP promotes both survival and neuritogenesis in PC12 cells by activating NF-κB pathway, most likely via classical and alternative signaling cascades involving ERK1/2 kinases, Ca(2+), and c-Rel/p52 dimers.
authors.affiliation: INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, University of Rouen, 76821 Mont-Saint-Aignan, France.
authors.forename: Destiny-Love
authors.initials: DL
authors.lastname: Manecka
authors.forename: Sardar Faisal
authors.initials: SF
authors.lastname: Mahmood
authors.forename: Luca
authors.initials: L
authors.lastname: Grumolato
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lihrmann
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D052003:NF-kappa B p52 Subunit; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020569:Proto-Oncogene Proteins c-rel; D048052:Mitogen-Activated Protein Kinase 3
keywords: Calcium; Cell Differentiation; Cell Survival; ERK; NF-κB; Neurite Outgrowth; Neuropeptide; Neurotrophic Factor; PACAP; PC12 Cells
references.citation: Ann N Y Acad Sci. 2006 Jul;1070:550-60
references.pmid: 16888224
references.citation: J Neurosci Res. 1998 May 15;52(4):380-9
references.pmid: 9589383
references.citation: FASEB J. 2012 Aug;26(8):3199-211
references.pmid: 22532442
references.citation: Mol Cell Biol. 2000 Apr;20(8):2687-95
references.pmid: 10733571
references.citation: Science. 2001 Aug 24;293(5534):1495-9
references.pmid: 11520989
references.citation: Mol Cell Biol. 1990 Oct;10(10):5473-85
references.pmid: 2204816
references.citation: Eur J Neurosci. 2002 May;15(9):1451-60
references.pmid: 12028355
references.citation: Eur J Neurosci. 2003 Jan;17(1):71-82
references.pmid: 12534970
references.citation: Biochem Pharmacol. 2006 Oct 30;72(9):1161-79
references.pmid: 16970925
references.citation: Cell Res. 2011 Feb;21(2):223-44
references.pmid: 21243012
references.citation: Mol Pharmacol. 1998 Sep;54(3):547-58
references.pmid: 9730914
references.citation: J Neurosci. 2002 Mar 1;22(5):1583-91
references.pmid: 11880488
references.citation: Immunol Rev. 2012 Mar;246(1):36-58
references.pmid: 22435546
references.citation: Science. 1996 Nov 1;274(5288):782-4
references.pmid: 8864118
references.citation: Cell Mol Life Sci. 2011 Dec;68(23):3823-41
references.pmid: 21744067
references.citation: Biochim Biophys Acta. 2005 Sep 30;1745(3):287-99
references.pmid: 15993497
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):461-6
references.pmid: 11756684
references.citation: Mol Immunol. 2010 Apr;47(7-8):1426-37
references.pmid: 20233629
references.citation: Trends Neurosci. 1997 Jun;20(6):252-8
references.pmid: 9185306
references.citation: J Neurochem. 2001 Feb;76(4):1188-98
references.pmid: 11181838
references.citation: J Biol Chem. 2000 Nov 3;275(44):34021-4
references.pmid: 10980190
references.citation: J Immunol Methods. 2008 Jan 1;329(1-2):194-200
references.pmid: 18036607
references.citation: J Neurochem. 2012 Dec;123(5):652-61
references.pmid: 22994539
references.citation: J Neurochem. 2006 Nov;99(4):1237-50
references.pmid: 17026529
references.citation: Peptides. 2007 Sep;28(9):1746-52
references.pmid: 17544170
references.citation: Peptides. 2001 Jul;22(7):1111-7
references.pmid: 11445242
references.citation: J Neurochem. 2005 Jun;93(6):1487-501
references.pmid: 15935065
references.citation: Dev Neurobiol. 2010 Apr;70(5):332-8
references.pmid: 20186712
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2637-42
references.pmid: 15695581
references.citation: Genes Dev. 1995 Nov 15;9(22):2723-35
references.pmid: 7590248
references.citation: J Cell Biol. 2001 Feb 19;152(4):753-64
references.pmid: 11266466
references.citation: Ann N Y Acad Sci. 2002 Oct;971:491-6
references.pmid: 12438169
references.citation: J Biol Chem. 2010 Mar 26;285(13):9749-9761
references.pmid: 20093365
references.citation: J Neurosci. 2002 Oct 1;22(19):8466-75
references.pmid: 12351721
references.citation: Mol Cell. 2001 Feb;7(2):401-9
references.pmid: 11239468
references.citation: Cell Death Differ. 2005 Jul;12(7):761-72
references.pmid: 15818410
references.citation: Pharmacol Rev. 2009 Sep;61(3):283-357
references.pmid: 19805477
references.citation: Endocr Rev. 2000 Dec;21(6):619-70
references.pmid: 11133067
references.citation: Immunol Rev. 2012 Mar;246(1):193-204
references.pmid: 22435556
references.citation: Dev Biol. 2000 Mar 15;219(2):197-213
references.pmid: 10694416
references.citation: Endocrinology. 2003 Jun;144(6):2368-79
references.pmid: 12746297
references.citation: Development. 2005 Apr;132(7):1713-26
references.pmid: 15743881
references.citation: Brain Res. 1996 Nov 25;741(1-2):82-8
references.pmid: 9001708
references.citation: J Neurosci. 2000 Oct 15;20(20):7556-63
references.pmid: 11027214
references.citation: J Biol Chem. 2004 Jul 16;279(29):30099-105
references.pmid: 15140882
references.citation: J Biol Chem. 1992 Mar 15;267(8):5108-13
references.pmid: 1312085
references.citation: Regul Pept. 2008 Jan 10;145(1-3):105-15
references.pmid: 17981349
references.citation: J Neurosci Res. 1998 Dec 1;54(5):698-706
references.pmid: 9843161
references.citation: Oncogene. 1993 Aug;8(8):2275-81
references.pmid: 8336950
references.citation: J Neurosci Res. 1997 Jan 15;47(2):155-62
references.pmid: 9008146
references.citation: Am J Physiol Renal Physiol. 2010 May;298(5):F1197-204
references.pmid: 20181667
references.citation: J Neurochem. 2006 Jul;98(2):321-9
references.pmid: 16805827
references.citation: EMBO J. 2000 Dec 1;19(23):6351-60
references.pmid: 11101508
references.citation: Front Neuroendocrinol. 2008 Jan;29(1):128-41
references.pmid: 18048093
references.citation: FEBS J. 2011 Apr;278(6):862-76
references.pmid: 21232017