title: Nerve growth factor regulates the expression of the cholinergic locus and the high-affinity choline transporter via the Akt/PKB signaling pathway.
abstract: Nerve growth factor (NGF) is a trophic and survival factor for cholinergic neurons, and it induces the expression of several genes that are essential for synthesis and storage of acetylcholine (ACh), specifically choline acetyltransferase, vesicular ACh transporter (VAChT), and choline transporter. We have found previously that the phosphatidylinositol 3'-kinase pathway, but not the MEK/MAPK pathway, is the mediator of NGF-induced cholinergic differentiation. Here we demonstrate, in the rat pheochromocytoma cell line PC12 and in primary mouse neuronal cultures, that NGF-evoked up-regulation of these three cholinergic-specific genes is mediated by the anti-apoptotic signaling molecule Akt/protein kinase B. Inhibition of Akt activation by the pharmacological inhibitor 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO), or by a peptide fragment derived from the proto-oncogene TLC1, eliminated NGF-stimulated increases in cholinergic gene expression, as demonstrated by RT-PCR and reporter gene assays. Moreover, treatment with HIMO reversed NGF-evoked increases in choline acetyltransferase activity and ACh production. In co-transfection assays with the reporter construct, a dominant-negative Akt plasmid and Akt1-specific small interfering RNA also attenuated NGF-induced cholinergic promoter activity. Our data indicate that, in addition to its well-described role in promoting neuronal survival, Akt can also mediate signals necessary for neurochemical differentiation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Madziar
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Martina
authors.initials: M
authors.lastname: Brock
authors.forename: Rebecca
authors.initials: R
authors.lastname: Burke
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lopez-Coviella
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Nickel
authors.forename: Esra Betul
authors.initials: EB
authors.lastname: Cakal
authors.forename: Jan Krzysztof
authors.initials: JK
authors.lastname: Blusztajn
authors.forename: Brygida
authors.initials: B
authors.lastname: Berse
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020665:Septum of Brain / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; C065637:choline transporter; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D000109:Acetylcholine
references.citation: Oncogene. 2005 Sep 29;24(43):6465-81
references.pmid: 16007182
references.citation: J Biol Chem. 2004 Dec 17;279(51):53407-18
references.pmid: 15459205
references.citation: Cell. 2006 Oct 6;127(1):125-37
references.pmid: 16962653
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: Neurosci Lett. 2007 Feb 14;413(2):110-4
references.pmid: 17182181
references.citation: Science. 1997 Jan 31;275(5300):661-5
references.pmid: 9005851
references.citation: Neurosci Lett. 1996 May 10;209(2):134-6
references.pmid: 8762000
references.citation: Mol Cell Neurosci. 2005 Feb;28(2):303-13
references.pmid: 15691711
references.citation: J Pharmacol Sci. 2005 Jul;98(3):205-11
references.pmid: 16006742
references.citation: EMBO J. 2004 Oct 13;23(20):3995-4006
references.pmid: 15385964
references.citation: J Comp Neurol. 2003 Aug 25;463(3):341-57
references.pmid: 12820166
references.citation: Mol Cell Biol. 2005 Aug;25(15):6592-602
references.pmid: 16024795
references.citation: J Biol Chem. 2005 Dec 9;280(49):40406-16
references.pmid: 16221682
references.citation: J Cell Mol Med. 2007 Jan-Feb;11(1):39-53
references.pmid: 17367500
references.citation: Neurosci Biobehav Rev. 2007;31(7):1046-63
references.pmid: 17544131
references.citation: J Med Chem. 2000 Aug 10;43(16):3045-51
references.pmid: 10956212
references.citation: J Neurosci. 2003 Oct 29;23(30):9697-709
references.pmid: 14585997
references.citation: Mol Cell Biol. 2002 Mar;22(5):1513-25
references.pmid: 11839817
references.citation: Curr Opin Neurobiol. 2000 Jun;10(3):381-91
references.pmid: 10851172
references.citation: Neurosci Lett. 2002 Jan 4;317(1):25-8
references.pmid: 11750988
references.citation: J Neurosci. 2004 Jun 16;24(24):5459-66
references.pmid: 15201317
references.citation: Brain Res Dev Brain Res. 2005 Jun 30;157(2):132-40
references.pmid: 15885806
references.citation: Trends Biochem Sci. 2004 May;29(5):233-42
references.pmid: 15130559
references.citation: Brain Res. 2007 Jun 2;1151:1-11
references.pmid: 17399691
references.citation: J Cell Physiol. 2005 Nov;205(2):270-7
references.pmid: 15887249
references.citation: Psychopharmacology (Berl). 2006 Nov;188(4):605-18
references.pmid: 16915384
references.citation: J Neurochem. 2005 Feb;92(4):767-79
references.pmid: 15686478
references.citation: Semin Cell Dev Biol. 2004 Apr;15(2):177-82
references.pmid: 15209377
references.citation: Oncogene. 2005 Feb 3;24(6):1021-31
references.pmid: 15592509
references.citation: Biochim Biophys Acta. 2004 Mar 11;1697(1-2):3-16
references.pmid: 15023346
references.citation: J Neurosci. 1995 Apr;15(4):2888-905
references.pmid: 7536822
references.citation: Biochem J. 1999 Sep 1;342 ( Pt 2):301-8
references.pmid: 10455015
references.citation: Curr Opin Cell Biol. 2005 Apr;17(2):150-7
references.pmid: 15780591
references.citation: J Am Chem Soc. 2003 Feb 5;125(5):1144-5
references.pmid: 12553797
references.citation: Endocrinology. 2006 Jun;147(6):3027-39
references.pmid: 16497810
references.citation: Immunol Rev. 2003 Apr;192:7-20
references.pmid: 12670391
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Anal Biochem. 1985 Oct;150(1):76-85
references.pmid: 3843705
references.citation: Cell Cycle. 2003 Jul-Aug;2(4):339-45
references.pmid: 12851486
references.citation: Brain Res. 2007 May 11;1145:1-10
references.pmid: 17320829
references.citation: Biochem Soc Trans. 2001 Nov;29(Pt 6):711-6
references.pmid: 11709061
references.citation: Sci Signal. 2008 Jun 17;1(24):pe29
references.pmid: 18560018
references.citation: J Neurosci Res. 1999 Aug 1;57(3):381-7
references.pmid: 10412029
references.citation: J Neurochem. 2000 Dec;75(6):2401-8
references.pmid: 11080191
references.citation: Trends Pharmacol Sci. 2007 Apr;28(4):166-72
references.pmid: 17349698
references.citation: Brain Res Mol Brain Res. 1998 Nov 12;62(1):25-34
references.pmid: 9795114
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: J Neurochem. 2004 Aug;90(4):952-61
references.pmid: 15287901
references.citation: Curr Opin Neurobiol. 2001 Jun;11(3):297-305
references.pmid: 11399427
references.citation: Mol Cell Endocrinol. 2000 Dec 22;170(1-2):211-5
references.pmid: 11162904
references.citation: Brain Dev. 1996 Sep-Oct;18(5):362-8
references.pmid: 8891230