title: cAMP response element-binding protein (CREB) is required for epidermal growth factor (EGF)-induced cell proliferation and serum response element activation in neural stem cells isolated from the forebrain subventricular zone of adult mice.
abstract: Neurogenesis, which occurs not only in the developing brain but also in restricted regions in the adult brain including the forebrain subventricular zone (SVZ), is regulated by a variety of environmental factors, extracellular signals, and intracellular signal transduction pathways.  We investigated whether the transcription factor cAMP response element (CRE)-binding protein (CREB) is involved in the regulation of cell proliferation of neural stem cells (NSCs) isolated from the SVZ of adult mice.  Treatment of NSCs with the protein kinase A (PKA) inhibitors H89 and KT5720 inhibited epidermal growth factor (EGF)-stimulated NSC proliferation.  Similar inhibition was observed when a dominant-negative mutant of CREB (MCREB) was expressed.  EGF treatment increased CRE-mediated transcriptional activity, but this increase was much less than that caused by treatment with the adenylate cyclase activator forskolin, which changed neither basal nor EGF-stimulated proliferation of NSCs.  Neither PKA inhibitors nor MCREB expression blocked EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK), a protein kinase mediating EGF's mitogenic action.  However, MCREB suppressed EGF-induced expression of several immediately early genes including c-fos, c-jun, jun-B, and fra-1 and subsequent AP-1 transcriptional activation.  MCREB expression also inhibited the ability of EGF to stimulate transcriptional activation mediated by the serum response element (SRE), a promoter sequence regulating c-fos gene expression.  These results suggest that basal activity of CREB is required for the mitogenic signaling of EGF in NSCs at a level between ERK activation and SRE-mediated transcriptional activation.
authors.affiliation: Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Iguchi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mitsui
authors.forename: Maho
authors.initials: M
authors.lastname: Ishida
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
authors.forename: Jun
authors.initials: J
authors.lastname: Arita
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D027602:Serum Response Element; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C057416:KT 5720; D004815:Epidermal Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide