title: The Notch intracellular domain represses CRE-dependent transcription.
abstract: Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression.
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Rania
authors.initials: R
authors.lastname: Hallaq
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via Pietro Castellino 111, 80131 Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Volpicelli
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Cuchillo-Ibanez
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Claudie
authors.initials: C
authors.lastname: Hooper
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Dafe
authors.initials: D
authors.lastname: Uwanogho
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Mirsada
authors.initials: M
authors.lastname: Causevic
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Ayodeji
authors.initials: A
authors.lastname: Asuni
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Alvina
authors.initials: A
authors.lastname: To
authors.affiliation: Department of Anatomy, Loma Linda University School of Medicine, Loma Linda, Evans Hall B08, 24785 Stewart Street, Loma Linda, CA 92354, USA.
authors.forename: Salvador
authors.initials: S
authors.lastname: Soriano
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: K Peter
authors.initials: KP
authors.lastname: Giese
authors.affiliation: University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. Electronic address: richard.1.killick@kcl.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Killick
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D057567:Memory, Long-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C497761:NOTCH1 protein, human; D020033:Protein Isoforms; D051881:Receptor, Notch1; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; CREB; Memory; NICD; PKA