The Notch intracellular domain represses CRE-dependent transcription

Rania Hallaq; Floriana Volpicelli; Inmaculada Cuchillo-Ibanez; Claudie Hooper; Keiko Mizuno; Dafe Uwanogho; Mirsada Causevic; Ayodeji Asuni; Alvina To; Salvador Soriano; K Peter Giese; Simon Lovestone; Richard Killick

doi:10.1016/j.cellsig.2014.11.034

The Notch intracellular domain represses CRE-dependent transcription

Rania Hallaq, Floriana Volpicelli, Inmaculada Cuchillo-Ibanez, Claudie Hooper, Keiko Mizuno, Dafe Uwanogho, Mirsada Causevic, Ayodeji Asuni, Alvina To, Salvador Soriano, K Peter Giese, Simon Lovestone, Richard Killick

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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.

Original language	English
Pages (from-to)	621–629
Number of pages	9
Journal	Cellular Signalling
Volume	27
Issue number	3
Early online date	3 Dec 2014
DOIs	https://doi.org/10.1016/j.cellsig.2014.11.034
Publication status	Published - Mar 2015

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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.",

author = "Rania Hallaq and Floriana Volpicelli and Inmaculada Cuchillo-Ibanez and Claudie Hooper and Keiko Mizuno and Dafe Uwanogho and Mirsada Causevic and Ayodeji Asuni and Alvina To and Salvador Soriano and Giese, {K Peter} and Simon Lovestone and Richard Killick",

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language = "English",

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T1 - The Notch intracellular domain represses CRE-dependent transcription

AU - Hallaq, Rania

AU - Volpicelli, Floriana

AU - Cuchillo-Ibanez, Inmaculada

AU - Hooper, Claudie

AU - Mizuno, Keiko

AU - Uwanogho, Dafe

AU - Causevic, Mirsada

AU - Asuni, Ayodeji

AU - To, Alvina

AU - Soriano, Salvador

AU - Giese, K Peter

AU - Lovestone, Simon

AU - Killick, Richard

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

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DO - 10.1016/j.cellsig.2014.11.034

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SN - 0898-6568

VL - 27

SP - 621

EP - 629

JO - Cellular Signalling

JF - Cellular Signalling

IS - 3

ER -

The Notch intracellular domain represses CRE-dependent transcription

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