Notch细胞内结构域抑制CRE依赖的转录。

The Notch intracellular domain represses CRE-dependent transcription.

作者信息

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

机构信息

King's College London, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.

Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via Pietro Castellino 111, 80131 Naples, Italy.

出版信息

Cell Signal. 2015 Mar;27(3):621-9. doi: 10.1016/j.cellsig.2014.11.034. Epub 2014 Dec 3.

DOI:10.1016/j.cellsig.2014.11.034

PMID:25479589

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.

摘要

环磷酸腺苷反应元件结合蛋白（CREB）转录因子家族的成员调节长期记忆形成所需基因的表达。Notch缺失会损害果蝇和哺乳动物的长期记忆，但不会损害短期记忆。我们研究了Notch-1（N1）是否对CREB依赖的基因转录产生影响。我们观察到N1以γ-分泌酶依赖的方式抑制CREB介导的含环磷酸腺苷反应元件（CRE）启动子的激活。我们接着发现，γ切割的N1细胞内结构域（N1ICD）隔离核CREB1α，抑制cAMP/PKA介导的神经突生长，并抑制原代皮层神经元中与学习和记忆相关的特定CREB调节基因的表达。N2ICD、N3ICD和N4ICD也观察到类似的转录效应。总之，这些观察结果表明，Notch对学习和记忆的影响至少部分是通过对CREB调节的基因表达产生作用。