title: cAMP-response elements in Aplysia creb1, creb2, and Ap-uch promoters: implications for feedback loops modulating long term memory.
abstract: The Aplysia genes encoding for cAMP-response element-binding protein 1 (CREB1), CREB2, and ubiquitin C-terminal hydrolase (Ap-uch) have been implicated in the formation of long term memory. However, nothing is known about the promoter regions of these genes or the transcription factors that regulate them. We cloned the promoter regions of creb1, creb2, and Ap-uch and identified a canonical cAMP-response element (CRE) in the promoter region of creb1. Variants of the canonical CRE were identified in all three promoters. TATA boxes and C/EBP-binding motifs are also present in the promoter regions of these genes. Promoter immunoprecipitation assays and chromatin immunoprecipitation assays indicated that CREB1 and CREB2 bind to the promoter regions of creb1 and creb2, suggesting that feedback loops modulate the formation of long term memory. In a positive feedback loop, phosphorylated CREB1 might induce its own gene via CREs. In support of this suggestion, treatment with serotonin enhanced binding of CREB1 to its promoter region and increased mRNA levels of creb1. Levels of Ap-uch mRNA also increased in response to serotonin; however, binding of CREB1 or CREB2 to the promoter region of Ap-uch was not detected. The finding that the promoter region of creb2 has a CRE raises the intriguing possibility that its expression is regulated by CREB1 and/or CREB2. CREB2 may repress its own gene, forming a negative feedback loop, and CREB2 up-regulation via CREB1 may limit the activity of the CREB1-mediated positive feedback loop.
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, the University of Texas Medical School, Houston, Texas 77030, USA.
authors.forename: Habib A
authors.initials: HA
authors.lastname: Mohamed
authors.forename: Weizhe
authors.initials: W
authors.lastname: Yao
authors.forename: Diasinou
authors.initials: D
authors.lastname: Fioravante
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smolen
authors.forename: John H
authors.initials: JH
authors.lastname: Byrne
mesh_terms: D000818:Animals; D001048:Aplysia; D003001:Cloning, Molecular; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D025461:Feedback, Physiological / Q000235:genetics*; D008568:Memory; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D020218:Response Elements / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: C097204:ApCREB2 protein, Aplysia californica; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D012701:Serotonin; D000242:Cyclic AMP