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Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1.

Mitsuda, N; Ohkubo, N; Tamatani, M; Lee, YD; Taniguchi, M; Namikawa, K; Kiyama, H; Yamaguchi, A; Sato, N; Sakata, K; Ogihara, T; Vitek, MP; Tohyama, M
The Journal of biological chemistry, 276(13):9688-9698, 2001
Journal Title
The Journal of biological chemistry
Upon binding to the cAMP-response element of a gene's promoter, the transcription factor known as cAMP-response element-binding protein (CREB) facilitates transcription of many different neuronal genes including those involved with synaptic function. Based on our previous reports of gene structure (GenBank accession number AF029701 ), we now demonstrate that activated CREB binds to the proximal promoter of the human presenilin-1 (PS-1) gene to activate PS-1 transcription in rat and in human neuronal cells. Specific stimulation of the N-methyl-d-aspartate subtype of neuronal glutamate receptors activates CREB and results in increased PS-1 expression. Similarly, treatment with brain-derived neurotrophic factor activates CREB and increases PS-1 expression in a dose-dependent fashion. By using adenovirus vectors expressing dominant negative forms of CREB, we were able to show that induction of PS-1 expression requires the activation of CREB. Conversely, constitutive expression of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) results in activation of CREB and increased PS-1 expression that can be blocked by the addition of selective MEK inhibitors. Our findings suggest a hypothesis where stimulation of N-methyl-d-aspartate receptors signals CREB activation to enhance PS-1 gene product expression that contributes to normal neuronal functions.
MeSH terms
Adenoviridae/geneticsAnimalsBase SequenceBinding SitesBlotting, NorthernBrain-Derived Neurotrophic Factor/pharmacologyCells, CulturedCyclic AMP/metabolism*Cyclic AMP Response Element-Binding Protein/geneticsCyclic AMP Response Element-Binding Protein/metabolism*Dose-Response Relationship, DrugElectrophoresis, Polyacrylamide GelExonsGene Expression Regulation*Genes, DominantHippocampus/metabolismHumansIntronsLuciferases/metabolismMembrane Proteins/biosynthesisMembrane Proteins/genetics*Membrane Proteins/metabolism*Membrane Proteins/physiologyMitogen-Activated Protein Kinases/antagonists & inhibitorsMitogen-Activated Protein Kinases/metabolismModels, GeneticMolecular Sequence DataN-Methylaspartate/metabolismNeurons/metabolism*Presenilin-1Promoter Regions, GeneticProtein BindingRNA, Messenger/metabolismRatsReceptors, Glutamate/metabolismReceptors, N-Methyl-D-Aspartate/metabolismSequence Analysis, DNASignal TransductionTime FactorsTranscription, GeneticTransfectionTumor Cells, Cultured
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Journal Papers > School of Medicine / Graduate School of Medicine > Anatomy
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