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

Upon binding to the cAMP-response element of a gene's promoter, the transcr iption factor known as cAMP-response element-binding protein (CREB) facilit ates transcription of many different neuronal genes including those involve d with synaptic function. Based on our previous reports of gene structure ( GenBank (TM) accession number AF029701), we now demonstrate that activated CREB binds to the proximal promoter of the human presenilin-1 (PS-1) gene t o activate PS-l transcription in rat and in human neuronal cells. Specific stimulation of the N-methyl-D-aspartate subtype of neuronal glutamate recep tors activates CREB and results in increased PS-l expression. Similarly, tr eatment with brain-derived neurotrophic factor activates CREB and increases PS-l expression in a dose-dependent fashion. By using adenovirus vectors e xpressing dominant negative forms of CREB, we were able to show that induct ion of PS-l expression requires the activation of CREB, Conversely, constit utive expression of mitogen-activated protein kinase/extracellular signal-r egulated kinase (MEK) results in activation of CREB and increased PS-1 expr ession that can be blocked by the addition of selective MEK inhibitors. Our findings suggest a hypothesis where stimulation of N-methyl-D-aspartate re ceptors signals CREB activation to enhance PS-l gene product expression tha t contributes to normal neuronal functions.