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Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV
Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. --- Old month value: Apr 11
Activity-regulated transcription has been implicated in adaptive plasticity in the CNS. In many instances, this plasticity depends upon the transcription factor CREB. Precisely how neuronal activity regulates CREB remains unclear. To address this issue, we examined the phosphorylation state of components of the CREB transcriptional pathway. We show that NMDA activates transcription of CREB-responsive genes in hippocampal neurons, with ERK responsible for persistent CREB phosphorylation and CaM kinase IV (CaMKIV) responsible for phosphorylating the CREB coactivator, CBP. Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.
Amino Acid Sequence/genetics Animals COS Cells CREB-Binding Protein Calcium-Calmodulin-Dependent Protein Kinase Type 4 Calcium-Calmodulin-Dependent Protein Kinases/*physiology Cyclic AMP Response Element-Binding Protein/physiology Excitatory Amino Acid Agonists/pharmacology Gene Expression Regulation/physiology Mitogen-Activated Protein Kinases/physiology N-Methylaspartate/pharmacology Neurons/*physiology Nuclear Proteins/genetics/*metabolism Phosphorylation/drug effects Rats Receptors, N-Methyl-D-Aspartate/physiology Signal Transduction/physiology Trans-Activators/genetics/*metabolism Transcription, Genetic/genetics/*physiology
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