Phosphorylation-dependent degradation of transgenic CREB protein initiated by heterodimerization

Show simple item record Muravlev, AI en Young, Deborah en During, Matthew en 2012-03-27T20:52:34Z en 2007 en
dc.identifier.citation BRAIN RESEARCH 1130(1):31-37 26 Jan 2007 en
dc.identifier.issn 0006-8993 en
dc.identifier.uri en
dc.description.abstract The transcription factor CREB (cyclic AMP response element binding protein) is implicated in diverse brain functions and represents a prospective target in gene therapy for human disorders. However, the transgenic expression and stability of exogenously expressed CREB within the cell remains poorly characterized. Here we found that transient expression of a CREB dominant interfering mutant A-CREB or the inducible cAMP early repressor, ICER, led to the dramatic decrease of exogenously co-expressed CREB in 293 human embryonic kidney cells. Elevation of protein kinase A activity within the cells restored CREB protein levels. A-CREB did not effect the transient expression of a truncated CREB lacking the leucine zipper domain demonstrating a specific effect of heterodimerization on CREB protein stability. Somatic gene transfer into the rat brain using a recombinant adeno-associated virus vector provided robust expression of both transgenic CREB and ICER mRNAs under the control of a constitutive neuron specific enolase (NSE) promoter. In contrast to ICER, the expression of the transgenic CREB mRNA did not result in elevation of CREB protein levels within dentate granule cells of the hippocampus, suggesting its prompt degradation under basal conditions. However, following tetanization of the perforant pathway, which is known to induce CREB phosphorylation, there was a significant increase in the amount of transgenic CREB protein within dentate granule cells. Hence, heterodimerization of unphosphorylated CREB with either A-CREB or ICER triggers CREB protein degradation, whereas phosphorylation prevents CREB from such degradation both in vitro and in vivo. en
dc.publisher Elsevier en
dc.relation.ispartofseries Brain Research en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.title Phosphorylation-dependent degradation of transgenic CREB protein initiated by heterodimerization en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.brainres.2006.10.076 en
pubs.issue 1 en
pubs.begin-page 31 en
pubs.volume 1130 en
dc.rights.holder Copyright: Elsevier en
dc.identifier.pmid 17169345 en
pubs.end-page 37 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 75339 en Medical and Health Sciences en Medical Sciences en Pharmacology en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 17169345 en

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