Document Detail

Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels.
MedLine Citation:
PMID:  20940047     Owner:  NLM     Status:  MEDLINE    
CREB is a ubiquitously expressed transcription factor regulating gene expression via binding to a CRE DNA element. Previous work showed that the dual leucine zipper kinase (DLK) reduced CREB-dependent gene transcription at least in part via inhibition of the coactivator CBP. Here we demonstrate that DLK also inhibits CREB activity by affecting the interaction of CREB with its second coactivator TORC. DLK acted on TORC-dependent transcription by distinct mechanisms. An interaction between DLK and all three TORC isoforms was demonstrated by in vitro protein-protein interaction assays and in cells by coimmunoprecipitation that required the N-terminus of TORC and the leucine zipper of dimerized DLK. Overexpressed DLK induced the phosphorylation of TORC2 and TORC1 on Ser-171 and 167, respectively and on additional residues. Since a kinase-dead DLK mutant did not prevent the nuclear localization of TORC and did not reduce TORC transcriptional activity to the same extent as wild-type DLK, we suggest that DLK-induced phosphorylation of TORC contributes to DLK's inhibitory action. Both the interaction with and the phosphorylation of TORC by DLK might account for the reduced recruitment of TORC to a CRE containing promoter as revealed by chromatin immunoprecipitation assay. These results show for the first time the inhibition of TORC function by a mitogen-activated kinase. Given the dependence on TORC in CREB-directed gene transcription, DLK and its downstream kinases thus contribute to the finely tuned regulation of CREB-dependent effects.
Do Thanh Phu; Manuel Wallbach; Chantal Depatie; Accalia Fu; Robert A Screaton; Elke Oetjen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-19
Journal Detail:
Title:  Cellular signalling     Volume:  23     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2010-12-07     Completed Date:  2011-04-15     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  344-53     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
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MeSH Terms
Cell Line
Cyclic AMP Response Element-Binding Protein / genetics,  physiology*
MAP Kinase Kinase Kinases / physiology*
Promoter Regions, Genetic
Protein Structure, Tertiary
Transcription Factors / genetics,  metabolism*
Transcription, Genetic
Grant Support
MOP 84244//Canadian Institutes of Health Research
Reg. No./Substance:
0/Cyclic AMP Response Element-Binding Protein; 0/Transcription Factors; EC Kinase Kinase Kinases; EC protein kinase kinase kinase 12

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