Role of salt-inducible kinase 1 in the activation of MEF2-dependent transcription by BDNF.

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License: CC BY 4.0
Serval ID
serval:BIB_AB4DFF32CF82
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Role of salt-inducible kinase 1 in the activation of MEF2-dependent transcription by BDNF.
Journal
Plos One
Author(s)
Finsterwald C., Carrard A., Martin J.L.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2013
Volume
8
Number
1
Pages
e54545
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
Substantial evidence supports a role for myocyte enhancer factor 2 (MEF2)-mediated transcription in neuronal survival, differentiation and synaptic function. In developing neurons, it has been shown that MEF2-dependent transcription is regulated by neurotrophins. Despite these observations, little is known about the cellular mechanisms by which neurotrophins activate MEF2 transcriptional activity. In this study, we examined the role of salt-inducible kinase 1 (SIK1), a member of the AMP-activated protein kinase (AMPK) family, in the regulation of MEF2-mediated transcription by the neurotrophin brain-derived neurotrophic factor (BDNF). We show that BDNF increases the expression of SIK1 in primary cultures of rat cortical neurons through the extracellular signal-regulated kinase 1/2 (ERK1/2)-signaling pathway. In addition to inducing SIK1 expression, BDNF triggers the phosphorylation of SIK1 at Thr182 and its translocation from the cytoplasm to the nucleus of cortical neurons. The effects of BDNF on the expression, phosphorylation and, translocation of SIK1 are followed by the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5). Blockade of SIK activity with a low concentration of staurosporine abolished BDNF-induced phosphorylation and nuclear export of HDAC5 in cortical neurons. Importantly, stimulation of HDAC5 phosphorylation and nuclear export by BDNF is accompanied by the activation of MEF2-mediated transcription, an effect that is suppressed by staurosporine. Consistent with these data, BDNF induces the expression of the MEF2 target genes Arc and Nur77, in a staurosporine-sensitive manner. In further support of the role of SIK1 in the regulation of MEF2-dependent transcription by BDNF, we found that expression of wild-type SIK1 or S577A SIK1, a mutated form of SIK1 which is retained in the nucleus of transfected cells, is sufficient to enhance MEF2 transcriptional activity in cortical neurons. Together, these data identify a previously unrecognized mechanism by which SIK1 mediates the activation of MEF2-dependent transcription by BDNF.
Keywords
Animals, Brain-Derived Neurotrophic Factor/genetics, Brain-Derived Neurotrophic Factor/metabolism, Histone Deacetylases/metabolism, MADS Domain Proteins/genetics, MADS Domain Proteins/metabolism, MAP Kinase Signaling System/genetics, Myogenic Regulatory Factors/genetics, Myogenic Regulatory Factors/metabolism, Neurons/drug effects, Neurons/metabolism, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/metabolism, Rats, Signal Transduction/drug effects, Staurosporine/pharmacology, Transcriptional Activation/drug effects, Transcriptional Activation/genetics
Pubmed
Web of science
Open Access
Yes
Create date
19/09/2013 20:11
Last modification date
20/08/2019 15:15
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