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1.
J Neurosci ; 32(5): 1826-46, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22302822

ABSTRACT

The GluR1 subunit of the AMPA receptor plays an important role in excitatory synaptic transmission and synaptic plasticity in the brain, but the regulation mechanism for GluR1 expression is largely unknown. Hairy and enhancer of split 1 (Hes-1) is a mammalian transcription repressor that regulates neuronal differentiation and development, but the role of Hes-1 in differentiated neurons is also less known. Here, we examined the molecular mechanism in regulation of GluR1 expression in rat cultured cortical neurons. We found that Hes-1 suppressed GluR1 promoter activity and decreased GluR1 expression through direct binding to the N-box and through preventing Mash1/E47 from binding to the E-box of GluR1 promoter. We also found that Hes-1 could be regulated by c-Jun N-terminal kinase (JNK1). JNK1 directly phosphorylates Hes-1 at Ser-263. Furthermore, JNK1 phosphorylation of Hes-1 stabilized the Hes-1 protein and enhanced the suppressing effect of Hes-1 on GluR1 expression. These effects were demonstrated both in the soma and at the synapse. Moreover, this JNK1-mediated signaling pathway was found to inhibit AMPA-evoked calcium influx in cortical neurons and this regulation mechanism is Notch independent. Here, we provided the first evidence that Hes-1 plays an important role in synaptic function in differentiated neurons. We also identified a novel JNK1-Hes-1 signaling pathway that regulates GluR1 expression involved in synaptic function in rat cortical neurons.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Calcium/metabolism , Gene Expression Regulation , Homeodomain Proteins/metabolism , Mitogen-Activated Protein Kinase 8/metabolism , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/biosynthesis , Animals , Cells, Cultured , Cerebral Cortex/metabolism , Cerebral Cortex/physiology , Hippocampus/metabolism , Hippocampus/physiology , Male , Phosphorylation/physiology , Protein Stability , Rats , Rats, Sprague-Dawley , Receptors, AMPA/physiology , Transcription Factor HES-1
2.
Mol Cell Biol ; 26(22): 8357-70, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16982696

ABSTRACT

Serum- and glucocorticoid-inducible kinase 1 (SGK1) is a member of the Ser/Thr protein kinase family that regulates a variety of cell functions. Recently, SGK1 was shown to increase dendritic growth but the mechanism underlying the increase is unknown. Here we demonstrated that SGK1 increased the neurite formation of cultured hippocampal neurons through microtubule (MT) depolymerization via two distinct mechanisms. First, SGK1 directly depolymerized MTs. In vitro MT depolymerization experiments revealed that SGK1, especially N-truncated SGK1, directly disassembled self-polymerized MTs and taxol-stabilized MTs in a dose-dependent and ATP-independent manner. The transfection of sgk1 to HeLa cells also inhibited MT assembly in vivo. Second, SGK1 indirectly depolymerized MTs through the phosphorylation of tau at Ser214. An in vitro kinase assay revealed that active SGK1 phosphorylated tau Ser214 specifically. In vivo transfection of sgk1 also phosphorylated tau Ser214 in HEK293T cells and hippocampal neurons. Further, sgk1 transfection significantly increased the number of primary neurites and shortened the length of the total process in cultured hippocampal neurons. These effects were antagonized by the cotransfection of the tauS214A mutant plasmid. Dexamethasone, a synthetic glucocorticoid, mimics the effect of sgk1 overexpression. Together, these results suggest that SGK1 enhances neurite formation through MT depolymerization by a direct action of SGK1 and by the SGK1 phosphorylation of tau.


Subject(s)
Immediate-Early Proteins/physiology , Microtubules/physiology , Neurites/physiology , Protein Serine-Threonine Kinases/physiology , tau Proteins/metabolism , Animals , Cells, Cultured , Female , Hippocampus/cytology , Hippocampus/enzymology , Immediate-Early Proteins/genetics , Immediate-Early Proteins/metabolism , Neurites/enzymology , Neurons/enzymology , Neurons/physiology , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Serine , Transfection
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