PMID- 23083128
OWN - NLM
STAT- MEDLINE
DCOM- 20130207
LR  - 20220129
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 124
IP  - 1
DP  - 2013 Jan
TI  - SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their 
      CaM kinase phosphorylation sites.
PG  - 26-35
LID - 10.1111/jnc.12058 [doi]
AB  - The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal 
      survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal 
      sites promote their nuclear export. We investigated whether non-canonical 
      signaling routes to Class IIa HDAC export exist because of their association with 
      the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors 
      (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal 
      phosphorylation sites (HDAC4(MUT), HDAC5(MUT)) are constitutively nuclear, 
      co-expression with SMRT renders them exportable by signals that trigger SMRT 
      export, such as synaptic activity, HDAC inhibition, and Brain Derived 
      Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 
      (RD3) is critical for co-shuttling of HDAC5(MUT), consistent with the role for 
      this domain in Class IIa HDAC association. In the context of BDNF signaling, we 
      found that HDAC5(WT), which was more cytoplasmic than HDAC5(MUT), accumulated in 
      the nucleus after BDNF treatment. However, co-expression of SMRT blocked 
      BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated 
      HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation 
      observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs 
      exportable by a wider range of signals than those which simply promote direct 
      phosphorylation.
CI  - (c) 2012 International Society for Neurochemistry.
FAU - Soriano, Francesc X
AU  - Soriano FX
AD  - Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK. 
      f.x.soriano@ub.edu
FAU - Chawla, Sangeeta
AU  - Chawla S
FAU - Skehel, Paul
AU  - Skehel P
FAU - Hardingham, Giles E
AU  - Hardingham GE
LA  - eng
GR  - 087491/Wellcome Trust/United Kingdom
GR  - BB/D011388/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - G0902044/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121115
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Nuclear Receptor Co-Repressor 2)
RN  - 0 (silencing mediator of retinoic acid and thyroid hormone receptors, rat)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 3X2S926L3Z (trichostatin A)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism/pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinases/genetics/*metabolism
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Embryo, Mammalian
MH  - Green Fluorescent Proteins/genetics
MH  - Histone Deacetylase Inhibitors/pharmacology
MH  - Histone Deacetylases/genetics/*metabolism
MH  - Hydroxamic Acids/pharmacology
MH  - Mutation/genetics
MH  - Neurons
MH  - Nuclear Receptor Co-Repressor 2/genetics/*metabolism
MH  - Phosphorylation/physiology
MH  - Protein Transport/drug effects/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects/genetics
MH  - Transfection
PMC - PMC3557716
EDAT- 2012/10/23 06:00
MHDA- 2013/02/08 06:00
CRDT- 2012/10/23 06:00
PHST- 2012/05/30 00:00 [received]
PHST- 2012/09/28 00:00 [revised]
PHST- 2012/10/07 00:00 [accepted]
PHST- 2012/10/23 06:00 [entrez]
PHST- 2012/10/23 06:00 [pubmed]
PHST- 2013/02/08 06:00 [medline]
AID - 10.1111/jnc.12058 [doi]
PST - ppublish
SO  - J Neurochem. 2013 Jan;124(1):26-35. doi: 10.1111/jnc.12058. Epub 2012 Nov 15.