PMID- 22422769
OWN - NLM
STAT- MEDLINE
DCOM- 20121009
LR  - 20211021
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 21
IP  - 12
DP  - 2012 Jun 15
TI  - DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in 
      ATF4-mediated transcription.
PG  - 2779-92
LID - 10.1093/hmg/dds106 [doi]
AB  - Disrupted-In-Schizophrenia 1 (DISC1), a strong genetic candidate for psychiatric 
      illness, encodes a multicompartmentalized molecular scaffold that regulates 
      interacting proteins with key roles in neurodevelopment and plasticity. Missense 
      DISC1 variants are associated with the risk of mental illness and with brain 
      abnormalities in healthy carriers, but the underlying mechanisms are unclear. We 
      examined the effect of rare and common DISC1 amino acid substitutions on 
      subcellular targeting. We report that both the rare putatively causal variant 37W 
      and the common variant 607F independently disrupt DISC1 nuclear targeting in a 
      dominant-negative fashion, predicting that DISC1 nuclear expression is impaired 
      in 37W and 607F carriers. In the nucleus, DISC1 interacts with the transcription 
      factor Activating Transcription Factor 4 (ATF4), which is involved in the 
      regulation of cellular stress responses, emotional behaviour and memory 
      consolidation. At basal cAMP levels, wild-type DISC1 inhibits the transcriptional 
      activity of ATF4, an effect that is weakened by both 37W and 607F independently, 
      most likely as a consequence of their defective nuclear targeting. The common 
      variant 607F additionally reduces DISC1/ATF4 interaction, which likely 
      contributes to its weakened inhibitory effect. We also demonstrate that DISC1 
      modulates transcriptional responses to endoplasmic reticulum stress, and that 
      this modulatory effect is ablated by 37W and 607F. By showing that DISC1 amino 
      acid substitutions associated with psychiatric illness affect its regulatory 
      function in ATF4-mediated transcription, our study highlights a potential 
      mechanism by which these variants may impact on transcriptional events mediating 
      cognition, emotional reactivity and stress responses, all processes of direct 
      relevance to psychiatric illness.
FAU - Malavasi, Elise L V
AU  - Malavasi EL
AD  - The Centre for Molecular Medicine at the Medical Research Council Institute of 
      Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
FAU - Ogawa, Fumiaki
AU  - Ogawa F
FAU - Porteous, David J
AU  - Porteous DJ
FAU - Millar, J Kirsty
AU  - Millar JK
LA  - eng
GR  - G0100266/MRC_/Medical Research Council/United Kingdom
GR  - G0600214/MRC_/Medical Research Council/United Kingdom
GR  - G0902166/MRC_/Medical Research Council/United Kingdom
GR  - 083210/Z/07/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120315
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (ATF4 protein, human)
RN  - 0 (DISC1 protein, human)
RN  - 0 (Nerve Tissue Proteins)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Activating Transcription Factor 4/genetics/*metabolism
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Blotting, Western
MH  - COS Cells
MH  - Cell Line, Tumor
MH  - Cell Nucleus/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Hybrid Cells
MH  - Immunoprecipitation
MH  - Luciferases/genetics/metabolism
MH  - Microscopy, Confocal
MH  - *Mutation
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Oligodendroglia
MH  - Protein Binding
MH  - Rhabdomyosarcoma
MH  - *Transcription, Genetic
MH  - Transfection
PMC - PMC3363331
EDAT- 2012/03/17 06:00
MHDA- 2012/10/10 06:00
PMCR- 2012/03/15
CRDT- 2012/03/17 06:00
PHST- 2012/03/17 06:00 [entrez]
PHST- 2012/03/17 06:00 [pubmed]
PHST- 2012/10/10 06:00 [medline]
PHST- 2012/03/15 00:00 [pmc-release]
AID - dds106 [pii]
AID - 10.1093/hmg/dds106 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2012 Jun 15;21(12):2779-92. doi: 10.1093/hmg/dds106. Epub 2012 Mar 
      15.