PMID- 23737756
OWN - NLM
STAT- MEDLINE
DCOM- 20130910
LR  - 20211021
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 9
IP  - 5
DP  - 2013 May
TI  - GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic 
      beta cell apoptosis via regulation of a splice variant of the BH3-only protein 
      Bim.
PG  - e1003532
LID - 10.1371/journal.pgen.1003532 [doi]
LID - e1003532
AB  - Mutations in human Gli-similar (GLIS) 3 protein cause neonatal diabetes. The 
      GLIS3 gene region has also been identified as a susceptibility risk locus for 
      both type 1 and type 2 diabetes. GLIS3 plays a role in the generation of 
      pancreatic beta cells and in insulin gene expression, but there is no information 
      on the role of this gene on beta cell viability and/or susceptibility to immune- 
      and metabolic-induced stress. GLIS3 knockdown (KD) in INS-1E cells, primary 
      FACS-purified rat beta cells, and human islet cells decreased expression of MafA, 
      Ins2, and Glut2 and inhibited glucose oxidation and insulin secretion, confirming 
      the role of this transcription factor for the beta cell differentiated phenotype. 
      GLIS3 KD increased beta cell apoptosis basally and sensitized the cells to death 
      induced by pro-inflammatory cytokines (interleukin 1beta + interferon-gamma) or 
      palmitate, agents that may contribute to beta cell loss in respectively type 1 
      and 2 diabetes. The increased cell death was due to activation of the intrinsic 
      (mitochondrial) pathway of apoptosis, as indicated by cytochrome c release to the 
      cytosol, Bax translocation to the mitochondria and activation of caspases 9 and 
      3. Analysis of the pathways implicated in beta cell apoptosis following GLIS3 KD 
      indicated modulation of alternative splicing of the pro-apoptotic BH3-only 
      protein Bim, favouring expression of the pro-death variant BimS via inhibition of 
      the splicing factor SRp55. KD of Bim abrogated the pro-apoptotic effect of GLIS3 
      loss of function alone or in combination with cytokines or palmitate. The present 
      data suggest that altered expression of the candidate gene GLIS3 may contribute 
      to both type 1 and 2 type diabetes by favouring beta cell apoptosis. This is 
      mediated by alternative splicing of the pro-apoptotic protein Bim and exacerbated 
      formation of the most pro-apoptotic variant BimS.
FAU - Nogueira, Tatiane C
AU  - Nogueira TC
AD  - Laboratory of Experimental Medicine, Medical Faculty, Universite Libre de 
      Bruxelles, Brussels, Belgium.
FAU - Paula, Flavia M
AU  - Paula FM
FAU - Villate, Olatz
AU  - Villate O
FAU - Colli, Maikel L
AU  - Colli ML
FAU - Moura, Rodrigo F
AU  - Moura RF
FAU - Cunha, Daniel A
AU  - Cunha DA
FAU - Marselli, Lorella
AU  - Marselli L
FAU - Marchetti, Piero
AU  - Marchetti P
FAU - Cnop, Miriam
AU  - Cnop M
FAU - Julier, Cecile
AU  - Julier C
FAU - Eizirik, Decio L
AU  - Eizirik DL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130530
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BCL2L11 protein, human)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Bcl2l11 protein, mouse)
RN  - 0 (Bcl2l11 protein, rat)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (GLIS3 protein, human)
RN  - 0 (GLIS3 protein, rat)
RN  - 0 (Insulin)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Aged
MH  - Alternative Splicing/genetics
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Apoptosis Regulatory Proteins/*genetics/metabolism
MH  - Bcl-2-Like Protein 11
MH  - DNA-Binding Proteins
MH  - Diabetes Mellitus, Type 1/etiology/*genetics
MH  - Diabetes Mellitus, Type 2/etiology/*genetics
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Insulin/genetics
MH  - Insulin-Secreting Cells/metabolism/pathology
MH  - Male
MH  - Membrane Proteins/*genetics/metabolism
MH  - Mice
MH  - Middle Aged
MH  - Protein Isoforms/genetics
MH  - Proto-Oncogene Proteins/*genetics/metabolism
MH  - Rats
MH  - Repressor Proteins
MH  - Trans-Activators
MH  - Transcription Factors/*genetics
PMC - PMC3667755
COIS- The authors have declared that no competing interests exist.
EDAT- 2013/06/06 06:00
MHDA- 2013/09/11 06:00
PMCR- 2013/05/01
CRDT- 2013/06/06 06:00
PHST- 2012/10/29 00:00 [received]
PHST- 2013/04/12 00:00 [accepted]
PHST- 2013/06/06 06:00 [entrez]
PHST- 2013/06/06 06:00 [pubmed]
PHST- 2013/09/11 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - PGENETICS-D-12-02709 [pii]
AID - 10.1371/journal.pgen.1003532 [doi]
PST - ppublish
SO  - PLoS Genet. 2013 May;9(5):e1003532. doi: 10.1371/journal.pgen.1003532. Epub 2013 
      May 30.