PMID- 19825843
OWN - NLM
STAT- MEDLINE
DCOM- 20100309
LR  - 20211020
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 19
IP  - 1
DP  - 2010 Jan 1
TI  - MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic 
      beta-cell responses to the viral by-product double-stranded RNA.
PG  - 135-46
LID - 10.1093/hmg/ddp474 [doi]
AB  - beta-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of 
      a 'dialog' between beta-cells and immune system. This dialog may be affected by 
      the individual's genetic background. We presently evaluated whether modulation of 
      MDA5 and PTPN2, two candidate genes for T1D, affects beta-cell responses to 
      double-stranded RNA (dsRNA), a by-product of viral replication. These genes were 
      selected following comparison between known candidate genes for T1D and genes 
      expressed in pancreatic beta-cells, as identified in previous array analysis. 
      INS-1E cells and primary fluorescence-activated cell sorting-purified rat 
      beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 
      or PTPN2 and subsequently exposed to intracellular synthetic dsRNA 
      (polyinosinic-polycitidilic acid-PIC). Real-time RT-PCR, western blot and 
      viability assays were performed to characterize gene/protein expression and 
      viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by 
      the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and 
      this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not 
      modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced 
      cytokine and chemokine expression, although inhibition of PTPN2 induced minor or 
      no changes in these inflammatory mediators. These findings indicate that changes 
      in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates 
      inflammatory signals, whereas PTPN2 may function as a defence mechanism against 
      pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may 
      thus modulate beta-cell apoptosis and/or local release of inflammatory mediators 
      in the course of a viral infection by acting, at least in part, at the pancreatic 
      beta-cell level.
FAU - Colli, Maikel L
AU  - Colli ML
AD  - Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Brussels, 
      Belgium.
FAU - Moore, Fabrice
AU  - Moore F
FAU - Gurzov, Esteban N
AU  - Gurzov EN
FAU - Ortis, Fernanda
AU  - Ortis F
FAU - Eizirik, Decio L
AU  - Eizirik DL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Chemokines)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Double-Stranded)
RN  - 0 (RNA, Small Interfering)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 2)
RN  - EC 3.1.3.48 (Ptpn2 protein, rat)
RN  - EC 3.6.4.13 (DEAD-box RNA Helicases)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Chemokines/metabolism
MH  - DEAD-box RNA Helicases/*metabolism
MH  - Diabetes Mellitus, Type 1/*enzymology/*genetics
MH  - Enzyme Activation/drug effects
MH  - Insulin-Secreting Cells/enzymology/*pathology
MH  - Interferon-beta/genetics
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Male
MH  - NF-kappa B/metabolism
MH  - Poly I-C/pharmacology
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 2/*metabolism
MH  - RNA, Double-Stranded/*pharmacology
MH  - RNA, Small Interfering/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Viruses/*metabolism
PMC - PMC2792153
EDAT- 2009/10/15 06:00
MHDA- 2010/03/10 06:00
PMCR- 2009/10/13
CRDT- 2009/10/15 06:00
PHST- 2009/10/15 06:00 [entrez]
PHST- 2009/10/15 06:00 [pubmed]
PHST- 2010/03/10 06:00 [medline]
PHST- 2009/10/13 00:00 [pmc-release]
AID - ddp474 [pii]
AID - 10.1093/hmg/ddp474 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2010 Jan 1;19(1):135-46. doi: 10.1093/hmg/ddp474.