PMID- 22653339
OWN - NLM
STAT- MEDLINE
DCOM- 20130304
LR  - 20211021
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 19
IP  - 11
DP  - 2012 Nov
TI  - C/EBP homologous protein contributes to cytokine-induced pro-inflammatory 
      responses and apoptosis in beta-cells.
PG  - 1836-46
LID - 10.1038/cdd.2012.67 [doi]
AB  - Induction of the C/EBP homologous protein (CHOP) is considered a key event for 
      endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is 
      characterized by an autoimmune destruction of the pancreatic beta-cells. 
      Pro-inflammatory cytokines are early mediators of beta-cell death in T1D. Cytokines 
      induce ER stress and CHOP overexpression in beta-cells, but the role for CHOP 
      overexpression in cytokine-induced beta-cell apoptosis remains controversial. We 
      presently observed that CHOP knockdown (KD) prevents cytokine-mediated 
      degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid 
      cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner 
      caspases 9 and 3, and apoptosis. Nuclear factor-kappaB (NF-kappaB) is a crucial 
      transcription factor regulating beta-cell apoptosis and inflammation. CHOP KD 
      resulted in reduced cytokine-induced NF-kappaB activity and expression of key NF-kappaB 
      target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, 
      IL-15, CCL5 and CXCL10. This was due to decreased IkappaB degradation and p65 
      translocation to the nucleus. The present data suggest that CHOP has a dual role 
      in promoting beta-cell death: (1) CHOP directly contributes to cytokine-induced 
      beta-cell apoptosis by promoting cytokine-induced mitochondrial pathways of 
      apoptosis; and (2) by supporting the NF-kappaB activation and subsequent 
      cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo 
      attraction of mononuclear cells to the islets during insulitis.
FAU - Allagnat, F
AU  - Allagnat F
AD  - Laboratoire de Medecine Experimentale, Universite Libre de Bruxelles, Brussels, 
      Belgium.
FAU - Fukaya, M
AU  - Fukaya M
FAU - Nogueira, T C
AU  - Nogueira TC
FAU - Delaroche, D
AU  - Delaroche D
FAU - Welsh, N
AU  - Welsh N
FAU - Marselli, L
AU  - Marselli L
FAU - Marchetti, P
AU  - Marchetti P
FAU - Haefliger, J A
AU  - Haefliger JA
FAU - Eizirik, D L
AU  - Eizirik DL
FAU - Cardozo, A K
AU  - Cardozo AK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120601
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Mcl1 protein, rat)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (NF-kappa B)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Cytokines/*pharmacology
MH  - Diabetes Mellitus, Type 1/metabolism/pathology
MH  - Endoplasmic Reticulum Stress
MH  - I-kappa B Kinase/metabolism
MH  - Insulin-Secreting Cells/cytology/*metabolism
MH  - Interferon-gamma/pharmacology
MH  - Interleukin-1beta/pharmacology
MH  - Mitochondria/metabolism
MH  - Myeloid Cell Leukemia Sequence 1 Protein
MH  - NF-kappa B/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Rats
MH  - Transcription Factor CHOP/antagonists & inhibitors/genetics/*metabolism
MH  - Transcription Factor RelA/metabolism
MH  - Tumor Necrosis Factor-alpha/pharmacology
PMC - PMC3469067
EDAT- 2012/06/02 06:00
MHDA- 2013/03/05 06:00
PMCR- 2013/11/01
CRDT- 2012/06/02 06:00
PHST- 2012/06/02 06:00 [entrez]
PHST- 2012/06/02 06:00 [pubmed]
PHST- 2013/03/05 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - cdd201267 [pii]
AID - 10.1038/cdd.2012.67 [doi]
PST - ppublish
SO  - Cell Death Differ. 2012 Nov;19(11):1836-46. doi: 10.1038/cdd.2012.67. Epub 2012 
      Jun 1.