PMID- 30065031
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20181009
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 67
IP  - 10
DP  - 2018 Oct
TI  - The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory 
      Cytokines in Insulin-Producing Cells and Human Islets and Determine beta-Cell 
      Insulin Biosynthesis and Survival.
PG  - 2019-2037
LID - 10.2337/db18-0073 [doi]
AB  - Stress-related changes in beta-cell mRNA levels result from a balance between gene 
      transcription and mRNA decay. The regulation of RNA decay pathways has not been 
      investigated in pancreatic beta-cells. We found that no-go and nonsense-mediated RNA 
      decay pathway components (RDPCs) and exoribonuclease complexes were expressed in 
      INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were 
      upregulated by inflammatory cytokines in INS-1 cells under conditions where 
      central beta-cell mRNAs were downregulated. These changes in RDPC mRNA or 
      corresponding protein levels were largely confirmed in INS-1 cells and rat/human 
      islets. Cytokine-induced upregulation of Pelo, Xrn1, Dis3L2, Upf2, and Smg1/6 was 
      reduced by inducible nitric oxide synthase inhibition, as were endoplasmic 
      reticulum (ER) stress, inhibition of Ins1/2 mRNA, and accumulated insulin 
      secretion. Reactive oxygen species inhibition or iron chelation did not affect 
      RDPC expression. Pelo or Xrn1 knockdown (KD) aggravated, whereas Smg6 KD 
      ameliorated, cytokine-induced INS-1 cell death without affecting ER stress; both 
      increased insulin biosynthesis and medium accumulation but not glucose-stimulated 
      insulin secretion in cytokine-exposed INS-1 cells. In conclusion, RDPCs are 
      regulated by inflammatory stress in beta-cells. RDPC KD improved insulin 
      biosynthesis, likely by preventing Ins1/2 mRNA clearance. Pelo/Xrn1 KD 
      aggravated, but Smg6 KD ameliorated, cytokine-mediated beta-cell death, possibly 
      through prevention of proapoptotic and antiapoptotic mRNA degradation, 
      respectively.
CI  - (c) 2018 by the American Diabetes Association.
FAU - Ghiasi, Seyed Mojtaba
AU  - Ghiasi SM
AUID- ORCID: 0000-0001-8526-8513
AD  - Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Krogh, Nicolai
AU  - Krogh N
AD  - Department of Cellular and Molecular Medicine, University of Copenhagen, 
      Copenhagen, Denmark.
FAU - Tyrberg, Bjorn
AU  - Tyrberg B
AD  - Translational Science; Cardiovascular, Renal and Metabolism; and IMED Biotech 
      Unit, AstraZeneca, Gothenburg, Sweden.
FAU - Mandrup-Poulsen, Thomas
AU  - Mandrup-Poulsen T
AUID- ORCID: 0000-0002-3215-9273
AD  - Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark 
      tmpo@sund.ku.dk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180731
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Cytokines)
RN  - 0 (Insulin)
RN  - 0 (Nuclear Proteins)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 3.1.- (Exoribonucleases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Cytokines/*metabolism/pharmacology
MH  - Exoribonucleases/metabolism
MH  - Humans
MH  - Insulin/*metabolism
MH  - Insulin-Secreting Cells/*metabolism
MH  - Nuclear Proteins/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - RNA/*metabolism
MH  - RNA Stability/*genetics/physiology
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects
EDAT- 2018/08/02 06:00
MHDA- 2018/10/10 06:00
CRDT- 2018/08/02 06:00
PHST- 2018/01/17 00:00 [received]
PHST- 2018/07/23 00:00 [accepted]
PHST- 2018/08/02 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2018/08/02 06:00 [entrez]
AID - db18-0073 [pii]
AID - 10.2337/db18-0073 [doi]
PST - ppublish
SO  - Diabetes. 2018 Oct;67(10):2019-2037. doi: 10.2337/db18-0073. Epub 2018 Jul 31.