RGD Reference Report - STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation. - Rat Genome Database

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STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.

Authors: Moore, F  Naamane, N  Colli, ML  Bouckenooghe, T  Ortis, F  Gurzov, EN  Igoillo-Esteve, M  Mathieu, C  Bontempi, G  Thykjaer, T  Orntoft, TF  Eizirik, DL 
Citation: Moore F, etal., J Biol Chem. 2011 Jan 14;286(2):929-41. Epub 2010 Oct 27.
RGD ID: 5128774
Pubmed: PMID:20980260   (View Abstract at PubMed)
PMCID: PMC3020778   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M110.162131   (Journal Full-text)

Cytokines produced by islet-infiltrating immune cells induce beta-cell apoptosis in type 1 diabetes. The IFN-gamma-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on beta-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in beta-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1beta and IFN-gamma. Relevant microarray findings were further studied in INS-1E cells and primary rat beta-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated beta-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-gamma/STAT1/IRF-1 axis controls beta-cell function/differentiation, demise, and islet inflammation.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of tyrosine phosphorylation of STAT protein  IMP 5128774 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Jak-Stat signaling pathway   ISOIrf1 (Rattus norvegicus)5128774; 5128774 RGD 
Jak-Stat signaling pathway   IMP 5128774 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Irf1  (interferon regulatory factor 1)

Genes (Mus musculus)
Irf1  (interferon regulatory factor 1)

Genes (Homo sapiens)
IRF1  (interferon regulatory factor 1)


Additional Information