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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/E1067    most recent 00212.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mokhtari, D. Articles by Welsh, N. PubMed PubMed Citation Articles by Mokhtari, D. Articles by Welsh, N.

Overexpression of the nuclear factor-B subunit c-Rel protects against human islet cell death in vitro

¹Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; ²Hannover Medical School, Institute of Clinical Biochemistry, Hannover, Germany; and ³Institut de Biologie de Lille, Centre National de la Recherche Scientifique UMR 8161, Lille, France

Submitted 31 March 2009 ; accepted in final form 20 August 2009

The transcription factor nuclear factor (NF)-B is known to modulate rates of apoptosis and may therefore play a role in the increased β-cell death that occurs in type 1 and type 2 diabetes. The aim of the present investigation was to study the expression of NF-B subunits in human islet cells and whether overexpression of the NF-B subunit c-Rel affects islet cell survival. We detected expression of p65, Rel-B, p50, p105, p52, and the ribosomal protein S3 (rpS3) in human islet cells. Among these, only p65 and rpS3 were translocated from the cytosolic to the nuclear fraction in response to cytokines. Interestingly, rpS3 participated in p65 binding to the B-element in gel shift analysis experiments. We observed cytoplasmic c-Rel expression in vivo in 6J mice, and signs of nuclear translocation in β-cells of infiltrated nonobese diabetic islets. Human islet cells were also dispersed by trypsin treatment and transduced with a c-Rel adenoviral vector. This resulted in increased expression of c-Rel and inhibitory factor B, increased B-binding activity, and augmented protein levels of Bcl-X_L, c-IAP2, and heat shock protein 72. c-Rel expression in human islet cells protected against cytokine-induced caspase 3 activation and cell death. c-Rel protected also against streptozotocin- and H₂O₂-induced cell death, in both intact rat islets and human islet cells. We conclude that rpS3 participates in NF-B signaling and that a genetic increase in the activity of the NF-B subunit c-Rel results in protection against cell death in human islets.

β-cell apoptosis; ribosomal protein S3; Bcl-X_L; heat shock protein 72; caspase 3