Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells.

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Serval ID
serval:BIB_154499286590
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells.
Journal
Diabetologia
Author(s)
Roggli E., Gattesco S., Pautz A., Regazzi R.
ISSN
1432-0428 (Electronic)
ISSN-L
0012-186X
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
55
Number
6
Pages
1699-1708
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Abstract
AIMS/HYPOTHESIS: Chronic exposure of pancreatic beta cells to proinflammatory cytokines leads to impaired insulin secretion and apoptosis. ARE/poly(U)-binding factor 1 (AUF1) belongs to a protein family that controls mRNA stability and translation by associating with adenosine- and uridine-rich regions of target messengers. We investigated the involvement of AUF1 in cytokine-induced beta cell dysfunction.
METHODS: Production and subcellular distribution of AUF1 isoforms were analysed by western blotting. To test for their role in the control of beta cell functions, each isoform was overproduced individually in insulin-secreting cells. The contribution to cytokine-mediated beta cell dysfunction was evaluated by preventing the production of AUF1 isoforms by RNA interference. The effect of AUF1 on the production of potential targets was assessed by western blotting.
RESULTS: MIN6 cells and human pancreatic islets were found to produce four AUF1 isoforms (p42>p45>p37>p40). AUF1 isoforms were mainly localised in the nucleus but were partially translocated to the cytoplasm upon exposure of beta cells to cytokines and activation of the ERK pathway. Overproduction of AUF1 did not affect glucose-induced insulin secretion but promoted apoptosis. This effect was associated with a decrease in the production of the anti-apoptotic proteins, B cell leukaemia/lymphoma 2 (BCL2) and myeloid cell leukaemia sequence 1 (MCL1). Silencing of AUF1 isoforms restored the levels of the anti-apoptotic proteins, attenuated the activation of the nuclear factor-κB (NFκB) pathway, and protected the beta cells from cytokine-induced apoptosis.
CONCLUSIONS/INTERPRETATION: Our findings point to a contribution of AUF1 to the deleterious effects of cytokines on beta cell functions and suggest a role for this RNA-binding protein in the early phases of type 1 diabetes.
Keywords
Apoptosis/drug effects, Apoptosis/genetics, Blotting, Western, Cell Line, Heterogeneous-Nuclear Ribonucleoprotein D/genetics, Heterogeneous-Nuclear Ribonucleoprotein D/metabolism, Humans, Immunohistochemistry, Interferon-gamma/pharmacology, Interleukin-1beta/pharmacology, Islets of Langerhans/drug effects, Islets of Langerhans/metabolism, Protein Isoforms/genetics, Protein Isoforms/metabolism, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, RNA Interference
Pubmed
Web of science
Open Access
Yes
Create date
31/10/2012 14:06
Last modification date
25/09/2019 6:08
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