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Type: Artigo de Periódico
Title: A20 Inhibits Beta-cell Apoptosis By Multiple Mechanisms And Predicts Residual Beta-cell Function In Type 1 Diabetes
Author: Fukaya
M; Brorsson
CA; Meyerovich
K; Catrysse
L; Delaroche
D; Vanzela
EC; Ortis
F; Beyaert
R; Nielsen
LB; Andersen
ML; Mortensen
HB; Pociot
F; van Loo
G; Storling
J; Cardozo
Abstract: Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to beta-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-kappa B signaling and has strong antiapoptotic activities in beta-cells. Although the role of A20 on NF-kappa B inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the beta-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in beta-cells that are not restricted to inhibition of NF-kappa B. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual beta-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of beta-cell survival and unveil novel mechanisms by which A20 controls beta-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.
Subject: Endoplasmic-reticulum Stress
Insulinoma Cells
Candidate Gene
Jnk Inhibitor
Citation: Molecular Endocrinology. ENDOCRINE SOC, n. 30, n. 1, p. 48 - 61.
Rights: fechado
Identifier DOI: 10.1210/me.2015-1176
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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