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Title

Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death

Authors
Wobser, Hella
Düssmann, Heiko
Kögel, Donat
Reimertz, Claus
Byrne, Maria M
Prehn, Jochen H M
Published in Journal of Biological Chemistry. 2002, vol. 277, no. 8, p. 6413-21
Abstract Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable. Mitochondrial cytochrome c release and activation of caspase-9 accompanied DN-HNF-1 alpha-induced apoptosis, suggesting the involvement of the mitochondrial apoptosis pathway. Activation of caspases was preceded by mitochondrial hyperpolarization and decreased expression of the anti-apoptotic protein Bcl-xL. Transient overexpression of Bcl-xL was sufficient to rescue INS-1 cells from DN-HNF-1 alpha-induced apoptosis. Both WT- and DN-HNF-1 alpha-expressing cells demonstrated similar increases in apoptosis when cultured at high glucose (25 mm). In contrast, induction of DN-HNF-1 alpha highly sensitized cells to ceramide toxicity. In cells cultured at low glucose, DN-HNF-1 alpha induction also caused up-regulation of the cell cycle inhibitor p27(KIP1). Therefore, our data indicate that increased sensitivity to the mitochondrial apoptosis pathway and decreased cell proliferation may account for the progressive loss of beta-cell function seen in MODY 3 subjects.
Keywords AnimalsApoptosis/physiologyCell Death/drug effectsCell LineDNA-Binding Proteins/geneticsDiabetes Mellitus, Type 2/genetics/physiopathologyDoxycycline/pharmacologyGlucose/pharmacologyHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaHumansInsulinomaMitochondria/physiologyMutationNuclear ProteinsPancreatic NeoplasmsProto-Oncogene Proteins c-bcl-2/genetics/metabolismRatsRecombinant Proteins/biosynthesisSuppression, GeneticTranscription Factors/geneticsTranscriptional Activation/drug effectsTransfectionTumor Cells, CulturedBcl-X Protein
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PMID: 11724785
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WOBSER, Hella et al. Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. In: Journal of Biological Chemistry, 2002, vol. 277, n° 8, p. 6413-21. https://archive-ouverte.unige.ch/unige:34525

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Deposited on : 2014-02-28

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