Complexin I regulates glucose-induced secretion in pancreatic β-cells

Abderrahmani, Amar; Niederhäuser, Guy; Plaisance, Valérie; Roehrich, Marc-Estienne; Lenain, Vincent; Coppola, Thierry; Regazzi, Romano; Waeber, Gérard

doi:10.1242/jcs.01041

Cited by 63 publications

(54 citation statements)

References 51 publications

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“…The complementary target sequences of IB1 and thymidines are underlined and in bold, respectively. These primers are hybridized and ligated downstream of the H1-RNA promoter by HindIII/BglII sites of the pSUPER vector (31). A 19-nucleotide prevalidated siRNA duplex (siIB1) that corresponds to the shIB1 sequence was designed as recommended and was chemically synthesized by Mycrosynth (Balgach, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

Ferdaoussi

Abdelli²,

Yang³

et al. 2008

Diabetes

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133

113

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OBJECTIVE— The pro-inflammatory cytokine interleukin-1β (IL-1β) generates pancreatic β-cells apoptosis mainly through activation of the c-Jun NH2-terminal kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone glucagon-like peptide 1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against cytokine-induced β-cell apoptosis, could interfere with the JNK pathway. RESEARCH DESIGN AND METHODS— Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1β. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. RESULTS— Ex-4 inhibited induction of the JNK pathway elicited by IL-1β. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin was concomitant with a rise in the levels of islet-brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1β. CONCLUSIONS— The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1β and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.

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Section: Methodsmentioning

confidence: 99%

Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

Ferdaoussi

Abdelli²,

Yang³

et al. 2008

Diabetes

Self Cite

133

113

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“…Western Blotting Analysis and Immunoprecipitation-Nuclear proteins (50 g) from HeLa and ␤TC3 cells were prepared and subjected to Western blot as described (23). For co-immunoprecipitation experiments, 100 g of nuclear extracts were incubated with 0.5 g of the appropriate antibodies (Sp1 and green fluorescent protein (GFP) from Santa Cruz Biotechnology) for 16 h at 4°C in 500 l of immunoprecipitation buffer (20 mM Hepes-KOH, pH 7.9, 25% glycerol, 420 mM NaCl, 1.5 mM MgCl 2 , 0.2 mM EDTA, 0.5 mM dithiothreitol, and 0.2 mM phenylmethylsulfonyl fluoride).…”

Section: Methodsmentioning

confidence: 99%

“…We suggest that silencing of REST target genes in Huntington's disease could also be because of a loss of the Sp1-dependent activation resulting from the abnormal presence of REST in neuronal cells. The REST target genes play important roles in controlling neuronal differentiation and glucose-induced insulin secretion (15,16,23). The proper timing of REST target-gene expression during development is required for an appropriate terminal differentiation of the central nervous system (7).…”

Section: Fig 9 the C-terminal Repressor Domain Of Rest Abolishesmentioning

confidence: 99%

“…The absence of REST and the presence of its target genes in differentiated ␤-cells suggest a similar function for REST during pancreas development. The spatial and temporal silencing of REST is therefore thought to be related with the appearance of ␤-cells and neuronal cell phenotypes during pancreas and neuronal development (15,16,23). Conversely, Sp1 expression is postulated to be required for the maintenance of terminally differentiated cells (49).…”

Section: Fig 9 the C-terminal Repressor Domain Of Rest Abolishesmentioning

confidence: 99%

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The Repressor Element Silencing Transcription Factor (REST)-mediated Transcriptional Repression Requires the Inhibition of Sp1

Plaisance

Niederhäuser

Azzouz

et al. 2005

Journal of Biological Chemistry

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The terminal differentiation of neuronal and pancreatic ␤-cells requires the specific expression of genes that are targets of an important transcriptional repressor named RE-1 silencing transcription factor (REST). The molecular mechanism by which these REST target genes are expressed only in neuronal and ␤-cells and are repressed by REST in other tissues is a central issue in differentiation program of neuronal and ␤-cells. Herein, we showed that the transcriptional factor Sp1 was required for expression of most REST target genes both in insulin-secreting cells and neuronal-like cells where REST is absent. Inhibition of REST in a non-␤ and a non-neuronal cell model restored the transcriptional activity of Sp1. This activity was also restored by trichostatin A indicating the requirement of histone deacetylases for the REST-mediated silencing of Sp1. Conversely, exogenous introduction of REST blocked Sp1-mediated transcriptional activity. The REST inhibitory effect was mediated through its C-terminal repressor domain, which could interact with Sp1. Taken together, these data show that the inhibition of Sp1 by REST is required for the silencing of its target genes expression in non-neuronal and in non-␤-cells. We conclude that the interplay between REST and Sp1 determines the cell-specific expression of REST target genes.

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“…In the brain, complexins I and II are expressed by distinct subsets of neurons (Eastwood et al 2000, Freeman & Morton 2004. They are encoded by two different genes and differently regulated (Abderrahmani et al 2004); however, they have a similar function, to regulate SNARE-mediated exocytosis (McMahon et al 1995). A recent study using permeabilized sperm suggested that either complexin I or II is necessary to promote acrosomal exocytosis (Roggero et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Complexin-I-deficient sperm are subfertile due to a defect in zona pellucida penetration

2008

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Upon adhesion to the zona pellucida, sperm undergo regulated exocytosis of the acrosome. Although it is necessary for sperm to penetrate the zona pellucida and fertilize an egg, the acrosomal membrane fusion process is poorly understood. Complexins I and II are small, cytosolic proteins that bind to a complex of proteins termed the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex to regulate synaptic vesicle exocytosis. Complexin-II-deficient mice are fertile but the fertility of sperm from complexin-I-deficient male mice is unclear because the mice have ataxia and cannot mate. Here, we show that the genes encoding complexins I and II are expressed in primary spermatocytes and spermatids. Complexin proteins were found in/near the developing acrosome in spermatids and in or around the acrosome of mature sperm. Cell fractionation demonstrated that complexins I and II were predominantly found in the cytosolic fraction. Furthermore, sperm from complexin-I-deficient mice had normal morphology, number, and only small differences in motility, as assessed by computer-assisted semen analysis. Complexin-I-deficient sperm capacitated normally and bound to the zona pellucida. But when sperm from complexin-I-deficient mice were inseminated into females, a defect in fertility was observed, in concordance with previous data showing that in vitro fertilization rate was also reduced. If the zona pellucida was removed prior to in vitro fertilization, fertility was normal, demonstrating that zona pellucida penetration was defective, a step requiring acrosomal exocytosis. Therefore, complexin-I-deficient sperm are subfertile due to faulty zona pellucida penetration.

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Complexin I regulates glucose-induced secretion in pancreatic β-cells

Cited by 63 publications

References 51 publications

Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

The Repressor Element Silencing Transcription Factor (REST)-mediated Transcriptional Repression Requires the Inhibition of Sp1

Complexin-I-deficient sperm are subfertile due to a defect in zona pellucida penetration

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