The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Brun, Thierry; Duhamel, Dominique; He, Kai; Wollheim, Claes B.; Gauthier, Benoit R.

doi:10.1038/sj.onc.1210205

Cited by 41 publications

(33 citation statements)

References 48 publications

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“…apoptotic rate in control INS-1E cells was ϳ2%, in agreement with previous observations (31). Single 10-min oxidative stress induced 20 -25% TUNEL-positive cells 8-h post-stress, an apoptotic rate maintained throughout a 5-day period post-stress (Fig.…”

Section: Ins-1e Cell Apoptosis and Proliferation Post-stress-basalsupporting

confidence: 80%

Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

Brun

Cnop

et al. 2009

Journal of Biological Chemistry

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Transient exposure of ␤-cells to oxidative stress interrupts the transduction of signals normally coupling glucose metabolism to insulin secretion. We investigated putative persistence of effects induced by one transient oxidative stress (200 M H 2 O 2 , 10 min) on insulin secreting cells following recovery periods of days and weeks. Three days after oxidative stress INS-1E cells and rat islets exhibited persistent dysfunction. In particular, the secretory response to 15 mM glucose was reduced by 40% in INS-1E cells stressed 3 days before compared with naïve cells. Compared with non-stressed INS-1E cells, we observed reduced oxygen consumption (؊43%) and impaired glucose-induced ATP generation (؊46%). These parameters correlated with increased mitochondrial reactive oxygen species formation (؉60%) accompanied with down-regulation of subunits of the respiratory chain and decreased expression of genes responsible for mitochondrial biogenesis (TFAM, ؊24%; PGC-1␣, ؊67%). Three weeks after single oxidative stress, both mitochondrial respiration and secretory responses were recovered. Moreover, such recovered INS-1E cells exhibited partial resistance to a second transient oxidative stress and up-regulation of UCP2 (؉78%) compared with naïve cells. In conclusion, one acute oxidative stress induces ␤-cell dysfunction lasting over days, explained by persistent damages in mitochondrial components.Pancreatic ␤-cells are poised to sense blood glucose to regulate insulin exocytosis and thereby glucose homeostasis. The conversion from metabolic signals to secretory responses is mediated through mitochondrial metabolism (1). Failure of the insulin secreting ␤-cells, a common characteristic of both type 1 and type 2 diabetes, derives from various origins, among them mitochondrial impairment secondary to oxidative stress is a proposed mechanism (2).Oxidative stress is characterized by a persistent imbalance between excessive production of reactive oxygen species (ROS) 3 and limited antioxidant defenses. Examples of ROS include superoxide (O 2 . ), hydroxyl radical (OH ⅐ ), and hydrogen peroxide (H 2 O 2 ). Superoxide can be converted to less reactive H 2 O 2 by superoxide dismutase (SOD) and then to oxygen and water by catalase (CAT), glutathione peroxidase (GPx), and peroxiredoxin, which constitute antioxidant defenses. Increased oxidative stress and free radical damages have been proposed to participate in the diabetic state (3). In type 1 diabetes, ROS are implicated in ␤-cell dysfunction caused by autoimmune reactions and inflammatory cytokines (4). In the context of type 2 diabetes, excessive ROS could promote deficient insulin synthesis (5, 6) and apoptotic pathways in ␤-cells (5, 7). Of note, ROS fluctuations may also contribute to physiological control of cell functions (8), including the control of insulin secretion (9). It should also be stressed that metabolism of physiological nutrient increases ROS without causing deleterious effects on cell function. However, uncontrolled increase of oxidants, or reduction of the...

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Section: Ins-1e Cell Apoptosis and Proliferation Post-stress-basalsupporting

confidence: 80%

Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

Brun

Cnop

et al. 2009

Journal of Biological Chemistry

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“…Consistent with the latter, elevated expression levels of Pax4 are found in both human and rat insulinomas when compared with mature b-cells (Miyamoto et al 2001, Brun et al 2007). Furthermore, a novel Pax4 spliced variant, lacking the carboxy-terminal (Cterminal) end of the protein involved in mediating repression of gene transcription, was also identified in human insulinomas (Miyamoto et al 2001).…”

Section: Pax4 As An Oncogenesupporting

confidence: 67%

“…To address the potential oncogenic function of Pax4, the latter was suppressed by RNA interference in the insulinoma INS-1E cell line. Inhibition of Pax4 provoked spontaneous apoptosis and further sensitized cells to cytokine-mediated cell death without altering cell proliferation, suggesting that the transcription factor acts as a survival gene rather than promoting replication in this cell line (Brun et al 2007). The latter study highlights potential pitfalls of using transformed cell lines to delineate the functional role of factors implicated in the regulation of cell replication and apoptosis.…”

Section: Pax4 As An Oncogenementioning

confidence: 92%

A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

Brun¹,

Gauthier

2007

Journal of Molecular Endocrinology

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Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet b-and a-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet b-cells. Autoimmune destruction of b-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of b-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs b-cell mass plasticity may provide a means to develop strategies to countera,ct b-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the b-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature b-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet b-cell physiology and its contribution to pathophysiology when deregulated.

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“…In brief, five 19-nucleotide shRNAs against rat ATGL (GenBank TM accession number NM_001108509) with a 9-nucleotide loop were synthesized, annealed, and ligated to the PmeI and XbaI sites of pDLDU6 (37). Efficiency of the various shRNA constructs on ATGL mRNA levels was verified in INS832/13 cells, and the most efficient shRNA was chosen for subsequent experiments.…”

Section: Methodsmentioning

confidence: 99%

Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

Peyot

Guay

Latour

et al. 2009

Journal of Biological Chemistry

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Free fatty acids (FFA)5 and other lipid molecules are important for proper glucose-stimulated insulin secretion (GSIS) by ␤-cells. Thus, deprivation of fatty acids (FA) in vivo (1) diminishes GSIS, whereas a short term exposure to FFA enhances it (1-3). In contrast, a sustained provision of FA, particularly in the presence of high glucose in vitro, is detrimental to ␤-cells in that it reduces insulin gene expression (4) and secretion (5) and induces ␤-cell apoptosis (6). The FA supply to the ␤-cells can be from exogenous sources, such as plasma FFAs and lipoproteins, or endogenous sources, such as intracellular triglyceride (TG) stores. Studies from our laboratory (7-10) and others (11,12) support the concept that the hydrolysis of endogenous TG plays an important role in fuel-induced insulin secretion because TG depletion with leptin (13) or inhibition of TG lipolysis by lipase inhibitors such as 3,5-dimethylpyrazole (7) or orlistat (11, 12) markedly curtail GSIS in rat islets. Furthermore, mice with ␤-cell-specific knock-out of hormone-sensitive lipase (HSL), which hydrolyzes both TG and diacylglycerol (DAG), show defective first phase GSIS in vivo and in vitro (14).Lipolysis is an integral part of an essential metabolic pathway, the TG/FFA cycle, in which FFA esterification onto a glycerol backbone leading to the synthesis of TG is followed by its hydrolysis with the release of the FFA that can then be re-esterified.

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The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Cited by 41 publications

References 48 publications

Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

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