Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction

Harashima, Shin‐ichi; Harashima, Chie; Nishimura, Takuya; Y, Hu; Notkins, Abner Louis

doi:10.1111/j.1365-2249.2007.03455.x

Cited by 11 publications

(18 citation statements)

References 46 publications

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“…Considerable new information has accumulated over the last few years on the function of IA-2 and IA-2ß (Harashima et al, 2005, Mziaut et al, 2006, Harashima et al, 2007). Both are transmembrane DCV proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Both are transmembrane DCV proteins. The knockout of IA-2 results in a decrease in the number and content of DCV and the amount of insulin secreted (Saeki et al, 2002, Kubosaki et al, 2004, Harashima et al, 2005, Kubosaki et al, 2005, Mziaut et al, 2006, Harashima et al, 2007). The knockdown of IA-2 with siRNA in MIN-6 cells also results in a decrease in the secretion of insulin (Harashima et al , 2005).…”

Section: Discussionmentioning

confidence: 99%

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Disturbances in the secretion of neurotransmitters in IA-2/IA-2β null mice: Changes in behavior, learning and lifespan

et al. 2009

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Islet-associated protein 2 (IA-2) and IA-2β are major autoantigens in type 1 diabetes and transmembrane proteins in dense core secretory vesicles (DCV) of neuroendocrine cells. The deletion of these genes results in a decrease in insulin secretion. The present study was initiated to test the hypothesis that this deletion not only affects the secretion of insulin, but has a more global effect on neuroendocrine secretion that leads to disturbances in behavior and learning. Measurement of neurotransmitters showed that norepinephrine, dopamine and serotonin were significantly decreased in the brain of double knockout (DKO) mice (P< 0.05 to <0.001). In tests evaluating anxiety-like behavior and conditioned-learning, the DKO mice showed a highly significant increase in anxietylike behavior (P<0.01 to <0.001) and impairment of conditioned learning (P<0.01) as compared to WT mice. The DKO mice also displayed an increase in spontaneous and induced seizures (P<0.01) and age-related death. Contrary to the generally held view that IA-2 and IA-2β are expressed exclusively in DCV, subcellular fractionation studies revealed that IA-2β, but not IA-2, co-purifies with fractions rich in synaptic vesicles (SV), and that the secretion of dopamine, GABA and glutamate from the synaptosomes of the DKO mice was significantly decreased as was the number of SV (P<0.01). Taken together, these findings show that IA-2β is present in both DCV and SV, and that the deletion of IA-2/IA-2β has a global effect on the secretion of neurotransmitters. The impairment of secretion leads to behavioral and learning disturbances, seizures and reduced life span.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disturbances in the secretion of neurotransmitters in IA-2/IA-2β null mice: Changes in behavior, learning and lifespan

et al. 2009

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“…Mouse pancreatic beta cells Min6 [17],[20] and HEK293 cells were cultured in DMEM containing 25 mM glucose, 1 mM sodium pyruvate, 10% fetal bovine serum plus 100 µM penicillin G and 100 mg/ml streptomycin. Cells were infected independently or co-infected with empty vector (EV), the constructs of CIP (residues 154 to 279 of p35), p25 (residues 98 to 307 of p35), p35, wild-type Cdk5 and dominant negative Cdk5.…”

Section: Methodsmentioning

confidence: 99%

Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage

Zheng

et al. 2013

PLoS ONE

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Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG) results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4–12 hrs), however was detectable in the long exposure in HG cells (24 hrs and 48 hrs). Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5) with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

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“…IA‐2 and IA‐2β, encoded by protein tyrosine phosphatase receptor, type N ( PTPRN ) and PTPRN2 , respectively, are integral membrane proteins of dense core vesicles (DCVs) and are highly expressed in neuroendocrine cells throughout the body (2). These 2 proteins are members of the transmembrane protein tyrosine phosphatase (PTP) family but are enzymatically inactive with known substrates because of a critical amino acid substitution in the PTP domain (3). Recent studies have shown that IA‐2β has low phosphatidylinositol phosphatase activity (4).…”

mentioning

confidence: 99%

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA‐2, IA‐2β, and GAD65

Abuhatzira

Tahhan

et al. 2015

FASEB j.

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Islet antigen (IA)-2, IA-2b, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA2b, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens.-Abuhatzira, L., Xu, H., Tahhan, G., Boulougoura, A., Schäffer, A. A., Notkins, A. L. Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2b, and GAD65. FASEB J. 29, 4374-4383 (2015). www.fasebj.org

show abstract

Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction

Cited by 11 publications

References 46 publications

Disturbances in the secretion of neurotransmitters in IA-2/IA-2β null mice: Changes in behavior, learning and lifespan

Disturbances in the secretion of neurotransmitters in IA-2/IA-2β null mice: Changes in behavior, learning and lifespan

Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA‐2, IA‐2β, and GAD65

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