Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells

Tanioka, Toshihiro; Tamura, Yoshiaki; Fukaya, Makiko; Shinozaki, Shohei; Mao, Ji; Kim, Minhye; Shimizu, Nobuyuki; Kitamura, Tadahiro; Kaneki, Masao

doi:10.1074/jbc.m110.192732

Cited by 26 publications

(15 citation statements)

References 56 publications

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“…The nuclear localization of GSK-3β effects on the cell viability We also measured cell viability using FACS analysis to determine whether the subcellular localization of GSK-3β influenced the cell viability (Ku et al, 2011;Tanioka et al, 2011). As shown in Table 1, our FACS results indicate that the GSK-3β PY NLS mutants (R113A, Y117A) increased the cell survival rate significantly, compared to the HA-GSK-3β WT or K292R mutant which interacts with Kap β.…”

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confidence: 79%

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The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

Sein

Lee

Chun

et al. 2012

Molecules and Cells

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Glycogen synthase kinase-3β(GSK-3β), which is a member of the serine/threonine kinase family, has been shown to be crucial for cellular survival, differentiation, and metabolism. Here, we present evidence that GSK-3β is associated with the karyopherin β2 (Kap β2) (102-kDa), which functions as a substrate for transportation into the nucleus. A potential PY-NLS motif ( 109 IVRLRYFFY 117) was observed, which is similar with the consensus PY NLS motif (R/K/H)X 2-5 PY in the GSK-3β catalytic domain. Using a pull down approach, we observed that GSK-3β physically interacts with Kap β2 both in vivo and in vitro. Secondly, GSK-3β and Kap β2 were shown to be co-localized by confocal microscopy. The localization of GSK-3β to the nuclear region was disrupted by putative Kap β2 binding site mutation. Furthermore, in transient transfection assays, the Kap β2 binding site mutant induced a substantial reduction in the in vivo serine/threonine phosphorylation of GSK-3β, where-as the GSK-3β wild type did not. Thus, our observations indicated that Kap β2 imports GSK-3β through its putative PY NLS motif from the cytoplasm to the nucleus and increases its kinase activity.

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confidence: 79%

“…Thus GSK-3β WT, or K292R mutant seems to be more active than GSK-3β PY mutant (R111A or Y117A). It has been reported that the Ser 9 residue of GSK-3β is phosphorylated and inhibited its activity by Akt or SGK (Moule et al, 1997;Tanioka et al, 2011). However, it is not Fig.…”

mentioning

confidence: 80%

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

Sein

Lee

Chun

et al. 2012

Molecules and Cells

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“…To examine whether increased iNOS or NF-B activity is responsible for the impaired secretion induced by SENP1 upregulation, intact mouse islets were concomitantly transduced with Ad-GFP or Ad-GFP-SENP1 and treated with either the iNOS inhibitor L-NIL (47) or the NF-B inhibitor, PDTC (18). Both L-NIL (n ϭ 4; Fig.…”

Section: Pharmacological Inhibition Of Inos or Nf-b Ameliorates Senp1mentioning

confidence: 99%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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tional modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMOspecific proteases (SENPs). While increased SUMOylation reduces ␤-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca 2ϩ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca 2ϩ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of ␤-cell death, iNOS and NF-B, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1␤-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-B. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation. islets of Langerhans; SUMOylation; inducible nitric oxide synthase; sentrin/SUMO-specific protease 1; SENP1 SMALL UBIQUITIN-RELATED MODIFIER (SUMO) peptides are involved in the posttranslational modification of numerous cellular proteins (19,20,26). SUMO modification, known as SUMOylation, occurs through a cascade of well-characterized enzymatic events that rely on the E2 conjugating enzyme Ubc9 (19,20,22). SUMOylation is made reversible by the sentrin/ SUMO-specific proteases (SENPs), which remove SUMO from target proteins (49). Due to the large number of SUMOylatable targets, the cellular outcomes of SUMO modification are diverse, ranging from the control of DNA repair to the regulation of transcription factors and plasma membrane proteins (9,10,20,28,39,42,44). SUMO1 modification has a negative impact on ␤-cell secretory function (35). Upregulation of SUMO1 decreases insulin gene expression (28, 44), glucagon-like peptide-1 (GLP-1) receptor signaling (42), and both glucose-and exendin-4-stimulated insulin secretion (10, 42), suggesting that deSUMOylation may improve secretory function. Indeed, knockdown of the SUMOylating enzyme Ubc9 enhances exendin-4-stimulated insulin secretion (42), and upregulation of the deSUMOylating enzyme SENP1 increases exocytosis from rodent ␤-cells at low glucose (10, 48). Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10). Thus, while increased SUMOylation results in secretory impairment (10, 42, 48), the effect of the deSUMOylating enzyme SENP1 remains unknown.SUMOyla...

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“…40 Finally, NO indirectly promotes other post-translational modifications that negatively alter the stability of proteins involved in cell survival, such as insulin receptor substrate (IRS) family proteins. Thus, iNOS activation and high concentrations of NO donors provoke a decrease in IRS-2 expression in pancreatic β-cells 75 and IRS-1 in skeletal muscle cells, 76 without any effect on their mRNA levels. A probable mechanism is the increase of ubiquitination and proteasomal degradation through the activation of glycogen synthase kinase-3β (GSK-3β) and JNK/SAPK.…”

Section: No Regulates Endoplasmic Reticulum Stressmentioning

confidence: 99%

“…A probable mechanism is the increase of ubiquitination and proteasomal degradation through the activation of glycogen synthase kinase-3β (GSK-3β) and JNK/SAPK. 75 As described above, tyrosine nitration is dependent on ONOO -generation and is a consequence of high concentration of NO. Tyrosine nitration has effects on stability of proteín-protein interaction, influences the proteins compartmentalization and affects their stability and activity.…”

Section: No Regulates Endoplasmic Reticulum Stressmentioning

confidence: 99%

Regulation of pancreatic β-cell survival by nitric oxide

Bedoya¹,

Salguero-Aranda

Cahuana

et al. 2012

Islets

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Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells

Abstract: Insulin receptor substrate-2 (IRS-2

Cited by 26 publications

References 56 publications

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

The Nuclear Localization of Glycogen Synthase Kinase 3β Is Required Its Putative PY-Nuclear Localization Sequences

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Regulation of pancreatic β-cell survival by nitric oxide

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