<i>CTSH</i>
            regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

Fløyel, Tina; Brorsson, Caroline; Nielsen, L.B.; Miani, Michela; Bang-Berthelsen, Claus Heiner; Friedrichsen, Martin; Overgaard, Jesper; Berchtold, Lukas Adrian; Wiberg, Anna; Poulsen, Pernille; Hansen, Lars; Rosinger, Silke; Boehm, Bernhard O.; Ramesh, Ram; Nguyen, Quang Tri; Mehta, Munish; Morahan, Grant; Concannon, Patrick; Bergholdt, Regine; Nielsen, Jens Høiriis; Reinheckel, Thomas; Herrath, Matthias von; Vaag, Allan; Eizirik, Décio L.; Mortensen, Henrik B.; Størling, Joachim; Pociot, Flemming

doi:10.1073/pnas.1402571111

Cited by 77 publications

(97 citation statements)

References 39 publications

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“…INS-1E cells were cultured as previously described (Fløyel et al, 2014). Cells were transfected with 30 nM of siRNA.…”

Section: Culture and Transfection Of Ins-1e Cellsmentioning

confidence: 99%

“…Expression was represented by deltaCT method with GAPDH as the reference gene. Additionally, expression of lncRNAs NONHSAG011348, NON-HSAG011349, NONHSAG011351 and ERBB3 was also measured in HapMap lymphoblastoid cell lines of individuals of European descent (CEU, n ¼ 50) (Fløyel et al, 2014).…”

Section: Expression Of Erbb3 and Its Associated Lncrnas In Human Islementioning

confidence: 99%

“…INS-1E cells were lysed in M-PER Mammalian Protein Extraction Reagent supplemented with Halt Protease & Phosphatase Inhibitor Cocktail (all from Pierce). Western blotting was performed as previously described (Fløyel et al, 2014). Antibodies used were anti-ERBB3 (12708, Cell Signaling, Danvers, MA, USA), anti-cleaved caspase-3 (9661, Cell Signaling), anti-a-tubulin (T8203, SigmaeAldrich, St. Louis, MO, USA), anti-GAPDH (ABS16, Millipore, Billerica, MA, USA), anti-rabbit IgG (7074, Cell Signaling), and antimouse IgG (7076, Cell Signaling).…”

Section: Western Blottingmentioning

confidence: 99%

“…Apoptosis was determined using Cell Death Detection ELISA (Roche, Basel, Switzerland) as previously described (Fløyel et al, 2014). The activities of caspases 3 and 7 were measured by the Caspase-GLO 3/7 assay (Promega, Madison, WI, USA) using 50 ml Caspase-GLO reagent per well.…”

Section: Apoptosismentioning

confidence: 99%

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The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

Kaur

Mirza

Brorsson

et al. 2016

Molecular and Cellular Endocrinology

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a b s t r a c tThe study aimed to explore the role of ERBB3 in type 1 diabetes (T1D). We examined whether genetic variation of ERBB3 (rs2292239) affects residual b-cell function in T1D cases. Furthermore, we examined the expression of ERBB3 in human islets, the effect of ERBB3 knockdown on apoptosis in insulinproducing INS-1E cells and the genetic and regulatory architecture of the ERBB3 locus to provide insights to how rs2292239 may confer disease susceptibility. rs2292239 strongly correlated with residual b-cell function and metabolic control in children with T1D. ERBB3 locus associated lncRNA (NON-HSAG011351) was found to be expressed in human islets. ERBB3 was expressed and down-regulated by pro-inflammatory cytokines in human islets and INS-1E cells; knockdown of ERBB3 in INS-1E cells decreased basal and cytokine-induced apoptosis. Our data suggests an important functional role of ERBB3 and its potential regulators in the b-cells and may constitute novel targets to prevent b-cell destruction in T1D.

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“…INS-1E cells were cultured as previously described (Fløyel et al, 2014). Cells were transfected with 30 nM of siRNA.…”

Section: Culture and Transfection Of Ins-1e Cellsmentioning

confidence: 99%

Section: Expression Of Erbb3 and Its Associated Lncrnas In Human Islementioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Apoptosismentioning

confidence: 99%

See 2 more Smart Citations

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

Kaur

Mirza

Brorsson

et al. 2016

Molecular and Cellular Endocrinology

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“…Furthermore, another study comparing single nucleotide polymorphism (SNP) locations against chromatin maps for different cell types indicates a primary signature of T1D SNPs in T-cell enhancers but also a highly significant (P , 10 27 ) enrichment in pancreatic islet enhancers (10). These genes may contribute to type 1 diabetes by regulating important pathways in the b-cells, such as antiviral responses, innate immunity, and activation of apoptosis (6,(11)(12)(13).…”

mentioning

confidence: 99%

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

et al. 2015

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Pancreatic b-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic b-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human b-cells exposed to polyinosinicpolycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNa and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early b-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PICinduced b-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic b-cells via modulation of IFNa signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.

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Diabetes and Genetics: A Relationship Between Genetic Risk Alleles, Clinical Phenotypes and Therapeutic Approaches

Sayed

Nabi

2020

Advances in Experimental Medicine and Biology

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CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

Cited by 77 publications

References 39 publications

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

Diabetes and Genetics: A Relationship Between Genetic Risk Alleles, Clinical Phenotypes and Therapeutic Approaches

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