Cloning and characterization of hurpin (protease inhibitor 13): a new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family

Abts, Harry F.; Welss, Thomas; Mirmohammadsadegh, Alireza; Köhrer, Karl; Michel, G; Ruzicka, Thomas

doi:10.1006/jmbi.1999.3159

Cited by 30 publications

(41 citation statements)

References 52 publications

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“…Recent observations from our laboratory have revealed a novel autoantibody directed against the serpin B13 protease inhibitor (2,3) and demonstrated that it partially protects against early onset autoimmune diabetes (4). In T1D susceptible nonobese diabetic (NOD) mice, elevated secretion of anti-serpin B13 autoantibody is associated with protection from diabetes before 16 weeks of age, whereas decreased secretion of this antibody (Ab) in humans is associated with T1D onset before age 5 years (4).…”

Section: Type 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus

Kryvalap¹,

Lo²,

Manuylova

et al. 2016

Journal of Biological Chemistry

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Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces isletassociated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ϳ80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans. Type 1 diabetes mellitus (T1D)3 is an autoimmune condition that affects people of all ages. Although T1D was traditionally considered a pediatric disease, it has become clear that individuals over 20 years old can also develop detectable autoimmunity against pancreatic islets with concomitant sudden onset of insulin dependence (1). To date, the modifying factors that precipitate the clinical manifestation of autoimmune diabetes at different ages are largely unknown.We have focused on factors that regulate the timing of clinical onset of T1D. Recent observations from our laboratory have revealed a novel autoantibody directed against the serpin B13 protease inhibitor (2, 3) and demonstrated that it partially protects against early onset autoimmune diabetes (4). In T1D susceptible nonobese diabetic (NOD) mice, elevated secretion of anti-serpin B13 autoantibody is associated with protection from diabetes before 16 weeks of age, whereas decreased secretion of this antibody (Ab) in humans is associated with T1D onset before age 5 years (4). These observations suggest an inverse relationship between the serpin B13 autoantibody response and the appearance of the clinical features of T1D. We further linked the serpin Ab to reduced autoimmune inflammation in pancreatic islets, likely due to enhanced extracellular cleavage of key cell surface molecules expressed in T and B cells (5). Of note, serpins have been impl...

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Section: Type 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus

Kryvalap¹,

Lo²,

Manuylova

et al. 2016

Journal of Biological Chemistry

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“…10). The gene was independently discovered by Abts et al (11) on the basis of differential expression in UV-modulated keratinocytes. We then showed the inactivity of the functional promoter region of headpin in head and neck carcinoma lines, consistent with dysregulation of transcription as an explanation for the differential expression of headpin (12).…”

Section: Introductionmentioning

confidence: 99%

Headpin: A Serpin with Endogenous and Exogenous Suppression of Angiogenesis

Shellenberger¹,

Mazumdar²,

Henderson³

et al. 2005

Cancer Research

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Headpin is a novel serine proteinase inhibitor (serpin) with constitutive mRNA expression in histologically normal oral mucosa but with lost or down-regulated expression in head and neck squamous cell carcinoma. Several serpin family members are similarly lost in multiple cancer types and hold tumor suppressor functions including the inhibition of angiogenesis. However, the functional significance for the loss of headpin expression in cancer is not known. Using immunohistochemical analysis of invasive squamous cell carcinoma and matched normal squamous mucosa of patient specimens, headpin expression was lost or downregulated in the vast majority of tumor specimens. We investigated the functions of exogenous recombinant headpin and endogenously expressed headpin related to angiogenesis. In a rat corneal assay of neovascularization, recombinant headpin protein blocked in vivo angiogenesis mediated by interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF). In assays of cellular events in angiogenesis, headpin blocked the invasion, migration, and tube formation of endothelial cells. In light of our findings of nuclear subcellular localization of headpin, we investigated the expression and secretion of angiogenic factors and found reduced mRNA, protein, and promoter activities of IL-8 and VEGF. Finally, using a murine flank tumor model, headpin expression reduced growth and microvessel density in tumors derived from headpin-expressing UMSCC1 cells relative to those from vector control cells. These findings of nuclear regulatory functions of a serpin in the inhibition of angiogenesis bring new understanding to the cellular and molecular mechanisms of serpins. Therefore, this novel serpin targets diverse mechanisms against tumor angiogenesis on which to base therapeutic strategies. (Cancer Res 2005; 65(24): 11501-9)

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“…Excessive proteolysis can lead to diseases such as emphysema, thrombosis, rheumatoid arthritis (caused by the uncontrolled complement cascade), and hyperfibrinolytic hemorrhage (10)(11)(12). Incomplete proteolysis can be similarly catastrophic as seen in Alzheimer's disease (13,14), psorisis (15), tumor development (16), and infection by parasites and nematodes (17) (nematoic serpins protect the organism from proteolytic cleavage by host proteases).…”

mentioning

confidence: 99%

Modulation of protein–protein interactions by synthetic receptors: Design of molecules that disrupt serine protease–proteinaceous inhibitor interaction

Park

Lin

Hamilton³

2002

Proc. Natl. Acad. Sci. U.S.A.

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In the present article we describe the design and evaluation of a synthetic receptor that binds to the exterior surface of chymotrypsin and disrupts its interaction with proteinaceous inhibitors, such as soybean trypsin inhibitor, basic pancreatic trypsin inhibitor, ovomucoid turkey inhibitor, and Bowman-Birk inhibitor. Using enzyme kinetics, nondenaturing gel electrophoresis, and gel filtration chromatography we show that the receptor is particularly effective at blocking the chymotrypsin-soybean trypsin inhibitor complex and that the mechanism involves formation of an initial ternary complex followed by a time-dependent displacement of the proteinaceous inhibitor.

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Cloning and characterization of hurpin (protease inhibitor 13): a new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family

Cited by 30 publications

References 52 publications

Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus

Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus

Headpin: A Serpin with Endogenous and Exogenous Suppression of Angiogenesis

Modulation of protein–protein interactions by synthetic receptors: Design of molecules that disrupt serine protease–proteinaceous inhibitor interaction

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