المؤلفون: Kasper J. Mygind, Denise Nikodemus, Sebastian Gnosa, Ramya Kweder, Nicolai J. Wewer Albrechtsen, Marie Kveiborg, Janine T. Erler, Reidar Albrechtsen

المصدر: International Journal of Molecular Sciences, Vol 25, Iss 11, p 5871 (2024)

مصطلحات موضوعية: CD147/Basigin, disintegrin and metalloproteinase, extracellular matrix, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds β1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and β1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12—mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFβ signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/25/11/5871Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/825f5f9180ec45d2a84117c4c5f040baTest

المؤلفون: Anna Billeschou Bomholt, Christian Dall Johansen, Jens Bager Christensen, Sasha Alexandra Sampson Kjeldsen, Katrine Douglas Galsgaard, Marie Winther-Sørensen, Reza Serizawa, Mads Hornum, Esteban Porrini, Jens Pedersen, Cathrine Ørskov, Lise Lotte Gluud, Charlotte Mehlin Sørensen, Jens Juul Holst, Reidar Albrechtsen, Nicolai Jacob Wewer Albrechtsen

المصدر: Communications Biology, Vol 5, Iss 1, Pp 1-13 (2022)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: An assessment of all commercially available antibodies targeting the G-protein-coupled receptor (GPCR), glucagon receptor (GCGR) is used to highlight the most reliable antibody in immunostaining, including an antibody-independent verification.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2399-3642Test

الوصول الحر: https://doaj.org/article/4a18a287a3c5446eb2fd7dbcbe13d3e3Test

المؤلفون: Rune E. Kuhre, Nicolai J. Wewer Albrechtsen, Olav Larsen, Sara L. Jepsen, Emilie Balk-Møller, Daniel B. Andersen, Carolyn F. Deacon, Kristina Schoonjans, Frank Reimann, Fiona M. Gribble, Reidar Albrechtsen, Bolette Hartmann, Mette M. Rosenkilde, Jens J. Holst

المصدر: Molecular Metabolism, Vol 11, Iss , Pp 84-95 (2018)

مصطلحات موضوعية: Internal medicine, RC31-1245

الوصف: Objective: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. Methods: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. Results: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)>Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on α-cells or β-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. Conclusion: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5. Keywords: Bile-acids, GLP-1, Neurotensin, Insulin, PYY, TGR5

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877818301194Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/7e8b0269704c40bea7389e41b44cde95Test

المؤلفون: Nicolai J. Wewer Albrechtsen, Rune E. Kuhre, Daniel Hornburg, Christian Z. Jensen, Mads Hornum, Carsten Dirksen, Maria Svane, Lærke S. Gasbjerg, Nils B. Jørgensen, Maria N. Gabe, Emilie Balk-Møller, Reidar Albrechtsen, Marie Winther-Sørensen, Katrine D. Galsgaard, Felix Meissner, Tina Jorsal, Asger Lund, Tina Vilsbøll, Rasmus Eliasen, Kirstine N. Bojsen-Møller, Thomas Idorn, Carolyn F. Deacon, Filip K. Knop, Mette M. Rosenkilde, Bolette Hartmann, Bo Feldt-Rasmussen, Matthias Mann, Sten Madsbad, Jens J. Holst

المصدر: Cell Reports, Vol 21, Iss 6, Pp 1452-1460 (2017)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Summary: Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion. : Wewer Albrechtsen et al. identify a glucagon-like molecule, PG 1-61, in humans using mass-spectrometry-based proteomics. PG 1-61 activates the glucagon receptor, stimulates insulin secretion, and activates key gluconeogenic enzymes. In dysmetabolic conditions, PG 1-61 is upregulated and may therefore serve as a marker of alpha cell stress. Keywords: glucagon, GLP-1, alpha cells, diabetes, proglucagon, L-cells, proteomics

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124717314663Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/b5aa1694774f4b23bb8fed0e16aceb6aTest

المؤلفون: Nicolai J. Wewer Albrechtsen, Daniel Hornburg, Reidar Albrechtsen, Berit Svendsen, Signe Toräng, Sara L. Jepsen, Rune E. Kuhre, Marie Hansen, Charlotte Janus, Andrea Floyd, Asger Lund, Tina Vilsbøll, Filip K. Knop, Henrik Vestergaard, Carolyn F. Deacon, Felix Meissner, Matthias Mann, Jens J. Holst, Bolette Hartmann

المصدر: EBioMedicine, Vol 7, Iss C, Pp 112-120 (2016)

مصطلحات موضوعية: Gut hormones, GLP-1, Low-abundant peptides, Mass-spectrometry, Proteomics, Medicine, Medicine (General), R5-920

الوصف: Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1), is inactivated by the same protease (dipeptidyl peptidase-4) as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352396416301220Test; https://doaj.org/toc/2352-3964Test

الوصول الحر: https://doaj.org/article/18223ff3e5574a79a867add2c09dfbaeTest

المؤلفون: Stefka Tyanova, Reidar Albrechtsen, Pauliina Kronqvist, Juergen Cox, Matthias Mann, Tamar Geiger

المصدر: Nature Communications, Vol 7, Iss 1, Pp 1-11 (2016)

مصطلحات موضوعية: Science

الوصف: Breast cancers have been extensively studied at the genomic and transcriptomic levels in the hope of tailoring therapeutic regimens. Here the authors generate deep coverage proteomes from several clinical breast cancer samples, and use machine learning techniques to uncover biological processes altered in specific cancer subtypes.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/624efee6adce4116946c6179f2b085b2Test

المؤلفون: Reidar Albrechtsen, Nicolai J. Wewer Albrechtsen, Sebastian Gnosa, Jeanette Schwarz, Lars Dyrskjøt, Marie Kveiborg

المصدر: International Journal of Molecular Sciences, Vol 20, Iss 8, p 1957 (2019)

مصطلحات موضوعية: a disintegrin and metalloproteinase, EMMPRIN, CD147, ectodomain shedding, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: The transmembrane glycoprotein basigin, a member of the immunoglobulin superfamily, stimulates matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) degradation and thereby drives cancer cell invasion. Basigin is proteolytically shed from the cell surface and high concentrations of soluble basigin in the blood dictates poor prognosis in cancer patients. A positive correlation between basigin and a disintegrin and metalloproteinase (ADAM)-12 in serum from prostate cancer patients has been reported. Yet, the functional relevance of this correlation is unknown. Here, we show that ADAM12 interacts with basigin and cleaves it in the juxtamembrane region. Specifically, overexpression of ADAM12 increases ectodomain shedding of an alkaline phosphatase-tagged basigin reporter protein from the cell surface. Moreover, CRISPR/Cas9-mediated knockout of ADAM12 in human HeLa carcinoma cells results in reduced shedding of the basigin reporter, which can be rescued by ADAM12 re-expression. We detected endogenous basigin fragments, corresponding to the expected size of the ADAM12-generated ectodomain, in conditioned media from ADAM12 expressing cancer cell-lines, as well as serum samples from a healthy pregnant donor and five bladder cancer patients, known to contain high ADAM12 levels. Supporting the cancer relevance of our findings, we identified several cancer-associated mutations in the basigin membrane proximal region. Subsequent in vitro expression showed that some of these mutants are more prone to ADAM12-mediated shedding and that the shed ectodomain can enhance gelatin degradation by cancer cells. In conclusion, we identified ADAM12 as a novel basigin sheddase with a potential implication in cancer.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/20/8/1957Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/2170390abefc4c9facc1ad2515651ad9Test

المؤلفون: Daniel H Madsen, Henrik J Jürgensen, Signe Ingvarsen, Maria C Melander, Reidar Albrechtsen, Andreas Hald, Kenn Holmbeck, Thomas H Bugge, Niels Behrendt, Lars H Engelholm

المصدر: PLoS ONE, Vol 8, Iss 8, p e71261 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP-2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3734290?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/40e8c086b0fb4c2a89a940269289a9b0Test

المؤلفون: Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, Camilla Fröhlich

الوصف: PDF file - 300K, ADAM12 immunolocalization in a subcutanous Lewis Lung tumor. Immunohistochemical staining of ADAM12 in Lewis Lung tumors grown for 15 days in ADAM12+/- mice using A) 2�g/mL affinity purified ADAM12 polyclonal antibody from ProteinTech Group or B) 10 �g/mL normal rabbit IgG fraction (Dako) as primary antibodies. Sections were counterstained with hematoxylin. A and B use identical magnification with scale bar in B = 20�m Detection was performed using the DakoChemMate detection kit (Dako).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::89c1e3f51bec46df011d510835e2645bTest
https://doi.org/10.1158/1541-7786.22518852Test

المؤلفون: Ulla M. Wewer, Arthur M. Mercurio, Atsuko Sehara-Fujisawa, Marie Kveiborg, Pauliina Kronqvist, Reidar Albrechtsen, Camilla Nehammer, Camilla Fröhlich

الوصف: PDF file - 213K, A Pan-cytokeratin expression (green) in immortalized PyMT-A12hz and PyMT-A12null tumor cells. Blue represents DAPI staining. Bar = 12 �m. B. Mean (�SD) total tumor burden on FVB/N mice injected subcutaneously in the right flank with PyM-A12hz (n=11) or PyMT-A12null (n=15) tumor cells. *P < 0.05

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::53943fe2f36fc002b5b6dfd9eb90e5f2Test
https://doi.org/10.1158/1541-7786.22518861.v1Test