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3. Secretion in 3T3-L1 adipocytes

Author

Clarke, Mairi

Subjects
571.57
Abstract

Adipocytes secrete a range of proteins, called adipokines, with important roles in a variety of biological processes such as metabolism, cardiovascular function and immunity. ACRP30 (also known as adiponectin) is an adipokine that displays anti-diabetic and anti-inflammatory properties and may prevent atherosclerosis. It is secreted exclusively by adipocytes and circulating levels of ACRP30 are reduced in obesity and diabetes. Although this protein has been widely studied, little is known about the mechanisms of secretion of ACRP30 in adipocytes. Here I have examined secretion of ACRP30 in 3T3-L1 adipocytes with the aim of understanding the secretory pathways used by ACRP30 as it traffics to the cell surface. Using intracellular localisation techniques 1 have shown that ACRP30 overlaps with transferrin receptor positive membranes, evidence that ACRP30 traffics via the transferrin- receptor positive endosomal system. This was supported by results showing that ablation of the transferrin-receptor positive endosomes strongly inhibited ACRP30 secretion, I have also investigated the effects of overexpressing mutant forms of the small GTPases Rabl1 and Arf6, Overexpression of Rabl 1 S25N significantly reduced basal and insulin- stimulated ACRP30 secretion and I have demonstrated that Arf6 plays a role in ACRP30 secretion. With the aim of identifying new adipokines, I have conducted a proteomic analysis of the proteins secreted by 3T3-L1 adipocytes. In this study, I identified 25 proteins that had not previously been identified as adipocyte-secreted. In functional studies, two of these proteins, orosomucoid and Nm23 could be shown to affect insulin-stimulated glucose uptake. In monocyte adhesion assays orosomucoid had anti-inflammatory effects.

Published
2006

13. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis

Author

Jamieson, Thomas, Clarke, Mairi, Steele, Colin W., Samuel, Michael S., Neumann, Jens, Jung, Andreas, Huels, David, Olson, Michael F., Das, Sudipto, Nibbs, Robert J.B., and Sansom, Owen J.

Subjects
Adenoma -- Diagnosis -- Care and treatment, Papilloma -- Diagnosis -- Care and treatment, Gene expression -- Research, Neutrophils -- Genetic aspects, Cancer cells -- Genetic aspects, Health care industry
Abstract

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas ([Apc.sup.Min/+]) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER; [Apc.sup.fl/+]; [Pten.sup.fl/fl] mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in [Apc.sup.Min/+] mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-depen-dent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced [Apc.sup.Min/+] adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer., Introduction Inflammation and tumorigenesis are intimately linked. Chronic inflammation can drive tumorigenesis, and tumors are inherently proinflammatory, with infiltrating leukocytes thought to be critical for tumor maintenance and progression (1, [...]

Published
2012
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20. Stimuli‐Responsive Aggregation of High Molar Mass Poly(N,N‐Diethylacrylamide)‐b‐Poly(4‐Acryloylmorpholine) in Tetrahydrofuran.

Author

Plucinski, Alexander, Pavlovic, Marko, Clarke, Mairi, Bhella, David, and Schmidt, Bernhard V. K. J.

Subjects
MOLAR mass, TETRAHYDROFURAN, LIGHT scattering, CRITICAL temperature, ELECTRON microscopy, BLOCK copolymers, THERMORESPONSIVE polymers
Abstract

The self‐assembly of block copolymers constitutes a timely research area in polymer science with implications for applications like sensing or drug‐delivery. Here, the unprecedented aggregation behavior of high molar mass block copolymer poly(N,N‐diethylacrylamide)‐b‐poly(4‐acryloylmorpholine) (PDEA‐b‐PAM) (Mn>400 kg mol−1) in organic solvent tetrahydrofuran (THF) is investigated. To elucidate the aggregation, dynamic light scattering, cryo‐transmission electron microscopy, and turbidimetry are employed. The aggregate formation is assigned to the unprecedented upper critical solution temperature behavior of PAM in THF at elevated concentrations (> 6 wt.%) and high molar masses. Various future directions for this new thermo‐responsive block copolymer are envisioned, for example, in the areas of photonics or templating of inorganic structures. [ABSTRACT FROM AUTHOR]

Published
2022
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21. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

Author

Bird, Thomas G., primary, Müller, Miryam, additional, Boulter, Luke, additional, Vincent, David F., additional, Ridgway, Rachel A., additional, Lopez-Guadamillas, Elena, additional, Lu, Wei-Yu, additional, Jamieson, Thomas, additional, Govaere, Olivier, additional, Campbell, Andrew D., additional, Ferreira-Gonzalez, Sofía, additional, Cole, Alicia M., additional, Hay, Trevor, additional, Simpson, Kenneth J., additional, Clark, William, additional, Hedley, Ann, additional, Clarke, Mairi, additional, Gentaz, Pauline, additional, Nixon, Colin, additional, Bryce, Steven, additional, Kiourtis, Christos, additional, Sprangers, Joep, additional, Nibbs, Robert J. B., additional, Van Rooijen, Nico, additional, Bartholin, Laurent, additional, McGreal, Steven R., additional, Apte, Udayan, additional, Barry, Simon T., additional, Iredale, John P., additional, Clarke, Alan R., additional, Serrano, Manuel, additional, Roskams, Tania A., additional, Sansom, Owen J., additional, and Forbes, Stuart J., additional

Published
2018
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23. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma

Author

Steele, Colin W., primary, Karim, Saadia A., additional, Leach, Joshua D.G., additional, Bailey, Peter, additional, Upstill-Goddard, Rosanna, additional, Rishi, Loveena, additional, Foth, Mona, additional, Bryson, Sheila, additional, McDaid, Karen, additional, Wilson, Zena, additional, Eberlein, Catherine, additional, Candido, Juliana B., additional, Clarke, Mairi, additional, Nixon, Colin, additional, Connelly, John, additional, Jamieson, Nigel, additional, Carter, C. Ross, additional, Balkwill, Frances, additional, Chang, David K., additional, Evans, T.R. Jeffry, additional, Strathdee, Douglas, additional, Biankin, Andrew V., additional, Nibbs, Robert J.B., additional, Barry, Simon T., additional, Sansom, Owen J., additional, and Morton, Jennifer P., additional

Published
2016
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31. Generation of chimeric respiratory viruses with altered tropism by coinfection of influenza A virus and respiratory syncytial virus

Author

Haney, Joanne, Vijayakrishnan, Swetha, Streetley, James, Dee, Kieran, Goldfarb, Daniel Max, Clarke, Mairi, Mullin, Margaret, Carter, Stephen D., Bhella, David, and Murcia, Pablo R.

Abstract

Interactions between co-circulating respiratory viruses are recognized for their impact on viral transmission and clinical outcomes. However, the consequences of these virus-virus interactions at the cellular level are unclear. We coinfected human lung cells with influenza A virus (IAV) and respiratory syncytial virus (RSV). Super-resolution microscopy combined with live-cell imaging and scanning electron microscopy identified extracellular and membrane-associated filamentous structures, likely composed of elements of both IAV and RSV virions. Cryo-electron tomography confirmed the presence of chimeric virus particles exhibiting glycoproteins and ribonucleoproteins of both parental viruses. Functional assays revealed chimeric particles facilitate IAV infection in cells depleted of IAV receptors, demonstrating expanded tropism. Our observations define a previously unknown interaction that is likely to affect virus pathogenesis and have profound implications for infection biology.

32. Secretion in 3T3-L1 adipocytes

Author

Clarke, Mairi and Clarke, Mairi

Abstract

Adipocytes secrete a range of proteins, called adipokines, with important roles in a variety of biological processes such as metabolism, cardiovascular function and immunity. ACRP30 (also known as adiponectin) is an adipokine that displays anti-diabetic and anti-inflammatory properties and may prevent atherosclerosis. It is secreted exclusively by adipocytes and circulating levels of ACRP30 are reduced in obesity and diabetes. Although this protein has been widely studied, little is known about the mechanisms of secretion of ACRP30 in adipocytes. Here I have examined secretion of ACRP30 in 3T3-L1 adipocytes with the aim of understanding the secretory pathways used by ACRP30 as it traffics to the cell surface. Using intracellular localisation techniques 1 have shown that ACRP30 overlaps with transferrin receptor positive membranes, evidence that ACRP30 traffics via the transferrin- receptor positive endosomal system. This was supported by results showing that ablation of the transferrin-receptor positive endosomes strongly inhibited ACRP30 secretion, I have also investigated the effects of overexpressing mutant forms of the small GTPases Rabl1 and Arf6, Overexpression of Rabl 1 S25N significantly reduced basal and insulin- stimulated ACRP30 secretion and I have demonstrated that Arf6 plays a role in ACRP30 secretion. With the aim of identifying new adipokines, I have conducted a proteomic analysis of the proteins secreted by 3T3-L1 adipocytes. In this study, I identified 25 proteins that had not previously been identified as adipocyte-secreted. In functional studies, two of these proteins, orosomucoid and Nm23 could be shown to affect insulin-stimulated glucose uptake. In monocyte adhesion assays orosomucoid had anti-inflammatory effects.

33. Secretion in 3T3-L1 adipocytes

Author

Clarke, Mairi and Clarke, Mairi

Abstract

Adipocytes secrete a range of proteins, called adipokines, with important roles in a variety of biological processes such as metabolism, cardiovascular function and immunity. ACRP30 (also known as adiponectin) is an adipokine that displays anti-diabetic and anti-inflammatory properties and may prevent atherosclerosis. It is secreted exclusively by adipocytes and circulating levels of ACRP30 are reduced in obesity and diabetes. Although this protein has been widely studied, little is known about the mechanisms of secretion of ACRP30 in adipocytes. Here I have examined secretion of ACRP30 in 3T3-L1 adipocytes with the aim of understanding the secretory pathways used by ACRP30 as it traffics to the cell surface. Using intracellular localisation techniques 1 have shown that ACRP30 overlaps with transferrin receptor positive membranes, evidence that ACRP30 traffics via the transferrin- receptor positive endosomal system. This was supported by results showing that ablation of the transferrin-receptor positive endosomes strongly inhibited ACRP30 secretion, I have also investigated the effects of overexpressing mutant forms of the small GTPases Rabl1 and Arf6, Overexpression of Rabl 1 S25N significantly reduced basal and insulin- stimulated ACRP30 secretion and I have demonstrated that Arf6 plays a role in ACRP30 secretion. With the aim of identifying new adipokines, I have conducted a proteomic analysis of the proteins secreted by 3T3-L1 adipocytes. In this study, I identified 25 proteins that had not previously been identified as adipocyte-secreted. In functional studies, two of these proteins, orosomucoid and Nm23 could be shown to affect insulin-stimulated glucose uptake. In monocyte adhesion assays orosomucoid had anti-inflammatory effects.

34. Atypical Chemokine Receptor ACKR2 Mediates Chemokine Scavenging by Primary Human Trophoblasts and Can Regulate Fetal Growth, Placental Structure, and Neonatal Mortality in Mice.

Author

Pek Joo Teoh, Menzies, Fiona M., Hansell, Chris A. H., Clarke, Mairi, Waddell, Carolann, Burton, Graham J., Nelson, Scott M., and Nibbs, Robert J. B.

Subjects
*CHEMOKINE receptors, *LEUCOCYTES, *CELL migration, *NEONATAL mortality, *LABORATORY mice, *CHEMOKINES, *PROTEIN receptors
Abstract

Inflammatory chemokines produced in the placenta can direct the migration of placental leukocytes using chemokine receptors that decorate the surface of these cells. Fetal trophoblasts can also express receptors for inflammatory chemokines, and they are one of the few cell types that express atypical chemokine receptor 2 (ACKR2), previously known as D6. ACKR2 binds many inflammatory CC chemokines but cannot stimulate cell migration or activate signaling pathways used by conventional chemokine receptors. Existing evidence suggests that ACKR2 is a specialized chemokine scavenger, but its function in primary human trophoblasts has not been explored. In mice, ACKR2 is thought to be dispensable for the reproductive success of unchallenged females that have conceived naturally, but it can suppress inflammation-induced abortion and aid the survival of implanted allogeneic embryos. In this article, we demonstrate that cultured primary human trophoblasts express ACKR2 far more strongly than genes encoding conventional receptors for inflammatory CC chemokines. Moreover, these cells are capable of the rapid internalization and efficient scavenging of extracellular chemokine, and this is mediated by ACKR2. We also report that in unchallenged DBA/1j mice, Ackr2 deficiency increases the incidence of stillbirth and neonatal death, leads to structural defects in the placenta, and can decrease fetal weight. Loss of Ackr2 specifically from fetal cells makes a key contribution to the placental defects. Thus, primary human trophoblasts use ACKR2 to scavenge chemokines, and ACKR2 deficiency can cause abnormal placental structure and reduced neonatal survival. [ABSTRACT FROM AUTHOR]

Published
2014
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35. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis

Author

Robert J. B. Nibbs, Sudipto Das, Michael S. Samuel, Michael F. Olson, David J. Huels, Owen J. Sansom, Colin W. Steele, Mairi Clarke, Andreas Jung, Thomas Jamieson, Jens Neumann, Jamieson, Thomas, Clarke, Mairi, Steele, Colin W, Samuel, Michael S, Neumann, Jens, Jung, Andreas, Huels, David, Olson, Michael F, Das, Sudipto, Nibbs, Robert JB, and Sansom, Owen J

Subjects
Chemokine, Skin Neoplasms, Neutrophils, Gene Expression, Dermatitis, Contact, medicine.disease_cause, Receptors, Interleukin-8B, Mice, Chemokine receptor, CXC chemokine receptors, Mice, Knockout, Mice, Inbred BALB C, Dextran Sulfate, chemokine receptor, hemic and immune systems, General Medicine, respiratory system, Colitis, Tumor Burden, Cell Transformation, Neoplastic, Colonic Neoplasms, Tetradecanoylphorbol Acetate, Adenocarcinoma, medicine.symptom, Chemokines, CXC, Research Article, Animals, Inbred Strains, Adenoma, musculoskeletal diseases, Mice, 129 Strain, 9,10-Dimethyl-1,2-benzanthracene, Azoxymethane, Inflammation, Context (language use), Biology, Statistics, Nonparametric, medicine, Animals, Peroxidase, Papilloma, medicine.disease, biological factors, respiratory tract diseases, Mice, Inbred C57BL, tumorigenesis, CXCL2 chemokine, inflammation, Immunology, biology.protein, Carcinogenesis, Precancerous Conditions
Abstract

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation- driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2- activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer. Refereed/Peer-reviewed

Published
2012

36. Ebola and Marburg virus matrix layers are locally ordered assemblies of VP40 dimers

Author

Erica Ollmann Saphire, John A. G. Briggs, Stephan Becker, William Wan, Alexander Koehler, Larissa Kolesnikova, Mairi Clarke, Michael J. Norris, Zachary A. Bornholdt, Wan, William [0000-0003-2497-3010], Clarke, Mairi [0000-0002-9658-4308], Norris, Michael J [0000-0002-8325-5257], Bornholdt, Zachary A [0000-0002-7557-9219], Saphire, Erica Ollmann [0000-0002-1206-7451], Briggs, John Ag [0000-0003-3990-6910], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, QH301-705.5, Science, Structural Biology and Molecular Biophysics, viruses, infectious disease, matrix protein, Crystal structure, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Marburg virus, Viral Matrix Proteins, 03 medical and health sciences, Ebola virus, VP40, Viral envelope, medicine, molecular biophysics, structural biology, Biology (General), 030304 developmental biology, 0303 health sciences, Budding, Microbiology and Infectious Disease, Viral matrix protein, 030102 biochemistry & molecular biology, General Immunology and Microbiology, Chemistry, General Neuroscience, 030302 biochemistry & molecular biology, microbiology, Cell Membrane, General Medicine, Ebolavirus, Nucleoprotein, 030104 developmental biology, Membrane, Structural biology, Marburgvirus, Membrane curvature, Biophysics, Medicine, Other, Protein Multimerization, Research Article
Abstract

A key step in the life cycle of enveloped viruses is the budding of nascent virions from the host membrane. In filoviruses such as Ebola and Marburg virus, this process is achieved by the matrix protein VP40. When expressed alone, VP40 induces the budding of filamentous virus-like particles, suggesting that localization to the plasma membrane, oligomerization into a matrix layer, and the generation of membrane curvature are intrinsic properties of VP40. While a number of crystal structures of VP40 have been determined in various oligomerization states, there has been no direct information on the structure of assembled VP40 matrix layers within viruses or virus-like particles. Here, we present structures of Ebola and Marburg VP40 matrix layers in intact virus-like particles, as well as within intact Marburg viruses. We find that the matrix layers are formed from VP40 dimers which assemble into extended chains via C-terminal domain interactions. These chains stack into layers, forming a 2D lattice below the membrane surface. However, these 2D lattices are only locally ordered, forming a patchwork assembly across the membrane surfaces and suggesting that assembly may begin at multiple points. These observations define the structure and arrangement of the matrix protein layer that mediates the formation of filamentous filovirus particles.

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