| 1. |
- Aspenström-Fagerlund, Bitte, et al.
(författare)
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Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes
- 2007
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 237:1-3, s. 12-23
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Tidskriftsartikel (refereegranskat)abstract
- Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.
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| 2. |
- Aase, Karin, et al.
(författare)
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Angiomotin regulates endothelial cell migration during embryonic angiogenesis
- 2007
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 21:16, s. 2055-2068
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Tidskriftsartikel (refereegranskat)abstract
- The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
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| 3. |
- Aspenström, Pontus
(författare)
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Activated Rho GTPases in Cancer-The Beginning of a New Paradigm
- 2018
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 19:12
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Forskningsöversikt (refereegranskat)abstract
- Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an expose of current knowledge of the roles of activated Rho GTPases in cancers.
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| 4. |
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| 5. |
- Aspenström, Pontus
(författare)
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Integration of signalling pathways regulated by small GTPases and calcium
- 2004
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1742:1-3, s. 51-58
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Forskningsöversikt (refereegranskat)abstract
- The Ras superfamily of small GTPases constitutes a large group of structurally and functionally related proteins. They function as signalling switches in numerous signalling cascades in the cell. During the recent years, an increased awareness of a communication between signalling systems employing Ras-like GTPases and signalling systems employing calcium has emerged. For instance, the intensity of the activation of Ras-like GTPases is regulated by calcium-dependent mechanisms, acting on proteins that facilitate the activation or inactivation of the small GTPases. Other Ras-like GTPases have a direct influence on calcium signalling by regulating the activity of certain calcium channels. In addition, several small GTPases collaborate with calcium signalling in regulating cellular processes, such as cell adhesion, cell migration and exocytosis.
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| 6. |
- Aspenström, Pontus
(författare)
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Miro GTPases at the Crossroads of Cytoskeletal Dynamics and Mitochondrial Trafficking
- 2024
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 13:7
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Forskningsöversikt (refereegranskat)abstract
- Miro GTPases are key components in the machinery responsible for transporting mitochondria and peroxisomes along microtubules, and also play important roles in regulating calcium homeostasis and organizing contact sites between mitochondria and the endoplasmic reticulum. Moreover, Miro GTPases have been shown to interact with proteins that actively regulate cytoskeletal organization and dynamics, suggesting that these GTPases participate in organizing cytoskeletal functions and organelle transport. Derailed mitochondrial transport is associated with neuropathological conditions such as Parkinson's and Alzheimer's diseases. This review explores our recent understanding of the diverse roles of Miro GTPases under cytoskeletal control, both under normal conditions and during the course of human diseases such as neuropathological disorders.
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| 7. |
- Aspenström, Pontus, et al.
(författare)
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Pombe Cdc15 homology proteins : regulators of membrane dynamics and the actin cytoskeleton
- 2006
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Ingår i: TIBS -Trends in Biochemical Sciences. Regular ed.. - : Elsevier BV. - 0968-0004 .- 1362-4326. ; 31:12, s. 670-679
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Forskningsöversikt (refereegranskat)abstract
- Pombe Cdc15 homology (PCH) proteins have emerged in many species as important coordinators of signalling pathways that regulate actomyosin assembly and membrane dynamics. For example, the prototype PCH protein, Cdc15p of Schizosaccharomyces pombe, has a role in assembly of the contractile ring, which is needed to separate dividing cells. Recently, mammalian PCH proteins have been found to bind phospholipids and to participate in membrane deformation. These findings suggest that PCH proteins are crucial linkers of membrane dynamics and actin polymerization, for example, during the internalization of transmembrane receptors. Intriguingly, some members of the PCH protein family are mutated in neurodegenerative and inflammatory diseases, which has implications for the identification of cures for such disorders.
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| 8. |
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| 9. |
- Aspenström, Pontus, et al.
(författare)
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Rho GTPases have diverse effects on the organization of the actin filament system
- 2004
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 377:Pt 2, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- The Rho GTPases are related to the Ras proto-oncogenes and consist of 22 family members. These proteins have important roles in regulating the organization of the actin filament system, and thereby the morphogenesis of vertebrate cells as well as their ability to migrate. In an effort to compare the effects of all members of the Rho GTPase family, active Rho GTPases were transfected into porcine aortic endothelial cells and the effects on the actin filament system were monitored. Cdc42, TCL (TC10-like), Rac1-Rac3 and RhoG induced the formation of lamellipodia, whereas Cdc42, Rac1 and Rac2 also induced the formation of thick bundles of actin filaments. In contrast, transfection with TC10 or Chp resulted in the formation of focal adhesion-like structures, whereas Wrch-1 induced long and thin filopodia. Transfection with RhoA, RhoB or RhoC induced the assembly of stress fibres, whereas Rnd1-Rnd3 resulted in the loss of stress fibres, but this effect was associated with the formation of actin- and ezrin-containing dorsal microvilli. Cells expressing RhoD and Rif had extremely long and flexible filopodia. None of the RhoBTB or Miro GTPases had any major influence on the organization of the actin filament system; instead, RhoBTB1 and RhoBTB2 were present in vesicular structures, and Miro-1 and Miro-2 were present in mitochondria. Collectively, the data obtained in this study to some extent confirm earlier observations, but also allow the identification of previously undetected roles of the different members of the Rho GTPases.
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| 10. |
- Aspenström, Pontus
(författare)
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Roles of F-BAR/PCH Proteins in the Regulation of Membrane Dynamics and Actin Reorganization
- 2009
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Ingår i: International Review of Cell and Molecular Biology. ; 272, s. 1-31
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Forskningsöversikt (refereegranskat)abstract
- The Pombe Cdc15 Homology (PCH) proteins have emerged in many species as important coordinators of signaling pathways that regulate actomyosin assembly and membrane dynamics. The hallmark of the PCH proteins is the presence of a Fes/ClP4 homology-Bin/Amphiphysin/Rvsp (F-BAR) domain; therefore they are commonly referred to as F-BAR proteins. The prototype F-BAR protein, Cdc15p of Schizosaccharomyces pombe, has a role in the formation of the contractile actomyosin ring during cytokinesis. Vertebrate F-BAR proteins have an established role in binding phospholipids and they participate in membrane deformations, for instance, during the internalization of transmembrane receptors. This way the F-BAR proteins will function as linkers between the actin polymerization apparatus and the machinery regulating membrane dynamics. Interestingly, some members of the F-BAR proteins are implicated in inflammatory or neurodegenerative disorders and the observations can be expected to have clinical implications for the treatment of the diseases.
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