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| 2. |
- Christenson, Karin, et al.
(författare)
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Serum amyloid A inhibits apoptosis of human neutrophils via a P2X7-sensitive pathway independent of formyl peptide receptor-like 1
- 2008
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 83:1, s. 139-48
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil apoptosis is important for the termination of inflammatory reactions, in that it ensures placid clearance of these potently cytotoxic cells. Various proinflammatory cytokines delay neutrophil apoptosis, which may result in accumulation of these cells, sometimes accompanied by tissue destruction, potentially leading to various inflammatory disease states. Rheumatoid arthritis (RA) is characterized frequently by elevated levels of the acute-phase reactant serum amyloid A (SAA) in circulation and in tissues. SAA is emerging as a cytokine-like molecule with the ability to activate various proinflammatory processes, many of which involve signaling via the formyl peptide receptor-like 1 (FPRL1). In this study, we show that SAA, purified from plasma from RA patients or in recombinant form, suppressed apoptosis of human neutrophils. Blocking FPRL1 did not lessen the antiapoptotic effects of SAA, implying the action of a receptor distinct from FPRL1. In contrast, antagonists of the nucleotide receptor P2X7 abrogated the antiapoptotic effect of SAA completely but did not block intracellular calcium transients evoked by SAA stimulation. Based on these results and also the finding that blocking P2X7 inhibited antiapoptotic actions of unrelated stimuli (LPS and GM-CSF), we propose that P2X7 is a general mediator of antiapoptotic signaling in neutrophils rather than a bona fide SAA receptor.
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| 3. |
- Gul, Nadia, 1980, et al.
(författare)
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The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The mut-T homolog-1 (MTH1) inhibitor TH588 has shown promise in preclinical cancer studies but its targeting specificity has been questioned. Alternative mechanisms for the anti-cancer effects of TH588 have been suggested but the question remains unresolved. Here, we performed an unbiased CRISPR screen on human lung cancer cells to identify potential mechanisms behind the cytotoxic effect of TH588. The screen identified pathways and complexes involved in mitotic spindle regulation. Using immunofluorescence and live cell imaging, we showed that TH588 rapidly reduced microtubule plus-end mobility, disrupted mitotic spindles, and prolonged mitosis in a concentration-dependent but MTH1-independent manner. These effects activated a USP28-p53 pathway -the mitotic surveillance pathway -that blocked cell cycle reentry after prolonged mitosis; USP28 acted upstream of p53 to arrest TH588-treated cells in the G1-phase of the cell cycle. We conclude that TH588 is a microtubule-modulating agent that activates the mitotic surveillance pathway and thus prevents cancer cells from re-entering the cell cycle.
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| 4. |
- Schuberth, C. E., et al.
(författare)
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Self-organization of core Golgi material is independent of COPII-mediated endoplasmic reticulum export
- 2015
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:7, s. 1279-1293
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Tidskriftsartikel (refereegranskat)abstract
- The Golgi is a highly organized and dynamic organelle that receives and distributes material from and to the endoplasmic reticulum (ER) and the endocytic pathway. One open question about Golgi organization is whether it is solely based on ER-to-Golgi transport. Here, we analyzed the kinetics of Golgi breakdown in the absence of COPII-dependent ER export with high temporal and spatial resolution using quantitative fluorescence microscopy. We found that Golgi breakdown occurred in two phases. While Golgi enzymes continuously redistributed to the ER, we consistently observed extensive Golgi fragmentation at the beginning of the breakdown, followed by microtubule-dependent formation of a Golgi remnant structure (phase 1). Further Golgi disintegration occurred less uniformly (phase 2). Remarkably, cisternal Golgi morphology was lost early in phase 1 and Golgi fragments instead corresponded to variably sized vesicle clusters. These breakdown intermediates were devoid of COPI-dependent recycling material, but contained typical 'core' Golgi components. Furthermore, Golgi breakdown intermediates were able to disassemble and reassemble following cell division, indicating that they retained important regulatory capabilities. Taken together, these findings support the view that Golgi self-organization exists independently of ER-to-Golgi transport. © 2015. Published by The Company of Biologists Ltd.
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| 6. |
- Thorsen, Michael, 1974, et al.
(författare)
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The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast.
- 2006
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Ingår i: Molecular biology of the cell. - 1059-1524 .- 1939-4586. ; 17:10, s. 4400-10
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Tidskriftsartikel (refereegranskat)abstract
- Arsenic is widely distributed in nature and all organisms possess regulatory mechanisms to evade toxicity and acquire tolerance. Yet, little is known about arsenic sensing and signaling mechanisms or about their impact on tolerance and detoxification systems. Here, we describe a novel role of the S. cerevisiae mitogen-activated protein kinase Hog1p in protecting cells during exposure to arsenite and the related metalloid antimonite. Cells impaired in Hog1p function are metalloid hypersensitive, whereas cells with elevated Hog1p activity display improved tolerance. Hog1p is phosphorylated in response to arsenite and this phosphorylation requires Ssk1p and Pbs2p. Arsenite-activated Hog1p remains primarily cytoplasmic and does not mediate a major transcriptional response. Instead, hog1delta sensitivity is accompanied by elevated cellular arsenic levels and we demonstrate that increased arsenite influx is dependent on the aquaglyceroporin Fps1p. Fps1p is phosphorylated on threonine 231 in vivo and this phosphorylation critically affects Fps1p activity. Moreover, Hog1p is shown to affect Fps1p phosphorylation. Our data are the first to demonstrate Hog1p activation by metalloids and provides a mechanism by which this kinase contributes to tolerance acquisition. Understanding how arsenite/antimonite uptake and toxicity is modulated may prove of value for their use in medical therapy.
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