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See detailAngiotensin II regulates phosphorylation of actin-associated proteins in human podocytes
Schenk, Laura K; Möller-Kerutt, Annika; Klosowski, Rafael et al

in FASEB Journal (2017)

Within the kidney, angiotensin II (AngII) targets different cell types in the vasculature, tubuli, and glomeruli. An important part of the renal filtration barrier is composed of podocytes with their ... [more ▼]

Within the kidney, angiotensin II (AngII) targets different cell types in the vasculature, tubuli, and glomeruli. An important part of the renal filtration barrier is composed of podocytes with their actin-rich foot processes. In this study, we used stable isotope labeling with amino acids in cell culture coupled to mass spectrometry to characterize relative changes in the phosphoproteome of human podocytes in response to short-term treatment with AngII. In 4 replicates, we identified a total of 17,956 peptides that were traceable to 2081 distinct proteins. Bioinformatic analyses revealed that among the increasingly phosphorylated peptides are predominantly peptides that are related to actin filaments, cytoskeleton, lamellipodia, mammalian target of rapamycin, and MAPK signaling. Among others, this screening approach highlighted the increased phosphorylation of actin-bundling protein, L-plastin (LCP1). AngII-dependent phosphorylation of LCP1 in cultured podocytes was mediated by the kinases ERK, p90 ribosomal S6 kinase, PKA, or PKC. LCP1 phosphorylation increased filopodia formation. In addition, treatmentwith AngII led to LCP1 redistribution to the cell margins,membrane ruffling, and formation of lamellipodia. Our data highlight the importance of AngII-triggered actin cytoskeleton-associated signal transduction in podocytes. [less ▲]

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See detailL-plastin Ser5 phosphorylation in breast cancer cells and in vitro is mediated by RSK downstream of the ERK/MAPK pathway
Lommel, Maiti UL; Trairatphisan, Panuwat UL; Gäbler, Karoline UL et al

in FASEB Journal (2016)

Deregulated cell migration and invasion are hallmarks of metastatic cancer cells. Phosphorylation on residue Ser5 of the actin-bundling protein L-plastin activates L-plastin and has been reported to be ... [more ▼]

Deregulated cell migration and invasion are hallmarks of metastatic cancer cells. Phosphorylation on residue Ser5 of the actin-bundling protein L-plastin activates L-plastin and has been reported to be crucial for invasion and metastasis. Here, we investigate signal transduction leading to L-plastin Ser5 phosphorylation using 4 human breast cancer cell lines. Whole-genome microarray analysis comparing cell lines with different invasive capacities and corresponding variations in L-plastin Ser5 phosphorylation level revealed that genes of the ERK/MAPK pathway are differentially expressed. It is noteworthy that in vitro kinase assays showed that ERK/MAPK pathway downstream ribosomal protein S6 kinases α-1 (RSK1) and α-3 (RSK2) are able to directly phosphorylate L-plastin on Ser5. Small interfering RNA- or short hairpin RNA-mediated knockdown and activation/inhibition studies followed by immunoblot analysis and computational modeling confirmed that ribosomal S6 kinase (RSK) is an essential activator of L-plastin. Migration and invasion assays showed that RSK knockdown led to a decrease of up to 30% of migration and invasion of MDA-MB-435S cells. Although the presence of L-plastin was not necessary for migration/invasion of these cells, immunofluorescence assays illustrated RSK-dependent recruitment of Ser5-phosphorylated L-plastin to migratory structures. Altogether, we provide evidence that the ERK/MAPK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with RSK1 and RSK2 kinases able to directly phosphorylate L-plastin residue Ser5. [less ▲]

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See detailHind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging
Lescale, Chloé; Schenten, Véronique UL; Djeghloul, Dounia et al

in FASEB Journal (2015), 29(2), 455-63

Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure ... [more ▼]

Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis. [less ▲]

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See detailGravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis
Huin-Schohn, Cécile UL; Gueguinou, Nathan UL; Schenten, Véronique UL et al

in FASEB Journal (2013), 27(1), 333-341

Our previous research demonstrated that spaceflight conditions affect antibody production in response to an antigenic stimulation in adult amphibians. Here, we investigated whether antibody synthesis is ... [more ▼]

Our previous research demonstrated that spaceflight conditions affect antibody production in response to an antigenic stimulation in adult amphibians. Here, we investigated whether antibody synthesis is affected when animal development occurs onboard a space station. To answer this question, embryos of the Iberian ribbed newt, Pleurodeles waltl, were sent to the International Space Station (ISS) before the initiation of immunoglobulin heavy-chain expression. Thus, antibody synthesis began in space. On landing, we determined the effects of spaceflight on P. waltl development and IgM heavy-chain transcription. Results were compared with those obtained using embryos that developed on Earth. We find that IgM heavy-chain transcription is doubled at landing and that spaceflight does not affect P. waltl development and does not induce inflammation. We also recreated the environmental modifications encountered by the embryos during their development onboard the ISS. This strategy allowed us to demonstrate that gravity change is the factor responsible for antibody heavy-chain transcription modifications that are associated with NF-κB mRNA level variations. Taken together, and given that the larvae were not immunized, these data suggest a modification of lymphopoiesis when gravity changes occur during ontogeny.-Huin-Schohn, C., Guéguinou, N., Schenten, V., Bascove, M., Koch, G. G., Baatout, S., Tschirhart, E., Frippiat, J.-P. Gravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis. [less ▲]

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See detailAn alpaca single-domain antibody blocks filopodia formation by obstructing L-plastin-mediated F-actin bundling.
Delanote, Veerle; Vanloo, Berlinda; Catillon, Marie UL et al

in FASEB Journal (2010), 24(1), 105-18

L-plastin, a conserved modular F-actin bundling protein, is ectopically expressed in tumor cells and contributes to cell malignancy and invasion. The underlying molecular mechanisms involved remain ... [more ▼]

L-plastin, a conserved modular F-actin bundling protein, is ectopically expressed in tumor cells and contributes to cell malignancy and invasion. The underlying molecular mechanisms involved remain unclear, in part, because specific inhibitors of L-plastin are lacking. We used recombinant alpaca-derived L-plastin single-domain antibodies (nanobodies) as effector of L-plastin function in cells. [less ▲]

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See detailSpaceflight-associated changes in immunoglobulin VH gene expression in the amphibian Pleurodeles waltl
Bascove, Matthieu; Huin-Schohn, Cécile UL; Gueguinou, Nathan UL et al

in FASEB Journal (2009), 23(5), 1607-1615

Understanding why the immune system is depressed during spaceflight is of obvious importance for future human deep-space missions, such as the foreseen missions to Mars. However, little is known about the ... [more ▼]

Understanding why the immune system is depressed during spaceflight is of obvious importance for future human deep-space missions, such as the foreseen missions to Mars. However, little is known about the effects of these flights on humoral immunity. We previously immunized adult Pleurodeles waltl (urodele amphibian) onboard the Mir space station and showed that heavy-chain variable (VH) domains of specific IgM antibodies are encoded by genes belonging to the VHII and VHVI families. We have now determined how these animals use their individual VHII and VHVI genes by screening IgM heavy-chain cDNA libraries and by quantifying IgM heavy-chain transcripts encoded by these genes. Results were compared with those obtained using control animals immunized on Earth under the same conditions as onboard Mir. Our experiments revealed an increase in the expression of IgM heavy-chain mRNAs encoded by the VHII and VHVI.C genes and a strong decrease in the expression of IgM heavy-chain mRNAs encoded by the VHVI.A and VHVI.B genes in spaceflight animals. Consequently, different heavy-chain mRNAs are expressed by spaceflight animals, demonstrating that this environment affects the humoral response. These observations may be due to a change in B-cell selection under spaceflight conditions. [less ▲]

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See detailImpaired insulin secretory capacity in mice lacking a functional vitamin D receptor.
Zeitz, Ute; Weber, Karin; Soegiarto, Desi W. et al

in FASEB Journal (2003), 17(3), 509-11

It was the aim of this study to further explore the functional role of vitamin D in the endocrine pancreas. By gene targeting, we have recently generated mice in which a lacZ reporter gene is driven by ... [more ▼]

It was the aim of this study to further explore the functional role of vitamin D in the endocrine pancreas. By gene targeting, we have recently generated mice in which a lacZ reporter gene is driven by the endogenous vitamin D receptor (VDR) promoter. These mice express a functionally inactive mutant VDR. Pancreatic islets but not exocrine pancreas cells showed strong lacZ reporter gene expression in mutant mice. To rule out possible influences of hypocalcemia on pancreatic endocrine function, a rescue diet enriched with calcium, phosphorus, and lactose was fed to wild-type (WT) and VDR mutant mice. The rescue diet normalized body weight and mineral homeostasis in VDR mutants. In glucose tolerance tests, baseline blood glucose levels were unchanged in fasting VDR mutants. However, blood glucose was elevated after oral or subcutaneous glucose loading, and maximum serum insulin levels were reduced by approximately 60% in VDR mutants vs. WT mice on either diet. In addition, insulin mRNA levels were decreased in VDR mutant mice on both diets, whereas pancreatic beta cell mass, islet architecture, and islet neogenesis were normal. These findings clearly establish a molecular role of the vitamin D-responsive elements in pancreatic insulin synthesis and secretion in vivo. [less ▲]

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See detailAn MMP-9 mutant without gelatinolytic activity as a novel TIMP-1-antagonist
Roeb, E.; Behrmann, Iris UL; Grötzinger, J. et al

in FASEB Journal (2000), 14(12), 1671-3

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