| 1. |
- Aguado, T, et al.
(författare)
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The endocannabinoid system drives neural progenitor proliferation
- 2005
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 19:9, s. 1704-1704
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase ( FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.
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| 2. |
- Alvarado-Kristensson, Maria, et al.
(författare)
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p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.
- 2002
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 16:1, s. 31-129
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil apoptosis is essential for resolution of inflammatory reactions. Here, we studied the role of two apoptosis/survival-associated protein kinases in this process. We discovered a previously undetected early and transient inhibition of the activity of p38 mitogen-activated protein kinase (p38 MAPK) during both spontaneous and Fas-induced apoptosis. Pharmacological inhibition of this enzyme augmented the activation of caspases and the apoptotic response, which suggests that the p38 MAPK signals survival in neutrophils. Our finding that caspase-3 activity was initiated during the transient inhibition of p38 MAPK suggests that apoptosis is initiated during this inhibition. Furthermore, such transient inhibition was counteracted by granulocyte-macrophage colony-stimulating factor, which elicits survival. We also found that neither this inhibition of p38 MAPK nor the spontaneous apoptotic response depended on Fas. Instead, the early inhibition of p38 MAPK concurred with a Fas-induced activation of phosphatidylinositol 3-kinase, inhibition of which reduced apoptosis. Thus, the Fas-induced augmentation of spontaneous apoptosis can be explained by its activation of phosphatidylinositol 3-kinase. We conclude that p38 MAPK activity represents a survival signal that is inactivated transiently during both spontaneous and Fas-induced apoptosis, whereas Fas-induced phosphatidylinositol 3-kinase activity is a proapoptotic signal in isolated human neutrophils.
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| 3. |
- Ameye, L, et al.
(författare)
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Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis
- 2002
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 16:7, s. 673-680
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Tidskriftsartikel (refereegranskat)abstract
- Small leucine-rich proteoglycans (SLRPs) regulate extracellular matrix organization, a process essential in development, tissue repair, and metastasis. In vivo interactions of biglycan and fibromodulin, two SLRPs highly expressed in tendons and bones, were investigated by generating biglycan/fibromodulin double-deficient mice. Here we show that collagen fibrils in tendons from mice deficient in biglycan and/or fibromodulin are structurally and mechanically altered resulting in unstable joints. As a result, the mice develop successively and progressively 1) gait impairment, 2) ectopic tendon ossification, and 3) severe premature osteoarthritis. Forced use of the joints increases ectopic ossification and osteoarthritis in the double-deficient mice, further indicating that structurally weak tendons cause the phenotype. The study shows that mutations in SLRPs may predispose to osteoarthritis and offers a valuable and unique animal model for spontaneous osteoarthritis characterized by early onset and a rapid progression of the disease.
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| 4. |
- de Valdivia, Ernesto Gonzalez, et al.
(författare)
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Roles of PDZ-dependent Interactions and N-glycosylation in G Protein-coupled Estrogen Receptor 1 (GPER1)/GPR30-mediated Stimulation of ERK1/2 Activity
- 2018
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Ingår i: FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 32:1 Suppl, s. 6-685
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Konferensbidrag (refereegranskat)abstract
- G protein-coupled receptor 30 (GPR30) is a G protein-coupled receptor (GPCR) that is attracting considerable attention in breast cancer and cardiometabolic regulation. Following reports that GPR30 is required for some rapid estrogen responses, e.g. increased cAMP production and ERK1/2 activity, in estrogen receptor (ER)-negative cells, GPR30 was renamed G protein-coupled estrogen receptor 1 (GPER1). However, many questions remain about the identity of the cognate receptor ligand, receptor-effector coupling, and receptor membrane trafficking. To address the mechanism by which human GPR30 activates ERK1/2, we used HEK293 cells with and without ectopic expression of GPR30. Specifically, we investigated the role of the type I PSD-95/Discs-large/ZO-1 homology (PDZ) motif at the receptor C terminus (-SSAV) and three consensus sites for N glycosylation (N-X-S/T) in the receptor N-terminal domain (N25, N32, N44). We found previously that the C-terminal PDZ motif enables the receptor to interact with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, and this interaction is necessary for retaining the receptor in the plasma membrane and mediating a constitutive decrease in cAMP production that is not inhibited by pertussis toxin, thus independent of Gi/o. Here, we found that the receptor also constitutively increases ERK1/2 activity. Interestingly, this increase was inhibited by PTX as well as by wortmannin, but not by AG1478, indicating it is mediated by Gi/o and phosphoinositide 3-kinase (PI3K) but not epidermal growth factor receptor (EGFR) transactivation. Deleting the receptor PDZ motif or knocking down AKAP5 also inhibited the increase, showing that the PDZ interaction is also necessary for this response. Interestingly, the proposed GPR30 agonist G-1 increased ERK1/2 activity in a GPR30-dependent manner, but this increase was only observed at very low levels of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif, which completely inhibited the constitutive increase in ERK1/2 activity, did not inhibit the G-1-stimulated increase. Mutating the potential N-glycosylation residues N25 or N32 to I in the GPR30 N-terminal domain did not prevent receptor plasma membrane expression or ERK1/2 activation. On the other hand, mutating N44 to I completely prevented both plasma membrane expression and ERK1/2 activation, and caused receptor degradation. Thus, the PDZ-dependent receptor interaction with SAP97 and AKAP5, and therefore plasma membrane retention, is necessary for constitutive GPR30-mediated stimulation of ERK1/2 activation, whereas G-1-stimulated ERK1/2 activation may remain following constitutive internalization. On the other hand, N-glycosylation of N44 appears to be necessary for maturation of the receptor to the plasma membrane. Support or Funding Information Swedish Research Council and Swedish Cancer Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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| 5. |
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| 6. |
- Eklund, Greta, et al.
(författare)
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Nuclear localization of {gamma}-tubulin affects E2F transcriptional activity and S-phase progression.
- 2011
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 25:11, s. 3815-3827
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Tidskriftsartikel (refereegranskat)abstract
- We show that the centrosome- and microtubule-regulating protein γ-tubulin interacts with E2 promoter binding factors (E2Fs) to modulate E2F transcriptional activity and thereby control cell cycle progression. γ-Tubulin contains a C-terminal signal that results in its translocation to the nucleus during late G(1) to early S phase. γ-Tubulin mutants showed that the C terminus interacts with the transcription factor E2F1 and that the E2F1-γ-tubulin complex is formed during the G(1)/S transition, when E2F1 is transcriptionally active. Furthermore, E2F transcriptional activity is altered by reduced expression of γ-tubulin or by complex formation between γ-tubulin and E2F1, E2F2, or E2F3, but not E2F6. In addition, the γ-tubulin C terminus encodes a DNA-binding domain that interacts with E2F-regulated promoters, resulting in γ-tubulin-mediated transient activation of E2Fs. Thus, we report a novel mechanism regulating the activity of E2Fs, which can help explain how these proteins affect cell cycle progression in mammalian cells.-Höög, G., Zarrizi, R., von Stedingk, K., Jonsson, K., Alvarado-Kristensson, M. Nuclear localization of γ-tubulin affects E2F transcriptional activity and S-phase progression.
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| 7. |
- Escudero Esparza, Astrid, et al.
(författare)
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The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly.
- 2013
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 27:12, s. 5083-5093
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Tidskriftsartikel (refereegranskat)abstract
- CUB and Sushi multiple domains 1 (CSMD1) is a transmembrane protein containing 15 consecutive complement control protein (CCP) domains, which are characteristic for complement inhibitors. We expressed a membrane-bound fragment of human CSMD1 composed of the 15 C-terminal CCP domains and demonstrated that it inhibits deposition of C3b by the classical pathway on the surface of Chinese hamster ovary cells by 70% at 6% serum and of C9 (component of membrane attack complex) by 90% at 1.25% serum. Furthermore, this fragment of CSMD1 served as a cofactor to factor I-mediated degradation of C3b. In all functional assays performed, well-characterized complement inhibitors were used as positive controls, whereas Coxsackie adenovirus receptor, a protein with no effect on complement, was a negative control. Moreover, attenuation of expression in human T47 breast cancer cells that express endogenous CSMD1 significantly increased C3b deposition on these cells by 45% at 8% serum compared with that for the controls. Furthermore, by expressing a soluble 17-21 CCP fragment of CSMD1, we found that CSMD1 inhibits complement by promoting factor I-mediated C4b/C3b degradation and inhibition of MAC assembly at the level of C7. Our results revealed a novel complement inhibitor for the classical and lectin pathways.-Escudero-Esparza, A., Kalchishkova, N., Kurbasic, E., Jiang, W. G., Blom, A. M. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly.
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| 8. |
- García-Díaz, Carmen C., et al.
(författare)
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Plasticity of mitochondrial function safeguards phosphorylating respiration during in vitro simulation of rest-phase hypothermia
- 2023
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Ingår i: FASEB Journal. - 1530-6860. ; 37:4
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Tidskriftsartikel (refereegranskat)abstract
- Many animals downregulate body temperature to save energy when resting (rest-phase hypothermia). Small birds that winter at high latitudes have comparatively limited capacity for hypothermia and so pay large energy costs for thermoregulation during cold nights. Available evidence suggests this process is fueled by adenosine triphosphate (ATP)-dependent mechanisms. Most ATP is produced by oxidative phosphorylation in the mitochondria, but mitochondrial respiration may be lower during hypothermia because of the temperature dependence of biological processes. This can create conflict between increased organismal ATP demand and a lower mitochondrial capacity to provide it. We studied this in blood cell mitochondria of wild great tits (Parus major) by simulating rest-phase hypothermia via a 6°C reduction in assay temperature in vitro. The birds had spent the night preceding the experiment in thermoneutrality or in temperatures representing mild or very cold winter nights, but night temperatures never affected mitochondrial respiration. However, across temperature groups, endogenous respiration was 14% lower in hypothermia. This did not reflect general thermal suppression of mitochondrial function because phosphorylating respiration was unaffected by thermal state. Instead, hypothermia was associated with a threefold reduction of leak respiration, from 17% in normothermia to 4% in hypothermia. Thus, the coupling of total respiration to ATP production was 96% in hypothermia, compared to 83% in normothermia. Our study shows that the thermal insensitivity of phosphorylation combined with short-term plasticity of leak respiration may safeguard ATP production when endogenous respiration is suppressed. This casts new light on the process by which small birds endure harsh winter cold and warrants future tests across tissues in vivo.
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| 9. |
- Golec, Ewelina, et al.
(författare)
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A cryptic non-GPI-anchored cytosolic isoform of CD59 controls insulin exocytosis in pancreatic β-cells by interaction with SNARE proteins
- 2019
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 1530-6860. ; 33:11, s. 12425-12434
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Tidskriftsartikel (refereegranskat)abstract
- CD59 is a glycosylphosphatidylinositol (GPI)-anchored cell surface inhibitor of the complement membrane attack complex (MAC). We showed previously that CD59 is highly expressed in pancreatic islets but is down-regulated in rodent models of diabetes. CD59 knockdown but not enzymatic removal of cell surface CD59 led to a loss of glucose-stimulated insulin secretion (GSIS), suggesting that an intracellular pool of CD59 is required. In this current paper, we now report that non-GPI-anchored CD59 is present in the cytoplasm, colocalizes with exocytotic protein vesicle-associated membrane protein 2, and completely rescues GSIS in cells lacking endogenous CD59 expression. The involvement of cytosolic non-GPI-anchored CD59 in GSIS is supported in phosphatidylinositol glycan class A knockout GPI anchor-deficient β-cells, in which GSIS is still CD59 dependent. Furthermore, site-directed mutagenesis demonstrated different structural requirements of CD59 for its 2 functions, MAC inhibition and GSIS. Our results suggest that CD59 is retrotranslocated from the endoplasmic reticulum to the cytosol, a process mediated by recognition of trimmed N-linked oligosaccharides, supported by the partial glycosylation of non-GPI-anchored cytosolic CD59 as well as the failure of N-linked glycosylation site mutant CD59 to reach the cytosol or rescue GSIS. This study thus proposes the previously undescribed existence of non-GPI-anchored cytosolic CD59, which is required for insulin secretion.-Golec, E., Rosberg, R., Zhang, E., Renström, E., Blom, A. M., King, B. C. A cryptic non-GPI-anchored cytosolic isoform of CD59 controls insulin exocytosis in pancreatic β-cells by interaction with SNARE proteins.
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| 10. |
- Hafizi, Sassan, et al.
(författare)
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C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration
- 2005
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 19:8, s. 971-971
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified C1 domain-containing phosphatase and TENsin homologue (C1-TEN) as being an intracellular binding partner for Axl receptor tyrosine kinase (RTK). C1-TEN is a tensin-related protein that houses an N-terminal region with predicted structural similarity to PTEN. Here, we report our observations on the effects of ectopic expression of C1-TEN in HEK293 cells, which resulted in profound molecular and phenotypic changes. Stable expression of C1-TEN altered cellular morphology, with less cell spreading and weaker filamentous actin staining. Cells overexpressing C1-TEN were inhibited greatly in their proliferation and migration rates as compared with mock-transfected cells. Furthermore, serum starvation-induced apoptosis caused a twofold increase in caspase 3 activity in C1-TEN-overexpressing cells vs. mock cells. In addition, C1-TEN-overexpressing cells showed a markedly reduced phosphorylation of Akt/PKB kinase and its substrate GSK3, as well as reduced Akt enzymatic activity. No such effects on JNK were observed. Also, serum-stimulated activation of Akt was delayed in C1-TEN-overexpressing cells, while no difference in profile of ERK activation was observed. Furthermore, cells expressing a C1-TEN mutant where the putative phosphatase active site cysteine at position 231 was substituted for a serine displayed full restoration of both cell proliferation and Akt activation. In conclusion, C1-TEN appears to be a novel intracellular phosphatase that negatively regulates the Akt/PKB signaling cascade, and is similar to its relative PTEN in this respect. However, the particular domain organization of C1-TEN may enable it to regulate RTK and other signaling complexes that are linked to Akt/PKB signaling in a unique manner.
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