SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "L773:1477 9137 OR L773:0021 9533 "

Sökning: L773:1477 9137 OR L773:0021 9533

  • Resultat 1-50 av 201
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • Ackermann, F, et al. (författare)
  • CaMKIIalpha interacts with multi-PDZ domain protein MUPP1 in spermatozoa and prevents spontaneous acrosomal exocytosis
  • 2009
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 122:24Pt 24, s. 4547-4557
  • Tidskriftsartikel (refereegranskat)abstract
    • The success of acrosomal exocytosis, a complex process with a variety of inter-related steps, relies on the coordinated interaction of participating signaling molecules. Since the acrosome reaction resembles Ca2+-regulated exocytosis in neurons, we investigated whether cognate neuronal binding partners of the multi-PDZ domain protein MUPP1, which recruits molecules that control the initial tethering and/or docking between the acrosomal vesicle and the plasma membrane, are also expressed in spermatozoa, and whether they contribute to the regulation of acrosomal secretion. We observed that CaMKIIα colocalizes with MUPP1 in the acrosomal region of epididymal spermatozoa where the kinase selectively binds to a region encompassing PDZ domains 10-11 of MUPP1. Furthermore, we found that pre-treating mouse spermatozoa with a CaMKII inhibitor that directly blocks the catalytic region of the kinase, as well as a competitive displacement of CaMKIIα from PDZ domains 10-11, led to a significant increase in spontaneous acrosomal exocytosis. Since Ca2+-calmodulin releases CaMKIIα from the PDZ scaffolding protein, MUPP1 represents a central signaling platform to dynamically regulate the assembly and disassembly of binding partners pertinent to acrosomal secretion, thereby precisely adjusting an increase in Ca2+ to synchronized fusion pore formation.
  •  
2.
  •  
3.
  • Agostinho, A., et al. (författare)
  • Sexual dimorphism in the width of the mouse synaptonemal complex
  • 2018
  • Ingår i: Journal of Cell Science. - : Company of Biologists Ltd. - 0021-9533 .- 1477-9137. ; 131:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Sexual dimorphism has been used to describe morphological differences between the sexes, but can be extended to any biologically related process that varies between males and females. The synaptonemal complex (SC) is a tripartite structure that connects homologous chromosomes in meiosis. Here, aided by superresolution microscopy techniques, we show that the SC is subject to sexual dimorphism, in mouse germ cells. We have identified a significantly narrower SC in oocytes and have established that this difference does not arise from a different organization of the lateral elements nor from a different isoform of transverse filament protein SYCP1. Instead, we provide evidence for the existence of a narrower central element and a different integration site for the C-termini of SYCP1, in females. In addition to these female-specific features, we speculate that post-translation modifications affecting the SYCP1 coiled-coil region could render a more compact conformation, thus contributing to the narrower SC observed in females.
  •  
4.
  • Alfredsson-Timmins, Jenny, et al. (författare)
  • The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
  • 2007
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 120:11, s. 1935-1943
  • Tidskriftsartikel (refereegranskat)abstract
    • The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.
  •  
5.
  • Andersson, Stefanie, 1989, et al. (författare)
  • Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity
  • 2021
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 134:11
  • Tidskriftsartikel (refereegranskat)abstract
    • The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified Saccharomyces cerevisiae deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. This article has an associated First Person interview with the first authors of the paper.
  •  
6.
  • Anton, KA, et al. (författare)
  • PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium
  • 2014
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 127:16Pt 16, s. 3425-3433
  • Tidskriftsartikel (refereegranskat)abstract
    • At the early stages of carcinogenesis, transformation occurs in single cells within tissues. In an epithelial monolayer, such mutated cells are recognized by their normal neighbors and are often apically extruded. The apical extrusion requires cytoskeletal reorganization and cell shape changes, but it is poorly understood what molecular switches are involved in regulation of these processes. Here, using SILAC-based quantitative mass spectrometry we have identified proteins that are modulated in transformed cells upon their interaction with normal cells. Phosphorylation of VASP at serine 239 is specifically upregulated in RasV12-transformed cells when they are surrounded by normal cells. VASP phosphorylation is required for the cell shape changes and apical extrusion of Ras-transformed cells. Furthermore, PKA is activated in Ras-transformed cells surrounded by normal cells, leading to VASP phosphorylation. These results indicate that the PKA/VASP pathway is a crucial regulator for tumor cell extrusion from the epithelium and shed light on the events occurring at the early stage of carcinogenesis.
  •  
7.
  • Appelgren, Henrik, et al. (författare)
  • Distinct centromere domain structures with separate functions demonstrated in live fission yeast cells
  • 2003
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 116:19, s. 4035-4042
  • Tidskriftsartikel (refereegranskat)abstract
    • Fission yeast (Saccharomyces pombe) centromere DNA is organized in a central core region flanked on either side by a region of outer repeat (otr) sequences. The otr region is known to be heterochromatic and bound by the Swi6 protein whereas the central core region contains an unusual chromatin structure involving the histone H3 variant Cnp1 (S. pombe CENP-A). The central core is the base for formation of the kinetochore structure whereas the flanking region is important for sister centromere cohesion. We have previously shown that the ultrastructural domain structure of S. pombe centromeres in interphase is similar to that of human centromeres. Here we demonstrate that S. pombe centromeres are organized in cytologically distinct domains even in mitosis. Fluorescence in situ hybridization of fixed metaphase cells revealed that the otr regions of the centromere were still held together by cohesion even after the sister kinetochores had separated. In live cells, the central cores and kinetochores of sister chromosomes could be distinguished from one Another when they were subjected to mitotic tension. The function of the different centromeric domains was addressed. Transacting mutations affecting the kinetochore (nuf2) central core domain (mis6) and the heterochromatin domain (rik1) were analyzed in live cells. In interphase, both nuf2 and mis6 caused declustering of centromeres from the spindle pole body whereas centromere clustering was normal in rik1 despite an apparent decondensation defect. The declustering of centromeres in mis6 cells correlated with loss the Ndc80 kinetochore marker protein from the centromeres. Interestingly the declustered centromeres were still restricted to the nuclear periphery thus revealing a kinetochore-independent peripheral localization mechanism for heterochromatin. Time-lapse microscopy of live mis6 and nuf2-1 mutant cells in mitosis showed similar severe misaggregation phenotypes whereas the rik1 mutants showed a mild cohesion defect. Thus, S. pombe centromeres have two distinguishable domains even during mitosis, and our functional analyses support the previous observations that the kinetochore/central core and the heterochromatin domains have distinct functions both in interphase and mitosis.
  •  
8.
  • Appelqvist, Hanna, et al. (författare)
  • Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes
  • 2013
  • Ingår i: Journal of Cell Science. - : Company of Biologists. - 0021-9533 .- 1477-9137. ; 126:24, s. 5578-5584
  • Tidskriftsartikel (refereegranskat)abstract
    • Ultraviolet (UV) irradiation is a major environmental carcinogen involved in the development of skin cancer. To elucidate the initial signaling during UV-induced damage in human keratinocytes, we investigated lysosomal exocytosis and apoptosis induction. UVA, but not UVB, induced plasma membrane damage, which was repaired by Ca2+-dependent lysosomal exocytosis. The lysosomal exocytosis resulted in extracellular release of cathepsin D and acid sphingomyelinase (aSMase). Two hours after UVA irradiation, we detected activation of caspase-8, which was reduced by addition of anti-aSMAse. Furthermore, caspase-8 activation and apoptosis was reduced by prevention of endocytosis and by the use of cathepsin inhibitors. We conclude that lysosomal exocytosis is part of the keratinocyte response to UVA and is followed by cathepsin-dependent activation of caspase-8. The findings have implications for the understanding of UV-induced skin damage and emphasize that UVA and UVB initiate apoptosis through different signaling pathways in keratinocytes.
  •  
9.
  • Arabi, Azadeh, et al. (författare)
  • Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels
  • 2003
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 116:9, s. 1707-1717
  • Tidskriftsartikel (refereegranskat)abstract
    • c-Myc is a predominately nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.
  •  
10.
  • Barg, Sebastian, et al. (författare)
  • Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification
  • 2001
  • Ingår i: Journal of Cell Science. - 0021-9533 .- 1477-9137. ; 114:Pt 11, s. 2145-54
  • Tidskriftsartikel (refereegranskat)abstract
    • ATP-dependent priming of the secretory granules precedes Ca(2+)-regulated neuroendocrine secretion, but the exact nature of this reaction is not fully established in all secretory cell types. We have further investigated this reaction in the insulin-secreting pancreatic B-cell and demonstrate that granular acidification driven by a V-type H(+)-ATPase in the granular membrane is a decisive step in priming. This requires simultaneous Cl(-) uptake through granular ClC-3 Cl(-) channels. Accordingly, granule acidification and priming are inhibited by agents that prevent transgranular Cl(-) fluxes, such as 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and an antibody against the ClC-3 channels, but accelerated by increases in the intracellular ATP:ADP ratio or addition of hypoglycemic sulfonylureas. We suggest that this might represent an important mechanism for metabolic regulation of Ca(2+)-dependent exocytosis that is also likely to be operational in other secretory cell types.
  •  
11.
  • Behm, Mikaela, 1986-, et al. (författare)
  • Accumulation of nuclear ADAR2 regulates A-to-I RNA editing during neuronal development
  • 2017
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 130, s. 745-753
  • Tidskriftsartikel (refereegranskat)abstract
    • Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-a4 (encoded by Kpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops. 
  •  
12.
  • Behm, M, et al. (författare)
  • Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development
  • 2017
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 130:4, s. 745-753
  • Tidskriftsartikel (refereegranskat)abstract
    • Adenosine to inosine (A-to-I) RNA editing is important for a functional brain and most known sites of selective RNA editing has been found to diversify the number of protein isoforms involved in neurotransmission. In absence of the active editing enzymes, ADAR1 or ADAR2, mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development with low levels in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-α4, which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how nuclear editing of substrates important for neuronal function can increase as the brain develops.
  •  
13.
  • Bembenek, Joshua N., et al. (författare)
  • Meeting report - Cellular dynamics : membrane-cytoskeleton interface
  • 2017
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 130:17, s. 2775-2779
  • Tidskriftsartikel (refereegranskat)abstract
    • The first ever 'Cellular Dynamics' meeting on the membrane-cytoskeleton interface took place in Southbridge, MA on May 21-24, 2017 and was co-organized by Michael Way, Elizabeth Chen, Margaret Gardel and Jennifer Lippincott-Schwarz. Investigators from around the world studying a broad range of related topics shared their insights into the function and regulation of the cytoskeleton and membrane compartments. This provided great opportunities to learn about key questions in various cellular processes, from the basic organization and operation of the cell to higher-order interactions in adhesion, migration, metastasis, division and immune cell interactions in different model organisms. This unique and diverse mix of research interests created a stimulating and educational meeting that will hopefully continue to be a successful meeting for years to come.
  •  
14.
  • Bengtsson, T, et al. (författare)
  • Loss of alpha 10 beta 1 integrin expression leads to moderate dysfunction of growth plate chondrocytes
  • 2005
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:5, s. 929-936
  • Tidskriftsartikel (refereegranskat)abstract
    • Integrin alpha 10 beta 1 is a collagen-binding integrin expressed on chondrocytes. In order to unravel the role of the alpha 10 integrin during development, we generated mice carrying a constitutive deletion of the alpha 10 integrin gene. The mutant mice had a normal lifespan and were fertile but developed a growth retardation of the long bones. Analysis of the skeleton revealed defects in the growth plate after birth characterized by a disturbed columnar arrangement of chondrocytes, abnormal chondrocyte shape and reduced chondrocyte proliferation. Electron microscopy of growth plates from newborn mice revealed an increased number of apoptotic chondrocytes and reduced density of the collagen fibrillar network compared to these structures in control mice. These results demonstrate that integrin alpha 10 beta 1 plays a specific role in growth plate morphogenesis and function.
  •  
15.
  • Benz, PM, et al. (författare)
  • Differential VASP phosphorylation controls remodeling of the actin cytoskeleton
  • 2009
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 122:21Pt 21, s. 3954-3965
  • Tidskriftsartikel (refereegranskat)abstract
    • Proteins of the Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family link signal transduction pathways to actin cytoskeleton dynamics. VASP is substrate of cAMP-dependent, cGMP-dependent and AMP-activated protein kinases that primarily phosphorylate the sites S157, S239 and T278, respectively. Here, we systematically analyzed functions of VASP phosphorylation patterns for actin assembly and subcellular targeting in vivo and compared the phosphorylation effects of Ena/VASP family members. Methods used were the reconstitution of VASP-null cells with `locked' phosphomimetic VASP mutants, actin polymerization of VASP mutants in vitro and in living cells, site-specific kinase-mediated VASP phosphorylation, and analysis of the endogenous protein with phosphorylation-status-specific antibodies. Phosphorylation at S157 influenced VASP localization, but had a minor impact on F-actin assembly. Phosphorylation of the S157-equivalent site in the Ena/VASP family members Mena and EVL had no effect on the ratio of cellular F-actin to G-actin. By contrast, VASP phosphorylation at S239 (and the equivalent site in Mena) or T278 impaired VASP-driven actin filament formation. The data show that VASP functions are precisely regulated by differential phosphorylation and provide new insights into cytoskeletal control by serine/threonine kinase-dependent signaling pathways.
  •  
16.
  • Berger, Susanne, et al. (författare)
  • WASP and SCAR have distinct roles in activating the Arp2/3 complex during myoblast fusion
  • 2008
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 121:Pt 8, s. 1303-1313
  • Tidskriftsartikel (refereegranskat)abstract
    • Myoblast fusion takes place in two steps in mammals and in Drosophila. First, founder cells (FCs) and fusion-competent myoblasts (FCMs) fuse to form a trinucleated precursor, which then recruits further FCMs. This process depends on the formation of the fusion-restricted myogenic-adhesive structure (FuRMAS), which contains filamentous actin (F-actin) plugs at the sites of cell contact. Fusion relies on the HEM2 (NAP1) homolog Kette, as well as Blow and WASP, a member of the Wiskott-Aldrich-syndrome protein family. Here, we show the identification and characterization of schwächling--a new Arp3-null allele. Ultrastructural analyses demonstrate that Arp3 schwächling mutants can form a fusion pore, but fail to integrate the fusing FCM. Double-mutant experiments revealed that fusion is blocked completely in Arp3 and wasp double mutants, suggesting the involvement of a further F-actin regulator. Indeed, double-mutant analyses with scar/WAVE and with the WASP-interacting partner vrp1 (sltr, wip)/WIP show that the F-actin regulator scar also controls F-actin formation during myoblast fusion. Furthermore, the synergistic phenotype observed in Arp3 wasp and in scar vrp1 double mutants suggests that WASP and SCAR have distinct roles in controlling F-actin formation. From these findings we derived a new model for actin regulation during myoblast fusion.
  •  
17.
  • Bhattacharya, Resham, et al. (författare)
  • Distinct role of PLC{beta}3 in VEGF-mediated directional migration and vascular sprouting
  • 2009
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 122:7, s. 1025-1034
  • Tidskriftsartikel (refereegranskat)abstract
    • Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis. However, we show here that VEGF, specifically through VEGFR2, induces phosphorylation of two serine residues on PLCbeta3, and this was confirmed in an ex vivo embryoid body model. Knockdown of PLCbeta3 in HUVEC cells affects IP3 production, actin reorganization, migration and proliferation; whereas migration is inhibited, proliferation is enhanced. Our data suggest that enhanced proliferation is precipitated by an accelerated cell cycle, and decreased migration by an inability to activate CDC42. Given that PLCbeta3 is typically known as an effector of heterotrimeric G-proteins, our data demonstrate a unique crosstalk between the G-protein and receptor tyrosine kinase (RTK) axes and reveal a novel molecular mechanism of VEGF signaling and, thus, angiogenesis.
  •  
18.
  • Bidla, Gawa, et al. (författare)
  • Crystal cell rupture after injury in Drosophila requires the JNK pathway, small GTPases and the TNF homolog eiger
  • 2007
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 120:7, s. 1209-1215
  • Tidskriftsartikel (refereegranskat)abstract
    • The prophenoloxidase-activating cascade is a key component of arthropod immunity. Drosophila prophenoloxidase is stored in crystal cells, a specialized class of blood cells from which it is released through cell rupture. Within minutes after bleeding, prophenoloxidase is activated leading to visible melanization of the clot matrix. Using crystal cell rupture and melanization as readouts to screen mutants in signal transduction pathways, we show that prophenoloxidase release requires Jun N-terminal kinase, small Rho GTPases and Eiger, the Drosophila homolog of tumor necrosis factor. We also provide evidence that in addition to microbial products, endogenous signals from dying hemocytes contribute to triggering and/or assembly of the prophenoloxidase-activating cascade, and that this process can be inhibited in vitro and in vivo using the viral apoptotic inhibitor p35. Our results provide a more comprehensive view of immune signal transduction pathways, with implications for immune reactions where cell death is used as a terminal mode of cell activation.
  •  
19.
  • Biquand, A, et al. (författare)
  • Titin M-line insertion sequence 7 is required for proper cardiac function in mice
  • 2021
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 134:18
  • Tidskriftsartikel (refereegranskat)abstract
    • Titin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the M-line, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (ΔMex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. ΔMex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation–contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation–contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.
  •  
20.
  • Bjork, P, et al. (författare)
  • The Chironomus tentans translation initiation factor eIF4H is present in the nucleus but does not bind to mRNA until the mRNA reaches the cytoplasmic perinuclear region
  • 2003
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 116:22Pt 22, s. 4521-4532
  • Tidskriftsartikel (refereegranskat)abstract
    • In the cell nucleus, precursors to mRNA, pre-mRNAs, associate with a large number of proteins and are processed to mRNA-protein complexes, mRNPs. The mRNPs are then exported to the cytoplasm and the mRNAs are translated into proteins. The mRNAs containing in-frame premature stop codons are recognized and degraded in the nonsense-mediated mRNA decay process. This mRNA surveillence may also occur in the nucleus and presumably involves components of the translation machinery. Several translation factors have been detected in the nucleus, but their functional relationship to the dynamic protein composition of pre-mRNPs and mRNPs in the nucleus is still unclear.Here, we have identified and characterized the translation initiation factor eIF4H in the dipteran Chironomus tentans. In the cytoplasm, Ct-eIF4H is associated with poly(A+) RNA in polysomes. We show that a minor fraction of Ct-eIF4H enters the nucleus. This fraction is independent on the level of transcription. CteIF4H could not be detected in gene-specific pre-mRNPs or mRNPs, nor in bulk mRNPs in the nucleus. Our immunoelectron microscopy data suggest that Ct-eIF4H associates with mRNP in the cytoplasmic perinuclear region, immediately as the mRNP exits from the nuclear pore complex.
  •  
21.
  • Boban, Mirta, et al. (författare)
  • A nuclear ubiquitin-proteasome pathway targets the inner nuclear membrane protein Asi2 for degradation
  • 2014
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 127:16, s. 3603-3613
  • Tidskriftsartikel (refereegranskat)abstract
    • The nuclear envelope consists of inner and outer nuclear membranes. Whereas the outer membrane is an extension of the endoplasmic reticulum, the inner nuclear membrane (INM) represents a unique membranous environment containing specific proteins. The mechanisms of integral INM protein degradation are unknown. Here, we investigated the turnover of Asi2, an integral INM protein in Saccharomyces cerevisiae. We report that Asi2 is degraded by the proteasome independently of the vacuole and that it exhibited a half-life of similar to 45 min. Asi2 exhibits enhanced stability in mutants lacking the E2 ubiquitin conjugating enzymes Ubc6 or Ubc7, or the E3 ubiquitin ligase Doa10. Consistent with these data, Asi2 is post-translationally modified by poly-ubiquitylation in a Ubc7- and Doa10-dependent manner. Importantly Asi2 degradation is significantly reduced in a sts1-2 mutant that fails to accumulate proteasomes in the nucleus, indicating that Asi2 is degraded in the nucleus. Our results reveal a molecular pathway that affects the stability of integral proteins of the inner nuclear membrane and indicate that Asi2 is subject to protein quality control in the nucleus.
  •  
22.
  • Bot, C, et al. (författare)
  • Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage
  • 2017
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 130:6, s. 1134-1146
  • Tidskriftsartikel (refereegranskat)abstract
    • NIPBL is required to load the cohesin complex on to DNA. While the canonical role of cohesin is to couple replicated sister chromatids together until the onset of mitosis, it also promotes tolerance to DNA damage. Here we show that NIPBL is recruited to DNA damage throughout the cell cycle via independent mechanisms, influenced by type of damage. Firstly, the heterochromatin protein HP1γ recruits NIPBL to DSBs through the corresponding HP1-binding motif within the N-terminus. In contrast, the C-terminal HEAT repeat domain is unable to recruit NIPBL to DSBs but independently targets NIPBL to laser microirradiation induced DNA damage. Each mechanism is dependent on the RNF8/RNF168 ubiquitylation pathway, while the recruitment of the HEAT repeat domain requires further ATM/ATR activity. Thus, NIPBL has evolved a sophisticated response to damaged DNA that is influenced by the form of damage, suggesting a highly dynamic role for NIPBL in maintaining genomic stability.
  •  
23.
  • Bruinsma, W, et al. (författare)
  • Bora and Aurora-A continue to activate Plk1 in mitosis
  • 2014
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 127:4Pt 4, s. 801-811
  • Tidskriftsartikel (refereegranskat)abstract
    • Polo-like kinase-1 (Plk1) is required for proper cell division. Activation of Plk1 requires phosphorylation on a conserved threonine in the T-loop of the kinase domain (T210). Plk1 is first phosphorylated on T210 in G2 phase by the kinase Aurora-A, in concert with its cofactor Bora. However, Bora was shown to be degraded prior to entry into mitosis, and it is currently unclear how Plk1 activity is sustained in mitosis. Here we show that the Bora/Aurora-A complex remains the major activator of Plk1 in mitosis. We show that a small amount of Aurora-A activity is sufficient to phosphorylate and activate Plk1 in mitosis. In addition, a fraction of Bora is retained in mitosis, which is essential for continued Aurora-A dependent T210 phosphorylation of Plk1. We find that once Plk1 is activated, minimal amounts of the Bora/Aurora-A complex are sufficient to sustain Plk1 activity. Thus, the activation of Plk1 by Aurora-A may function as a bistable switch; highly sensitive to inhibition of Aurora-A in its initial activation, but refractory to fluctuations in Aurora-A activity once Plk1 is fully activated. This provides a cell with robust Plk1 activity once it has committed to mitosis.
  •  
24.
  • Bryja, V, et al. (författare)
  • Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism
  • 2007
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 120:4Pt 4, s. 586-595
  • Tidskriftsartikel (refereegranskat)abstract
    • Previously, we have shown that Wnt-5a strongly regulates dopaminergic neuron differentiation by inducing phosphorylation of Dishevelled (Dvl). Here, we identify additional components of the Wnt-5a-Dvl pathway in dopaminergic cells. Using in vitro gain-of-function and loss-of-function approaches, we reveal that casein kinase 1 (CK1) δ and CK1ϵ are crucial for Dvl phosphorylation by non-canonical Wnts. We show that in response to Wnt-5a, CK1ϵ binds Dvl and is subsequently phosphorylated. Moreover, in response to Wnt-5a or CK1ϵ, the distribution of Dvl changed from punctate to an even appearance within the cytoplasm. The opposite effect was induced by a CK1ϵ kinase-dead mutant or by CK1 inhibitors. As expected, Wnt-5a blocked the Wnt-3a-induced activation of β-catenin. However, both Wnt-3a and Wnt-5a activated Dvl2 by a CK1-dependent mechanism in a cooperative manner. Finally, we show that CK1 kinase activity is necessary for Wnt-5a-induced differentiation of primary dopaminergic precursors. Thus, our data identify CK1 as a component of Wnt-5a-induced signalling machinery that regulates dopaminergic differentiation, and suggest that CK1δ/ϵ-mediated phosphorylation of Dvl is a common step in both canonical and non-canonical Wnt signalling.
  •  
25.
  • Buch, Charlotta, et al. (författare)
  • An integral protein of the inner nuclear membrane localizes to the mitotic spindle in mammalian cells
  • 2009
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 122:12, s. 2100-2107
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, we characterize a transmembrane protein of the nuclear envelope that we name spindle-associated membrane protein 1 (Samp1). The protein is conserved in metazoa and fission yeast and is homologous to Net5 in rat and Ima1 in Schizosaccharomyces pombe. We show that, in human cells, the protein is a membrane-spanning polypeptide with an apparent molecular mass of 43 kDa. This is consistent with a predicted polypeptide of 392 amino acids that has five transmembrane segments and its C-terminus exposed to the nucleoplasm. During interphase, Samp1 was specifically distributed in the inner nuclear membrane. Post-transcriptional silencing of Samp1 expression resulted in separation of centrosomes from the nuclear envelope, indicating that it is functionally connected to the cytoskeleton. At the onset of mitosis, most of the protein dispersed out into the ER, as expected. However, during mitosis, a significant fraction of the protein specifically localized to the polar regions of the mitotic spindle. We demonstrate for the first time, in human cells, the existence of a membranous structure overlapping with the mitotic spindle. Interestingly, another integral inner nuclear membrane protein, emerin, was absent from the spindle-associated membranes. Thus, Samp1 defines a specific membrane domain associated with the mitotic spindle.
  •  
26.
  • Bullock, Simon L., et al. (författare)
  • Meeting report - Nuclear and cytoplasmic molecular machines at work
  • 2020
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 133:7
  • Tidskriftsartikel (refereegranskat)abstract
    • This report summarizes an international conference on molecular machines convened at New York University, Abu Dhabi by Piergiorgio Percipalle, George Shubeita and Serdal Kirmizialtin. The meeting was conceived around the epistemological question of what do we understand, or not understand (if we have open minds), about the degree to which cells operate by the individual actions of single enzymes or non-catalytic protein effectors, versus combinations of these in which their heterotypic association creates an entity that is more finely tuned and efficient - a machine. This theme was explored through a vivid series of talks, summarizing the latest findings on macromolecular complexes that operate in the nucleus or cytoplasm.
  •  
27.
  • Burghoorn, J, et al. (författare)
  • Dauer pheromone and G-protein signaling modulate the coordination of intraflagellar transport kinesin motor proteins in C. elegans
  • 2010
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 123:12Pt 12, s. 2076-2083
  • Tidskriftsartikel (refereegranskat)abstract
    • Cilia length and function are dynamically regulated by modulation of intraflagellar transport (IFT). The cilia of C. elegans amphid channel neurons provide an excellent model to study this process, since they use two different kinesins for anterograde transport: kinesin-II and OSM-3 kinesin together in the cilia middle segments, but only OSM-3 in the distal segments. To address whether sensory signaling modulates the coordination of the kinesins, we studied IFT protein motility in gpa-3 mutant animals, since dominant active mutation of this sensory Gα protein GPA-3QL) affects cilia length. In addition, we examined animals exposed to dauer pheromone, since dauer formation, which involves gpa-3, induces changes in cilia morphology. Live imaging of fluorescently tagged IFT proteins showed that in gpa-3 mutants and in larvae exposed to dauer pheromone, kinesin-II speed is decreased and OSM-3 speed is increased, whereas structural IFT proteins move at an intermediate speed. These results indicate that mutation of gpa-3 and exposure to dauer pheromone partially uncouple the two kinesins. We propose a model in which GPA-3-regulated docking of kinesin-II and/or OSM-3 determines entry of IFT particles into the cilia subdomains, allowing structural and functional plasticity of cilia in response to environmental cues.
  •  
28.
  • Burrinha, Tatiana, et al. (författare)
  • Up-regulation of APP endocytosis by neuronal aging drives amyloid dependent-synapse loss
  • 2021
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 134:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuronal aging increases the risk of late-onset Alzheimer's disease. During normal aging, synapses decline, and β-amyloid (Aβ) accumulates intraneuronally. However, little is known about the underlying cell biological mechanisms. We studied normal neuronal aging using normal aged brain and aged mouse primary neurons that accumulate lysosomal lipofuscin and show synapse loss. We identify the up-regulation of amyloid precursor protein (APP) endocytosis as a neuronal aging mechanism that potentiates APP processing and Aβ production in vitro and in vivo. The increased APP endocytosis may contribute to the observed early endosomes enlargement in the aged brain. Mechanistically, we show that clathrin-dependent APP endocytosis requires F-actin and that clathrin and endocytic F-actin increase with neuronal aging. Finally, Aβ production inhibition reverts synaptic decline in aged neurons while Aβ accumulation, promoted by endocytosis up-regulation in younger neurons, recapitulates aging-related synapse decline. Overall, we identify APP endocytosis up-regulation as a potential mechanism of neuronal aging and, thus, a novel target to prevent late-onset Alzheimer's disease.
  •  
29.
  • Busayavalasa, Kiran, et al. (författare)
  • The Nup155-mediated organisation of inner nuclear membrane proteins is independent of Nup155 anchoring to the metazoan nuclear pore complex
  • 2012
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 125:18, s. 4214-4218
  • Tidskriftsartikel (refereegranskat)abstract
    • The nuclear envelope (NE), an important barrier between the nucleus and the cytoplasm, is composed of three structures: the outer nuclear membrane, which is continuous with the ER, the inner nuclear membrane (INM), which interfaces with chromatin, and nuclear pore complexes (NPCs), which are essential for the exchange of macromolecules between the two compartments. The NPC protein Nup155 has an evolutionarily conserved role in the metazoan NE formation; but the in vivo analysis of Nup155 has been severely hampered by the essential function of this protein in cell viability. Here, we take advantage of the hypomorphicity of RNAi systems and use a combination of protein binding and rescue assays to map the interaction sites of two neighbouring NPC proteins Nup93 and Nup53 on Nup155, and to define the requirements of these interactions in INM protein organization. We show that different parts of Drosophila Nup155 have distinct functions: the Nup155 beta-propeller anchors the protein to the NPC, whereas the alpha-solenoid part of Nup155 is essential for the correct localisation of INM proteins lamin-B receptor (LBR) and otefin. Using chromatin extracts from semisynchronized cells, we also provide evidence that the Nup155 alpha-solenoid has a chromatin-binding activity that is stronger at the end of mitosis. Our results argue that the role of Nup155 in INM protein localisation is not mediated through the NPC anchoring activity of the protein and suggest that regions other than Nup155 beta-propeller are necessary for the targeting of proteins to the INM.
  •  
30.
  • Carlsson, Sven R, et al. (författare)
  • Membrane dynamics in autophagosome biogenesis
  • 2015
  • Ingår i: Journal of Cell Science. - : The Company of Biologists LTD. - 0021-9533 .- 1477-9137. ; 128:2, s. 193-205
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Bilayered phospholipid membranes are vital to the organization of the living cell. Based on fundamental principles of polarity, membranes create borders allowing defined spaces to be encapsulated. This compartmentalization is a prerequisite for the complex functional design of the eukaryotic cell, yielding localities that can differ in composition and operation. During macroautophagy, cytoplasmic components become enclosed by a growing double bilayered membrane, which upon closure creates a separate compartment, the autophagosome. The autophagosome is then primed for fusion with endosomal and lysosomal compartments, leading to degradation of the captured material. A large number of proteins have been found to be essential for autophagy, but little is known about the specific lipids that constitute the autophagic membranes and the membrane modeling events that are responsible for regulation of autophagosome shape and size. In this Commentary, we review the recent progress in our understanding of the membrane shaping and remodeling events that are required at different steps of the autophagy pathway.
  •  
31.
  • Carolina Touz, Maria, et al. (författare)
  • Arginine deiminase has multiple regulatory roles in the biology of Giardia lamblia
  • 2008
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 121:17, s. 2930-2938
  • Tidskriftsartikel (refereegranskat)abstract
    • The protozoan parasite Giardia lamblia uses arginine deiminase (ADI) to produce energy from free L-arginine under anaerobic conditions. In this work, we demonstrate that, in addition to its known role as a metabolic enzyme, it also functions as a peptidylarginine deiminase, converting protein-bound arginine into citrulline. G. lamblia ADI specifically binds to and citrullinates the arginine in the conserved CRGKA tail of variant-specific surface proteins (VSPs), affecting both antigenic switching and antibody-mediated cell death. During encystation, ADI translocates from the cytoplasm to the nuclei and appears to play a regulatory role in the expression of encystation-specific genes. ADI is also sumoylated, which might modulate its activity. Our findings reveal a dual role played by ADI and define novel regulatory pathways used by Giardia for survival.
  •  
32.
  • Castelo-Branco, G, et al. (författare)
  • GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
  • 2004
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 117:24Pt 24, s. 5731-5737
  • Tidskriftsartikel (refereegranskat)abstract
    • Wnts are important regulators of dopamine (DA) neuron differentiation in the developing ventral mesencephalon and could thus serve as potential tools in the treatment of Parkinson's disease. In this study, we investigate whether established intracellular Wnt signalling components could modulate the development of DA neurons. Two chemical inhibitors of glycogen synthase kinase (GSK)-3β, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3β-specific inhibitor kenpaullone increased the size of the DA neuron population through conversion of precursors expressing the orphan nuclear receptor-related factor 1 into tyrosine hydroxylase positive neurons, thereby mimicking an effect of Wnts. We show that GSK-3β inhibitors stabilized β-catenin and that overexpression of β-catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3β inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.
  •  
33.
  • Chapman, Hugh, et al. (författare)
  • Downregulation of the HERG (KCNH2) K(+) channel by ceramide : evidence for ubiquitin-mediated
  • 2005
  • Ingår i: J Cell Sci. - Minerva Fdn, Inst Med Res, Biomedicum, FI-00290 Helsinki, Finland. Abo Akad Univ, Dept Biol, FI-20520 Turku, Finland. Uppsala Univ, Dept Neurosci, Neurobiol Unit, BMC, SE-75123 Uppsala, Sweden. Univ Helsinki, Cent Hosp, Dept Cardiol, FI-00290 Helsinki, Finland. Cardiff Univ, Welsh Sch Pharm, Cardiff CF1 3XF, Wales. : COMPANY BIOLOGISTS LTD. - 0021-9533 .- 1477-9137. ; 118:Pt 22, s. 5325-34
  • Tidskriftsartikel (refereegranskat)
  •  
34.
  • Chen, YZ, et al. (författare)
  • Structure and function analysis of the C. elegans aminophospholipid translocase TAT-1
  • 2019
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 132:5
  • Tidskriftsartikel (refereegranskat)abstract
    • The C. elegans aminophospholipid translocase TAT–1 maintains phosphatidylserine (PS) asymmetry in the plasma membrane and regulates endocytic transport. Despite these important functions, the structure-function relationship of this protein is poorly understood. Taking advantage of the tat-1 mutations identified by the C. elegans million mutation project, we investigated the effects of 16 single amino-acid substitutions on the two functions of the TAT–1 protein. Two substitutions that alter a highly conserved PISL motif in the fourth transmembrane domain and a highly conserved DKTGT phosphorylation motif, respectively, disrupt both functions of TAT-1, leading to a vesicular gut defect and ectopic PS exposure on cell surface, whereas most other substitutions across the TAT-1 protein, often predicted to be deleterious by bioinformatics programs, do not affect the functions of TAT-1. These results provide in vivo evidence for the importance of the PISL and DKTGT motifs in P4–type adenosine triphosphatases (ATPases) and improve our understanding of the structure-function relationship of TAT-1. Our study also provides an example of how the C. elegans million mutation project helps decipher the structure, functions, and mechanisms of action of important genes.
  •  
35.
  • Cheviet, Severine, et al. (författare)
  • Tomosyn-1 is involved in a post-docking event required for pancreatic beta-cell exocytosis
  • 2006
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 119:14, s. 2912-2920
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the assembly of a ternary complex between the SNARE proteins syntaxin-1, SNAP25 and VAMP2 is known to be crucial for insulin exocytosis, the mechanisms controlling this key event are poorly understood. We found that pancreatic beta-cells express different isoforms of tomosyn-1, a syntaxin-1-binding protein possessing a SNARE-like motif. Using atomic force microscopy we show that the SNARE-like domain of tomosyn-1 can form a complex with syntaxin-1 and SNAP25 but displays binding forces that are weaker than those observed for VAMP2 (237 +/- 13 versus 279 +/- 3 pN). In pancreatic beta-cells tomosyn-1 was found to be concentrated in cellular compartments enriched in insulin-containing secretory granules. Silencing of tomosyn-1 in the rat beta-cell line INS-1E by RNA interference did not affect the number of secretory granules docked at the plasma membrane but led to a reduction in stimulus-induced exocytosis. Replacement of endogenous tomosyn-1 with mouse tomosyn-1, which differs in the nucleotide sequence from its rat homologue and escapes silencing, restored a normal secretory rate. Taken together, our data suggest that tomosyn-1 is involved in a post-docking event that prepares secretory granules for fusion and is necessary to sustain exocytosis of pancreatic beta-cells in response to insulin secretagogues.
  •  
36.
  • Cho, Kin-Sang, et al. (författare)
  • Re-establishing the regenerative potential of central nervous system axons in postnatal mice.
  • 2005
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:Pt 5, s. 863-72
  • Tidskriftsartikel (refereegranskat)abstract
    • At a certain point in development, axons in the mammalian central nervous system lose their ability to regenerate after injury. Using the optic nerve model, we show that this growth failure coincides with two developmental events: the loss of Bcl-2 expression by neurons and the maturation of astrocytes. Before postnatal day 4, when astrocytes are immature, overexpression of Bcl-2 alone supported robust and rapid optic nerve regeneration over long distances, leading to innervation of brain targets by day 4 in mice. As astrocytes matured after postnatal day 4, axonal regeneration was inhibited in mice overexpressing Bcl-2. Concurrent induction of Bcl-2 and attenuation of reactive gliosis reversed the failure of CNS axonal re-elongation in postnatal mice and led to rapid axonal regeneration over long distances and reinnervation of the brain targets by a majority of severed optic nerve fibers up to 2 weeks of age. These results suggest that an early postnatal downregulation of Bcl-2 and post-traumatic reactive gliosis are two important elements of axon regenerative failure in the CNS.
  •  
37.
  • Christis, C, et al. (författare)
  • Regulated increase in folding capacity prevents unfolded protein stress in the ER
  • 2010
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 123:5Pt 5, s. 787-794
  • Tidskriftsartikel (refereegranskat)abstract
    • Stimulation of thyrocytes with thyroid stimulating hormone (TSH) leads to a morphological change and a massive increase in thyroglobulin (Tg) production. Although Tg is a demanding client of the endoplasmic reticulum (ER), its increase did not result in significant accumulation of unfolded protein in the ER. Instead, ER chaperones and folding enzymes reached maximum synthesis rates immediately after TSH stimulation, before significant upregulation of Tg synthesis. The resulting increase in folding capacity before client protein production prevented cellular unfolded-protein stress, confirmed by the silence of the most conserved branch of the unfolded protein response. Thyrocytes set an example of physiological adaptation of cells to a future potentially stress-causing situation, which suggests a general strategy for both non-secretory and specialized secretory cells.
  •  
38.
  • Colo, GP, et al. (författare)
  • Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway
  • 2012
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 125:22Pt 22, s. 5338-5352
  • Tidskriftsartikel (refereegranskat)abstract
    • Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. RIAM is an adaptor protein mediating talin recruitment to the cell membrane, whose depletion leads to defective melanoma cell migration and invasion. Here we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally located at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly due to RIAM knocking down correlated with deficient integrin-dependent MEK-Erk1/2 activation, and importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted RhoA activation following integrin engagement was needed for subsequent Erk1/2 activation, and RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, suggesting a functional role also for RhoA downstream of RIAM, but upstream of Erk1/2. In addition, RIAM knock down led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and non-phosphorylatable mutants at these paxillin residues indicated that paxillin hyper-phosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened association between FA proteins, suggesting that it may play important adaptor roles for the correct assembly of adhesion complexes. Our data indicate that integrin-triggered, RIAM-dependent MEK activation may represent a key feed-back event required for efficient FA disassembly, which may contribute to explain the role of RIAM in cell migration and invasion.
  •  
39.
  • Corkery, Dale, et al. (författare)
  • Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy
  • 2021
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 134:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Autophagy plays an essential role in the defense against manymicrobial pathogens as a regulator of both innate and adaptive immunity. Some pathogens have evolved sophisticated mechanisms that promote their ability to evade or subvert host autophagy. Here, we describe a novel mechanism of autophagy modulation mediated by the recently discovered Vibrio cholerae cytotoxin, motility-associatedkilling factor A (MakA). pH-dependent endocytosis of MakA by host cells resulted in the formation of a cholesterol-rich endolysosomal membrane aggregate in the perinuclear region. Aggregate formation induced the noncanonical autophagy pathway driving unconventional LC3 (herein referring to MAP1LC3B) lipidation on endolysosomal membranes. Subsequent sequestration of the ATG12-ATG5-ATG16L1 E3-like enzyme complex, required for LC3 lipidation at the membranous aggregate, resulted in an inhibition of both canonical autophagy and autophagy-related processes, including the unconventional secretion of interleukin-1β (IL-1β). These findings identify a novel mechanismof host autophagy modulation and immune modulation employed by V. cholerae during bacterial infection.
  •  
40.
  • Costa, Y, et al. (författare)
  • Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis
  • 2005
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:12Pt 12, s. 2755-2762
  • Tidskriftsartikel (refereegranskat)abstract
    • Completion of meiosis in mammals depends on the formation of the synaptonemal complex, a tripartite structure that physically links homologous chromosomes during prophase I. Several components of the synaptonemal complex are known, including constituents of the cohesin core, the axial/lateral element and the transverse filaments. No protein has previously been identified as an exclusive component of the central element. Mutations in some synaptonemal-complex proteins results in impaired meiosis. In humans, cases of male infertility have been associated with failure to build the synaptonemal complex. To search for new components of the meiotic machinery, we have used data from microarray expression profiling and found two proteins localising solely to the central element of the mammalian synaptonemal complex. These new proteins, SYCE1 and CESC1, interact with the transverse filament protein SYCP1, and their localisation to the central element appears to depend on recruitment by SYCP1. This suggests a role for SYCE1 and CESC1 in synaptonemal-complex assembly, and perhaps also stability and recombination.
  •  
41.
  • de Boer, E, et al. (författare)
  • Meiotic interference among MLH1 foci requires neither an intact axial element structure nor full synapsis
  • 2007
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 120:5Pt 5, s. 731-736
  • Tidskriftsartikel (refereegranskat)abstract
    • During meiosis, homologous chromosomes (homologs) perform reciprocal exchanges (crossovers) at a high frequency. Crossovers display interference, i.e. their spacing is more even than would be expected if they were placed randomly along the chromosomes. Concomitantly with crossover formation, synaptonemal complexes (SCs) appear between homologs: each chromosome forms an axial structure, the axial element (AE); the AEs of homologs align, and numerous transverse filaments connect the AEs to form an SC. Both the AE and the SC have been implicated in the imposition of interference. We investigated whether intact AEs or SCs are required for crossover interference in the mouse, using a mutant lacking AE protein SYCP3, which displays structurally abnormal AEs and incomplete synapsis. We estimated the level of interference from the spacing of immunofluorescent MLH1 foci, which mark almost all crossover sites in the mouse, along the SCs. The levels of interference among MLH1 foci in wild-type and Sycp3–/– mice were comparable, implying that neither an intact AE structure nor full synapsis is required for wild-type levels of interference.
  •  
42.
  •  
43.
  • Dinic, Jelena, et al. (författare)
  • Actin filaments at the plasma membrane in live cells cause the formation of ordered lipid domains via phosphatidylinositol 4,5-bisphosphate
  • Ingår i: Journal of Cell Science. - 0021-9533 .- 1477-9137.
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationship between ordered plasma membrane nanodomains, known as lipid rafts, and actin filaments is the focus of this study. Plasma membrane order was followed in live cells at 37°C using laurdan and di-4-ANEPPDHQ to report on lipid packing. Disrupting actin polymerization decreased the fraction of ordered domains, which strongly argue that unstimulated cells have a basal level of ordered domains. Stabilising actin filaments had the opposite effect and increased the proportion of ordered domains. Decreasing the plasma membrane level of phosphatidylinositol 4,5-bisphosphate lowers the number of attachment points for actin filaments and reduced the proportion of ordered domains. Aggregation of plasma membrane molecules, both lipid raft and non-lipid raft markers, leads to the formation of ordered domains that is correlated with an increase in cell peripheral actin filaments. In membrane blebs, which are detached from the underlying actin filaments the fraction of ordered domains was low and GM1 could not be patched to form ordered domains. We conclude that ordered domains form where actin filaments attach to the plasma membrane via phosphatidylinositol 4,5-bisphosphate. This downplays lipid-lipid interactions as the main driving force behind the formation of ordered membrane domains in vivo, giving greater prominence to membrane-intracellular filament interactions.
  •  
44.
  • Dyachok, Oleg, et al. (författare)
  • Store-operated influx of Ca2+ in the pancreatic β-cells exhibits graded dependence on the filling of the endoplasmic reticulum
  • 2001
  • Ingår i: Journal of Cell Science. - 0021-9533 .- 1477-9137. ; 114:Pt 11, s. 2179-2186
  • Tidskriftsartikel (refereegranskat)abstract
    • The store-operated pathway for Ca2+ entry was studied in individual mouse pancreatic β-cells by measuring the cytoplasmic concentrations of Ca2+ ([Ca2+]i) and Mn2+ ([Mn2+]i) with the fluorescent indicator fura-2. Influx through the store-operated pathway was initially shut off by pre-exposure to 20 mM glucose, which maximally stimulates intracellular Ca2+ sequestration. To avoid interference with voltage-dependent Ca2+ entry the cells were hyperpolarized with diazoxide and the channel blocker methoxyverapamil was present. Activation of the store-operated pathway in response to Ca2+ depletion of the endoplasmic reticulum was estimated from the sustained elevation of [Ca2+]i or from the rate of increase in [Mn2+]i due to influx of these extracellular ions. Increasing concentrations of the inositol 1,4,5-trisphosphate-generating agonist carbachol or the sarco(endo)plasmatic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid (CPA) cause gradual activation of the store-operated pathway. In addition, the carbachol- and CPA-induced influx of Mn2+ depended on store filling in a graded manner. The store-operated influx of Ca2+/Mn2+ was inhibited by Gd3+ and 2-aminoethoxydiphenyl borate but neither of these agents discriminated between store-operated and voltage-dependent entry. The finely tuned regulation of the store-operated mechanisms in the β-cell has direct implications for the control of membrane potential and insulin secretion.
  •  
45.
  • Edgar, James R, et al. (författare)
  • ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular beta amyloid accumulation.
  • 2015
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:14, s. 2520-2528
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation and promoting Aβ secretion.
  •  
46.
  • Edlund, Sofia, et al. (författare)
  • Smad7 is required for TGF-ß-induced activation of the small GTPase Cdc42
  • 2004
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 117:Pt 9, s. 1835-1847
  • Tidskriftsartikel (refereegranskat)abstract
    • Transforming growth factor beta (TGF-beta) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-beta receptors. The inhibitory Smads, Smad6 and Smad7, are considered to function as negative regulators of the TGF-beta/Smad signaling cascade. In a previous study, we found that TGF-beta induces rearrangements of the actin filament system in human prostate carcinoma cells and that this response requires the small GTPases Cdc42 and RhoA. On the basis of the current view on the function of Smad7 in TGF-beta signaling, we hypothesized that Smad7 would function as a negative regulator of the TGF-beta-induced activation of Cdc42 and RhoA, but instead we found that the reverse is the case; Smad7 is required for the TGF-beta-induced activation of Cdc42 and the concomitant reorganization of the actin filament system. These observations propose a novel role for Smad7 in TGF-beta-dependent activation of Rho GTPases.
  •  
47.
  • Englund, JI, et al. (författare)
  • Laminin matrix adhesion regulates basal mammary epithelial cell identity
  • 2022
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 135:23
  • Tidskriftsartikel (refereegranskat)abstract
    • Mammary epithelium is a bilayered ductal network composed of luminal and basal epithelial cells, which together drive the growth and functional differentiation of the gland. Basal mammary epithelial cells (MECs) exhibit remarkable plasticity and progenitor activity that facilitate epithelial expansion. However, their activity must be tightly regulated to restrict excess basal cell activity. Here, we show that adhesion of basal cells to laminin α5-containing basement membrane matrix, which is produced by luminal cells, presents such a control mechanism. Adhesion to laminin α5 directs basal cells towards a luminal cell fate, and thereby results in a marked decrease of basal MEC progenitor activity in vitro and in vivo. Mechanistically, these effects are mediated through β4-integrin and activation of p21 (encoded by CDKN1A). Thus, we demonstrate that laminin matrix adhesion is a key determinant of basal identity and essential to building and maintaining a functional multicellular epithelium.
  •  
48.
  • Espigat-Georger, A, et al. (författare)
  • Nuclear alignment in myotubes requires centrosome proteins recruited by nesprin-1
  • 2016
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 129:22, s. 4227-4237
  • Tidskriftsartikel (refereegranskat)abstract
    • Myotubes are syncytial cells, generated by fusion of myoblasts. Among the numerous nuclei in myotubes of skeletal muscle fibres, the majority are equidistantly positioned at the periphery, except for clusters of multiple nuclei underneath the motor endplate. The correct positioning of nuclei is thought to be important for muscle function and requires nesprin-1, a protein of the nuclear envelope. Consistently, mice lacking functional nesprin-1 show defective nuclear positioning and mimic aspects of Emery-Dreifuss muscular dystrophy. In this study, we perform siRNA experiments in C2C12 myoblasts undergoing differentiation, demonstrating that the positioning of nuclei requires PCM-1, a protein of the centrosome that relocalizes to the nuclear envelope at the onset of differentiation, dependent on the presence of nesprin-1. PCM-1 itself is required for recruiting proteins of the dynein/dynactin complex and of kinesin motor complexes. This suggests that microtubule motors that are attached to the nuclear envelope support the movement of nuclei along microtubules, to ensure correct positioning in the myotube.
  •  
49.
  • Fauvarque, Marie-Odile, et al. (författare)
  • Drosophila cellular immunity : a story of migration and adhesion
  • 2011
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 124:9, s. 1373-1382
  • Tidskriftsartikel (refereegranskat)abstract
    • Research during the past 15 years has led to significant breakthroughs, providing evidence of a high degree of similarity between insect and mammalian innate immune responses, both humoural and cellular, and highlighting Drosophila melanogaster as a model system for studying the evolution of innate immunity. In a manner similar to cells of the mammalian monocyte and macrophage lineage, Drosophila immunosurveillance cells (haemocytes) have a number of roles. For example, they respond to wound signals, are involved in wound healing and contribute to the coagulation response. Moreover, they participate in the phagocytosis and encapsulation of invading pathogens, are involved in the removal of apoptotic bodies and produce components of the extracellular matrix. There are several reasons for using the Drosophila cellular immune response as a model to understand cell signalling during adhesion and migration in vivo: many genes involved in the regulation of Drosophila haematopoiesis and cellular immunity have been maintained across taxonomic groups ranging from flies to humans, many aspects of Drosophila and mammalian innate immunity seem to be conserved, and Drosophila is a simplified and well-studied genetic model system. In the present Commentary, we will discuss what is known about cellular adhesion and migration in the Drosophila cellular immune response, during both embryonic and larval development, and where possible compare it with related mechanisms in vertebrates.
  •  
50.
  • Filonova, LH, et al. (författare)
  • Two waves of programmed cell death occur during formation and development of somatic embryos in the gymnosperm, Norway spruce
  • 2000
  • Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 113113 Pt 24:24, s. 4399-4411
  • Tidskriftsartikel (refereegranskat)abstract
    • In the animal life cycle, the earliest manifestations of programmed cell death (PCD) can already be seen during embryogenesis. The aim of this work was to determine if PCD is also involved in the elimination of certain cells during plant embryogenesis. We used a model system of Norway spruce somatic embryogenesis, which represents a multistep developmental pathway with two broad phases. The first phase is represented by proliferating proembryogenic masses (PEMs). The second phase encompasses development of somatic embryos, which arise from PEMs and proceed through the same sequence of stages as described for their zygotic counterparts. Here we demonstrate two successive waves of PCD, which are implicated in the transition from PEMs to somatic embryos and in correct embryonic pattern formation, respectively. The first wave of PCD is responsible for the degradation of PEMs when they give rise to somatic embryos. We show that PCD in PEM cells and embryo formation are closely interlinked processes, both stimulated upon withdrawal or partial depletion of auxins and cytokinins. The second wave of PCD eliminates terminally differentiated embryo-suspensor cells during early embryogeny. During the dismantling phase of PCD, PEM and embryo-suspensor cells exhibit progressive autolysis, resulting in the formation of a large central vacuole. Autolytic degradation of the cytoplasm is accompanied by lobing and budding-like segmentation of the nucleus. Nuclear DNA undergoes fragmentation into both large fragments of about 50 kb and multiples of approximately 180 bp. The tonoplast rupture is delayed until lysis of the cytoplasm and organelles, including the nucleus, is almost complete. The protoplasm then disappears, leaving a cellular corpse represented by only the cell wall. This pathway of cell dismantling suggests overlapping of apoptotic and autophagic types of PCD during somatic embryogenesis in Norway spruce.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-50 av 201
Typ av publikation
tidskriftsartikel (198)
forskningsöversikt (3)
Typ av innehåll
refereegranskat (194)
övrigt vetenskapligt/konstnärligt (7)
Författare/redaktör
Hoog, C (10)
aut (8)
Kouznetsova, A. (6)
Lundmark, Richard (5)
Parmryd, Ingela (4)
Heldin, Carl-Henrik (4)
visa fler...
Tengholm, Anders (3)
Lendahl, U (3)
Ibanez, CF (3)
Dantuma, NP (3)
Rorsman, Patrik (3)
Benavente, R (3)
Novak, I (3)
Jessberger, R (3)
Arenas, E (3)
Funa, Keiko, 1949 (3)
Visa, Neus (3)
Östlund Farrants, An ... (3)
Daneholt, B (3)
Hansson, Gunnar C., ... (3)
Wang, H. (2)
Aspenström, Pontus (2)
Claesson-Welsh, Lena (2)
Fukuda, T. (2)
Dyachok, Oleg (2)
Renström, Erik (2)
Degerman, Eva (2)
Eriksson, M (2)
Patarroyo, M (2)
Larsson, Christer (2)
Tamás, Markus J., 19 ... (2)
Sandblad, Linda (2)
Alsheimer, M (2)
Adler, Jeremy (2)
Pfeiffer, A. (2)
Brundell, E. (2)
Ericson, J (2)
Hernández-Hernández, ... (2)
Massoumi, Ramin (2)
Göransson, Olga (2)
Lindqvist, A (2)
Rozell, B (2)
Los, Marek Jan (2)
Zhao, J (2)
Barg, Sebastian (2)
Schulte, G (2)
Eliasson, Lena (2)
Rawal, N (2)
Williams, Michael (2)
Ljungdahl, Per O. (2)
visa färre...
Lärosäte
Karolinska Institutet (80)
Uppsala universitet (35)
Stockholms universitet (29)
Lunds universitet (24)
Göteborgs universitet (22)
Umeå universitet (18)
visa fler...
Linköpings universitet (7)
Södertörns högskola (6)
Kungliga Tekniska Högskolan (4)
Chalmers tekniska högskola (3)
Linnéuniversitetet (2)
Örebro universitet (1)
Sveriges Lantbruksuniversitet (1)
visa färre...
Språk
Engelska (199)
Odefinierat språk (2)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (63)
Naturvetenskap (57)
Teknik (1)
Samhällsvetenskap (1)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy