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  1. Article ; Online: Vimentin intermediate filaments provide structural stability to the mammalian Golgi complex.

    Vitali, Teresa / Sanchez-Alvarez, Rosa / Witkos, Tomasz M / Bantounas, Ioannis / Cutiongco, Marie F A / Dudek, Michal / Yan, Guanhua / Mironov, Alexander A / Swift, Joe / Lowe, Martin

    Journal of cell science

    2023  Volume 136, Issue 20

    Abstract: The Golgi complex comprises a connected ribbon of stacked cisternal membranes localized to the perinuclear region in most vertebrate cells. The position and morphology of this organelle depends upon interactions with microtubules and the actin ... ...

    Abstract The Golgi complex comprises a connected ribbon of stacked cisternal membranes localized to the perinuclear region in most vertebrate cells. The position and morphology of this organelle depends upon interactions with microtubules and the actin cytoskeleton. In contrast, we know relatively little about the relationship of the Golgi complex with intermediate filaments (IFs). In this study, we show that the Golgi is in close physical proximity to vimentin IFs in cultured mouse and human cells. We also show that the trans-Golgi network coiled-coil protein GORAB can physically associate with vimentin IFs. Loss of vimentin and/or GORAB had a modest effect upon Golgi structure at the steady state. The Golgi underwent more rapid disassembly upon chemical disruption with brefeldin A or nocodazole, and slower reassembly upon drug washout, in vimentin knockout cells. Moreover, loss of vimentin caused reduced Golgi ribbon integrity when cells were cultured on high-stiffness hydrogels, which was exacerbated by loss of GORAB. These results indicate that vimentin IFs contribute to the structural stability of the Golgi complex and suggest a role for GORAB in this process.
    MeSH term(s) Mice ; Humans ; Animals ; Intermediate Filaments/metabolism ; Vimentin/metabolism ; Cytoskeleton/metabolism ; Microtubules/metabolism ; Golgi Apparatus/metabolism ; Mammals/metabolism
    Chemical Substances Vimentin
    Language English
    Publishing date 2023-10-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.260577
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1200: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 14: Show issues

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  2. Article ; Online: Practical Aspects of microRNA Target Prediction.

    Witkos, T M / Koscianska, E / Krzyzosiak, W J

    Current molecular medicine

    2011  Volume 11, Issue 2, Page(s) 93–109

    Abstract: microRNAs (miRNAs) are endogenous non-coding RNAs that control gene expression at the posttranscriptional level. These small regulatory molecules play a key role in the majority of biological processes and their expression is also tightly regulated. Both ...

    Abstract microRNAs (miRNAs) are endogenous non-coding RNAs that control gene expression at the posttranscriptional level. These small regulatory molecules play a key role in the majority of biological processes and their expression is also tightly regulated. Both the deregulation of genes controlled by miRNAs and the altered miRNA expression have been linked to many disorders, including cancer, cardiovascular, metabolic and neurodegenerative diseases. Therefore, it is of particular interest to reliably predict potential miRNA targets which might be involved in these diseases. However, interactions between miRNAs and their targets are complex and very often there are numerous putative miRNA recognition sites in mRNAs. Many miRNA targets have been computationally predicted but only a limited number of these were experimentally validated. Although a variety of miRNA target prediction algorithms are available, results of their application are often inconsistent. Hence, finding a functional miRNA target is still a challenging task. In this review, currently available and frequently used computational tools for miRNA target prediction, i.e., PicTar, TargetScan, DIANA-microT, miRanda, rna22 and PITA are outlined and various practical aspects of miRNA target analysis are extensively discussed. Moreover, the performance of three algorithms (PicTar, TargetScan and DIANA-microT) is both demonstrated and evaluated by performing an in-depth analysis of miRNA interactions with mRNAs derived from genes triggering hereditary neurological disorders known as trinucleotide repeat expansion diseases (TREDs), such as Huntington's disease (HD), a number of spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1).
    MeSH term(s) Algorithms ; Animals ; Computational Biology/methods ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; MicroRNAs/therapeutic use ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Trinucleotide Repeat Expansion/genetics
    Chemical Substances MicroRNAs ; RNA, Messenger
    Language English
    Publishing date 2011-03-21
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2064873-X
    ISSN 1875-5666 ; 1566-5240
    ISSN (online) 1875-5666
    ISSN 1566-5240
    DOI 10.2174/156652411794859250
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5580: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation.

    Witkos, Tomasz M / Chan, Wing Lee / Joensuu, Merja / Rhiel, Manuel / Pallister, Ed / Thomas-Oates, Jane / Mould, A Paul / Mironov, Alex A / Biot, Christophe / Guerardel, Yann / Morelle, Willy / Ungar, Daniel / Wieland, Felix T / Jokitalo, Eija / Tassabehji, May / Kornak, Uwe / Lowe, Martin

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 127

    Abstract: COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking ... ...

    Abstract COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.
    MeSH term(s) Adaptor Proteins, Vesicular Transport ; Bone Diseases/congenital ; Bone Diseases/genetics ; Bone Diseases/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cells, Cultured ; Coat Protein Complex I/genetics ; Coat Protein Complex I/metabolism ; DNA-Binding Proteins ; Dwarfism/genetics ; Dwarfism/metabolism ; Enzymes/metabolism ; Glycosylation ; Golgi Apparatus/metabolism ; Golgi Matrix Proteins ; HEK293 Cells ; HeLa Cells ; Humans ; Mutation ; Protein Binding ; Protein Transport ; RNA Interference ; Skin Diseases, Genetic/genetics ; Skin Diseases, Genetic/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Adaptor Proteins, Vesicular Transport ; Carrier Proteins ; Coat Protein Complex I ; DNA-Binding Proteins ; Enzymes ; GORAB protein, human ; Golgi Matrix Proteins ; SCYL1 protein, human ; Transcription Factors
    Language English
    Publishing date 2019-01-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-018-08044-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

    Tomasz M. Witkos / Wing Lee Chan / Merja Joensuu / Manuel Rhiel / Ed Pallister / Jane Thomas-Oates / A. Paul Mould / Alex A. Mironov / Christophe Biot / Yann Guerardel / Willy Morelle / Daniel Ungar / Felix T. Wieland / Eija Jokitalo / May Tassabehji / Uwe Kornak / Martin Lowe

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 18

    Abstract: COPI is recruited to the membrane by binding to Arf GTPases. Here the authors find that GORAB, a trans-Golgi protein, promotes COPI recruitment by forming membrane domains that also contain the COPI-interacting protein Scyl1, which is required for ... ...

    Abstract COPI is recruited to the membrane by binding to Arf GTPases. Here the authors find that GORAB, a trans-Golgi protein, promotes COPI recruitment by forming membrane domains that also contain the COPI-interacting protein Scyl1, which is required for efficient glycosylation of cargo proteins.
    Keywords Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  5. Article ; Online: GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

    Tomasz M. Witkos / Wing Lee Chan / Merja Joensuu / Manuel Rhiel / Ed Pallister / Jane Thomas-Oates / A. Paul Mould / Alex A. Mironov / Christophe Biot / Yann Guerardel / Willy Morelle / Daniel Ungar / Felix T. Wieland / Eija Jokitalo / May Tassabehji / Uwe Kornak / Martin Lowe

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 18

    Abstract: COPI is recruited to the membrane by binding to Arf GTPases. Here the authors find that GORAB, a trans-Golgi protein, promotes COPI recruitment by forming membrane domains that also contain the COPI-interacting protein Scyl1, which is required for ... ...

    Abstract COPI is recruited to the membrane by binding to Arf GTPases. Here the authors find that GORAB, a trans-Golgi protein, promotes COPI recruitment by forming membrane domains that also contain the COPI-interacting protein Scyl1, which is required for efficient glycosylation of cargo proteins.
    Keywords Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.

    Wehrle, Anika / Witkos, Tomasz M / Unger, Sheila / Schneider, Judith / Follit, John A / Hermann, Johannes / Welting, Tim / Fano, Virginia / Hietala, Marja / Vatanavicharn, Nithiwat / Schoner, Katharina / Spranger, Jürgen / Schmidts, Miriam / Zabel, Bernhard / Pazour, Gregory J / Bloch-Zupan, Agnes / Nishimura, Gen / Superti-Furga, Andrea / Lowe, Martin /
    Lausch, Ekkehart

    JCI insight

    2019  Volume 4, Issue 3

    Abstract: Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the ... ...

    Abstract Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.
    Language English
    Publishing date 2019-02-07
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.124701
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica.

    Chan, Wing Lee / Steiner, Magdalena / Witkos, Tomasz / Egerer, Johannes / Busse, Björn / Mizumoto, Shuji / Pestka, Jan M / Zhang, Haikuo / Hausser, Ingrid / Khayal, Layal Abo / Ott, Claus-Eric / Kolanczyk, Mateusz / Willie, Bettina / Schinke, Thorsten / Paganini, Chiara / Rossi, Antonio / Sugahara, Kazuyuki / Amling, Michael / Knaus, Petra /
    Chan, Danny / Lowe, Martin / Mundlos, Stefan / Kornak, Uwe

    PLoS genetics

    2018  Volume 14, Issue 3, Page(s) e1007242

    Abstract: Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full ... ...

    Abstract Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.
    MeSH term(s) Animals ; Bone Diseases/congenital ; Bone Diseases/metabolism ; Bone Diseases/pathology ; Cell Differentiation ; Decorin/metabolism ; Dermatan Sulfate/metabolism ; Disease Models, Animal ; Dwarfism/metabolism ; Dwarfism/pathology ; Female ; Fractures, Bone/genetics ; Glycosylation ; Golgi Matrix Proteins ; Mesenchymal Stem Cells/pathology ; Mesenchymal Stem Cells/physiology ; Mice, Inbred C57BL ; Mice, Transgenic ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Proteoglycans/metabolism ; Signal Transduction ; Skin Diseases, Genetic/metabolism ; Skin Diseases, Genetic/pathology ; Transforming Growth Factor beta/metabolism ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
    Chemical Substances Dcn protein, mouse ; Decorin ; Golgi Matrix Proteins ; Gorab protein, mouse ; Proteoglycans ; Transforming Growth Factor beta ; Vesicular Transport Proteins ; Dermatan Sulfate (24967-94-0)
    Language English
    Publishing date 2018-03-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1007242
    Database MEDical Literature Analysis and Retrieval System OnLINE

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