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  1. Artikel ; Online: Extra centrosomes delay DNA damage-driven tumorigenesis.

    Braun, Vincent Z / Karbon, Gerlinde / Schuler, Fabian / Schapfl, Marina A / Weiss, Johannes G / Petermann, Paul Y / Spierings, Diana C J / Tijhuis, Andrea E / Foijer, Floris / Labi, Verena / Villunger, Andreas

    Science advances

    2024  Band 10, Heft 13, Seite(n) eadk0564

    Abstract: Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can ... ...

    Abstract Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components,
    Mesh-Begriff(e) Humans ; Centrosome ; Apoptosis/genetics ; Neoplasms/metabolism ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; DNA Damage
    Sprache Englisch
    Erscheinungsdatum 2024-03-29
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adk0564
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases.

    Berner, Jakob / van de Wetering, Cheryl / Jimenez Heredia, Raul / Rashkova, Christina / Ferdinandusse, Sacha / Koster, Janet / Weiss, Johannes G / Frohne, Alexandra / Giuliani, Sarah / Waterham, Hans R / Castanon, Irinka / Brunner, Jürgen / Boztug, Kaan

    The Journal of allergy and clinical immunology

    2023  Band 152, Heft 4, Seite(n) 1025–1031.e2

    Abstract: Background: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic ... ...

    Abstract Background: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder MVK deficiency. So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported.
    Objectives: This study reports the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK.
    Methods: The investigators performed whole-exome sequencing and functional studies in cells from a patient who, on clinical and immunological evaluation, was suspected of an autoinflammatory disease.
    Results: The investigators identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities as well as distinct features compared to patients with MVK deficiency and responded well to therapeutic IL-1 inhibition.
    Conclusions: This study reported the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK, leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia and thus should be included in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.
    Sprache Englisch
    Erscheinungsdatum 2023-06-25
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2023.06.013
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis.

    Schuler, Fabian / Weiss, Johannes G / Lindner, Silke E / Lohmüller, Michael / Herzog, Sebastian / Spiegl, Simon F / Menke, Philipp / Geley, Stephan / Labi, Verena / Villunger, Andreas

    Nature communications

    2017  Band 8, Heft 1, Seite(n) 1697

    Abstract: Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 ...

    Abstract Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice. Moreover, total ablation of Chk1 in B-cells arrests their development at the pro-B cell stage, a block that, surprisingly, cannot be overcome by inhibition of mitochondrial apoptosis, as cell cycle arrest is initiated as an alternative fate to limit the spread of damaged DNA. Our findings define CHK1 as essential in B-cell development and potent target to treat blood cancer.
    Mesh-Begriff(e) Animals ; Apoptosis ; B-Lymphocytes/cytology ; B-Lymphocytes/enzymology ; Burkitt Lymphoma/drug therapy ; Burkitt Lymphoma/enzymology ; Burkitt Lymphoma/pathology ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Line, Tumor ; Cell Survival/genetics ; Cell Survival/physiology ; Checkpoint Kinase 1/antagonists & inhibitors ; Checkpoint Kinase 1/deficiency ; Checkpoint Kinase 1/genetics ; Checkpoint Kinase 1/physiology ; DNA Damage ; Genes, myc ; Haploinsufficiency ; Humans ; Lymphoma/enzymology ; Lymphoma/etiology ; Lymphoma/genetics ; Lymphopoiesis/genetics ; Lymphopoiesis/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Biological ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/enzymology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
    Chemische Substanzen CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Chek1 protein, mouse (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2017-11-22
    Erscheinungsland England
    Dokumenttyp 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/s41467-017-01850-4
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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