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  1. Article ; Online: Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer.

    Bei, Yi / Bramé, Luca / Kirchner, Marieluise / Fritsche-Guenther, Raphaela / Kunz, Severine / Bhattacharya, Animesh / Rusu, Mara-Camelia / Gürgen, Dennis / Dubios, Frank P B / Köppke, Julia K C / Proba, Jutta / Wittstruck, Nadine / Sidorova, Olga Alexandra / Chamorro González, Rocío / Dorado Garcia, Heathcliff / Brückner, Lotte / Xu, Robin / Giurgiu, Mădălina / Rodriguez-Fos, Elias /
    Yu, Qinghao / Spanjaard, Bastiaan / Koche, Richard P / Schmitt, Clemens A / Schulte, Johannes H / Eggert, Angelika / Haase, Kerstin / Kirwan, Jennifer / Hagemann, Anja I H / Mertins, Philipp / Dörr, Jan R / Henssen, Anton G

    Cancer discovery

    2024  Volume 14, Issue 3, Page(s) 492–507

    Abstract: DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR- ...

    Abstract DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities.
    Significance: We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384.
    MeSH term(s) Humans ; Oncogenes ; Neoplasms/genetics ; Medical Oncology ; Cell Death ; Mechanistic Target of Rapamycin Complex 1/genetics
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
    Language English
    Publishing date 2024-01-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-23-1189
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
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  2. Article ; Online: Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.

    Eckl, Katja-Martina / Krieg, Peter / Küster, Wolfgang / Traupe, Heiko / André, Françoise / Wittstruck, Nadine / Fürstenberger, Gerhard / Hennies, Hans Christian

    Human mutation

    2005  Volume 26, Issue 4, Page(s) 351–361

    Abstract: Autosomal-recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often ... ...

    Abstract Autosomal-recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3, respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy-11(R),12(R)-epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis.
    MeSH term(s) Arachidonate 12-Lipoxygenase/genetics ; Arachidonate 12-Lipoxygenase/physiology ; Catalysis ; Chromatography, High Pressure Liquid ; Epidermis/cytology ; Epidermis/enzymology ; Epidermis/metabolism ; Genes, Recessive ; Homozygote ; Humans ; Ichthyosiform Erythroderma, Congenital/genetics ; Ichthyosiform Erythroderma, Congenital/metabolism ; Lipoxygenase/genetics ; Lipoxygenase/metabolism ; Lipoxygenase/physiology ; Loss of Heterozygosity ; Microsatellite Repeats ; Phenotype ; Point Mutation ; Population Groups/genetics ; Protein Structure, Tertiary ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
    Chemical Substances Recombinant Proteins ; ALOXE3 protein, human (EC 1.13.11.12) ; Lipoxygenase (EC 1.13.11.12) ; Arachidonate 12-Lipoxygenase (EC 1.13.11.31) ; ALOX12 protein, human (EC 1.13.11.31.)
    Language English
    Publishing date 2005-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.20236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3586: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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