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  1. Article ; Online: Inducible Genome Editing with Conditional CRISPR/Cas9 Mice.

    Katigbak, Alexandra / Robert, Francis / Paquet, Marilène / Pelletier, Jerry

    G3 (Bethesda, Md.)

    2018  Volume 8, Issue 5, Page(s) 1627–1635

    Abstract: Genetically engineered mouse models (GEMMs) are powerful tools by which to probe gene ... ...

    Abstract Genetically engineered mouse models (GEMMs) are powerful tools by which to probe gene function
    MeSH term(s) Adoptive Transfer ; Animals ; CRISPR-Cas Systems/genetics ; Doxycycline/pharmacology ; Gene Editing ; Gene Expression/drug effects ; Genetic Engineering ; Genome ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Mice ; Mice, Transgenic ; Models, Animal ; Mouse Embryonic Stem Cells/drug effects ; Mouse Embryonic Stem Cells/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; RNA, Guide, CRISPR-Cas Systems/genetics
    Chemical Substances Proto-Oncogene Proteins c-myc ; RNA, Guide, CRISPR-Cas Systems ; Doxycycline (N12000U13O)
    Language English
    Publishing date 2018-05-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1534/g3.117.300327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A CRISPR/Cas9 Functional Screen Identifies Rare Tumor Suppressors.

    Katigbak, Alexandra / Cencic, Regina / Robert, Francis / Sénécha, Patrick / Scuoppo, Claudio / Pelletier, Jerry

    Scientific reports

    2016  Volume 6, Page(s) 38968

    Abstract: An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly ... ...

    Abstract An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly complicated in the case of rare mutations where frequency of occurrence alone or prediction of functional consequences are insufficient to distinguish driver from passenger or bystander mutations. We combine genome editing technology with a powerful mouse cancer model to uncover previously unsuspected rare oncogenic mutations in Burkitt's lymphoma. We identify two candidate tumor suppressors whose loss cooperate with MYC over-expression to accelerate lymphomagenesis. Our results highlight the utility of in vivo CRISPR/Cas9 screens combined with powerful mouse models to identify and validate rare oncogenic modifier events from tumor mutational data.
    Language English
    Publishing date 2016-12-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep38968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A.

    Chu, Jennifer / Galicia-Vázquez, Gabriela / Cencic, Regina / Mills, John R / Katigbak, Alexandra / Porco, John A / Pelletier, Jerry

    Cell reports

    2016  Volume 15, Issue 11, Page(s) 2340–2347

    Abstract: Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic ... ...

    Abstract Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
    MeSH term(s) Alleles ; Animals ; Base Sequence ; Benzofurans/pharmacology ; CRISPR-Cas Systems/genetics ; Drug Delivery Systems ; Drug Resistance/drug effects ; Eukaryotic Initiation Factor-4A/antagonists & inhibitors ; Eukaryotic Initiation Factor-4A/metabolism ; Female ; Genetic Loci ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mutation/genetics ; NIH 3T3 Cells ; Reproducibility of Results ; Triterpenes/pharmacology
    Chemical Substances Benzofurans ; Triterpenes ; silvestrol ; Eukaryotic Initiation Factor-4A (EC 2.7.7.-)
    Language English
    Publishing date 2016--14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2016.05.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A

    Chu, Jennifer / Galicia-Vázquez, Gabriela / Cencic, Regina / Mills, John R. / Katigbak, Alexandra / Porco, John A. / Pelletier, Jerry

    Cell Reports. 2016,

    2016  

    Abstract: Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic ... ...

    Abstract Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
    Keywords rocaglates ; eIF4A ; translational control ; chemical biology ; CRISPR/Cas9
    Language English
    Publishing place Elsevier Inc.
    Document type Article ; Online
    Note Pre-press version
    ZDB-ID 2649101-1
    ISSN 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2016.05.005
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Adapting CRISPR/Cas9 for functional genomics screens.

    Malina, Abba / Katigbak, Alexandra / Cencic, Regina / Maïga, Rayelle Itoua / Robert, Francis / Miura, Hisashi / Pelletier, Jerry

    Methods in enzymology

    2014  Volume 546, Page(s) 193–213

    Abstract: The use of CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) for targeted genome editing has been widely adopted and is considered a "game changing" technology. The ease and rapidity by which this approach ... ...

    Abstract The use of CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) for targeted genome editing has been widely adopted and is considered a "game changing" technology. The ease and rapidity by which this approach can be used to modify endogenous loci in a wide spectrum of cell types and organisms makes it a powerful tool for customizable genetic modifications as well as for large-scale functional genomics. The development of retrovirus-based expression platforms to simultaneously deliver the Cas9 nuclease and single guide (sg) RNAs provides unique opportunities by which to ensure stable and reproducible expression of the editing tools and a broad cell targeting spectrum, while remaining compatible with in vivo genetic screens. Here, we describe methods and highlight considerations for designing and generating sgRNA libraries in all-in-one retroviral vectors for such applications.
    MeSH term(s) Animals ; Base Sequence ; CRISPR-Associated Proteins/genetics ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genetic Testing/methods ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Genomics/methods ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction/methods ; RNA, Guide, CRISPR-Cas Systems/administration & dosage ; RNA, Guide, CRISPR-Cas Systems/genetics ; Retroviridae/genetics ; Transduction, Genetic/methods
    Chemical Substances CRISPR-Associated Proteins ; RNA, Guide, CRISPR-Cas Systems
    Language English
    Publishing date 2014-12-10
    Publishing country United States
    Document type Journal Article
    ISSN 1557-7988
    ISSN (online) 1557-7988
    DOI 10.1016/B978-0-12-801185-0.00010-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A

    Jennifer Chu / Gabriela Galicia-Vázquez / Regina Cencic / John R. Mills / Alexandra Katigbak / John A. Porco Jr. / Jerry Pelletier

    Cell Reports, Vol 15, Iss 11, Pp 2340-

    2016  Volume 2347

    Abstract: Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic ... ...

    Abstract Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
    Keywords rocaglates ; eIF4A ; translational control ; chemical biology ; CRISPR/Cas9 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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