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  1. Article ; Online: Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens

    Inês A. M. Barbosa / Rajaraman Gopalakrishnan / Samuele Mercan / Thanos P. Mourikis / Typhaine Martin / Simon Wengert / Caibin Sheng / Fei Ji / Rui Lopes / Judith Knehr / Marc Altorfer / Alicia Lindeman / Carsten Russ / Ulrike Naumann / Javad Golji / Kathleen Sprouffske / Louise Barys / Luca Tordella / Dirk Schübeler /
    Tobias Schmelzle / Giorgio G. Galli

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 15

    Abstract: Abstract YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo ... ...

    Abstract Abstract YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.
    Keywords Science ; Q
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance

    Martin Schröder / Martin Renatus / Xiaoyou Liang / Fabian Meili / Thomas Zoller / Sandrine Ferrand / Francois Gauter / Xiaoyan Li / Frederic Sigoillot / Scott Gleim / Therese-Marie Stachyra / Jason R. Thomas / Damien Begue / Maryam Khoshouei / Peggy Lefeuvre / Rita Andraos-Rey / BoYee Chung / Renate Ma / Benika Pinch /
    Andreas Hofmann / Markus Schirle / Niko Schmiedeberg / Patricia Imbach / Delphine Gorses / Keith Calkins / Beatrice Bauer-Probst / Magdalena Maschlej / Matt Niederst / Rob Maher / Martin Henault / John Alford / Erik Ahrne / Luca Tordella / Greg Hollingworth / Nicolas H. Thomä / Anna Vulpetti / Thomas Radimerski / Philipp Holzer / Seth Carbonneau / Claudio R. Thoma

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 19

    Abstract: Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug ... ...

    Abstract Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
    Keywords Science ; Q
    Subject code 571
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  3. Article ; Online: PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma

    Melusine Bleu / Swann Gaulis / Rui Lopes / Kathleen Sprouffske / Verena Apfel / Sjoerd Holwerda / Marco Pregnolato / Umut Yildiz / Valentina Cordoʹ / Antonella F. M. Dost / Judith Knehr / Walter Carbone / Felix Lohmann / Charles Y. Lin / James E. Bradner / Audrey Kauffmann / Luca Tordella / Guglielmo Roma / Giorgio G. Galli

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

    2019  Volume 10

    Abstract: Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in ... ...

    Abstract Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
    Keywords Science ; Q
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  4. Article ; Online: PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma

    Melusine Bleu / Swann Gaulis / Rui Lopes / Kathleen Sprouffske / Verena Apfel / Sjoerd Holwerda / Marco Pregnolato / Umut Yildiz / Valentina Cordoʹ / Antonella F. M. Dost / Judith Knehr / Walter Carbone / Felix Lohmann / Charles Y. Lin / James E. Bradner / Audrey Kauffmann / Luca Tordella / Guglielmo Roma / Giorgio G. Galli

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

    2019  Volume 10

    Abstract: Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in ... ...

    Abstract Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
    Keywords Science ; Q
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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