Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma
Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mit...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
10 June 2020
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| In: |
Oncogenesis
Year: 2020, Jahrgang: 9, Heft: 6, Pages: 1-14 |
| ISSN: | 2157-9024 |
| DOI: | 10.1038/s41389-020-0238-8 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41389-020-0238-8 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41389-020-0238-8 
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| Verfasserangaben: | Philip Weidner, Michaela Söhn, Torsten Schroeder, Laura Helm, Veronika Hauber, Tobias Gutting, Johannes Betge, Christoph Röcken, Florian N. Rohrbacher, Vijaya R. Pattabiraman, Jeffrey W. Bode, Rony Seger, Daniel Saar, Ariane Nunes-Alves, Rebecca C. Wade, Matthias P.A. Ebert and Elke Burgermeister |
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| 520 | |a Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mitigate these beneficial effects by promoting a negative feedback-loop comprising extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated kinase kinase 1/2 (MEK1/2)-dependent inactivation of PPARγ. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARγ. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARγ. Synthetic peptides were designed resembling the regulatory coiled-coil (CC) domain of MTMR7, and their activities studied in human cancer cell lines and C57BL6/J mice. MTMR7 formed a complex with PPARγ and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. MTMR7-CC peptides mimicked PPARγ-activation in vitro and in vivo due to LXXLL motifs in the CC domain. Molecular dynamics simulations and docking predicted that peptides interact with the steroid receptor coactivator 1 (SRC1)-binding site of PPARγ. Thus, MTMR7 is a positive regulator of PPARγ, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARγ. | ||
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