PMID- 32522977 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220418 IS - 2157-9024 (Print) IS - 2157-9024 (Electronic) IS - 2157-9024 (Linking) VI - 9 IP - 6 DP - 2020 Jun 10 TI - Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma. PG - 59 LID - 10.1038/s41389-020-0238-8 [doi] LID - 59 AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARgamma. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARgamma. 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 PPARgamma and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARgamma. MTMR7-CC peptides mimicked PPARgamma-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 PPARgamma. Thus, MTMR7 is a positive regulator of PPARgamma, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARgamma. FAU - Weidner, Philip AU - Weidner P AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Sohn, Michaela AU - Sohn M AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Schroeder, Torsten AU - Schroeder T AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Helm, Laura AU - Helm L AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Hauber, Veronika AU - Hauber V AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Gutting, Tobias AU - Gutting T AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Betge, Johannes AU - Betge J AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Rocken, Christoph AU - Rocken C AD - Department of Pathology, Christian-Albrechts University, Kiel, Germany. FAU - Rohrbacher, Florian N AU - Rohrbacher FN AD - Department of Organic Chemistry, ETH Zurich, Zurich, Switzerland. FAU - Pattabiraman, Vijaya R AU - Pattabiraman VR AD - Department of Organic Chemistry, ETH Zurich, Zurich, Switzerland. FAU - Bode, Jeffrey W AU - Bode JW AD - Department of Organic Chemistry, ETH Zurich, Zurich, Switzerland. FAU - Seger, Rony AU - Seger R AD - Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. FAU - Saar, Daniel AU - Saar D AUID- ORCID: 0000-0001-5197-4591 AD - Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany. FAU - Nunes-Alves, Ariane AU - Nunes-Alves A AUID- ORCID: 0000-0002-5488-4732 AD - Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany. AD - Zentrum fur Molekulare Biologie der Universitat Heidelberg (ZMBH), Heidelberg, Germany. FAU - Wade, Rebecca C AU - Wade RC AUID- ORCID: 0000-0001-5951-8670 AD - Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany. AD - Zentrum fur Molekulare Biologie der Universitat Heidelberg (ZMBH), Heidelberg, Germany. AD - Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany. FAU - Ebert, Matthias P A AU - Ebert MPA AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Burgermeister, Elke AU - Burgermeister E AD - Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. elke.burgermeister@medma.uni-heidelberg.de. LA - eng GR - Ca-158/Deutsches Krebsforschungszentrum (German Cancer Research Center)/ GR - Ca-158/Deutsches Krebsforschungszentrum (German Cancer Research Center)/ GR - Ca-158/Deutsches Krebsforschungszentrum (German Cancer Research Center)/ GR - 108287; 111086/Deutsche Krebshilfe (German Cancer Aid)/ PT - Journal Article DEP - 20200610 PL - United States TA - Oncogenesis JT - Oncogenesis JID - 101580004 PMC - PMC7286916 COIS- The authors declare that they have no conflict of interest. Parts of the cell line data have been deposited under 10.11588/heidok.00025716; 10.11588/heidok.00023843. EDAT- 2020/06/12 06:00 MHDA- 2020/06/12 06:01 PMCR- 2020/06/10 CRDT- 2020/06/12 06:00 PHST- 2019/12/03 00:00 [received] PHST- 2020/04/21 00:00 [accepted] PHST- 2020/04/15 00:00 [revised] PHST- 2020/06/12 06:00 [entrez] PHST- 2020/06/12 06:00 [pubmed] PHST- 2020/06/12 06:01 [medline] PHST- 2020/06/10 00:00 [pmc-release] AID - 10.1038/s41389-020-0238-8 [pii] AID - 238 [pii] AID - 10.1038/s41389-020-0238-8 [doi] PST - epublish SO - Oncogenesis. 2020 Jun 10;9(6):59. doi: 10.1038/s41389-020-0238-8.