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 mi...
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| Veröffentlicht in: | Oncogenesis (New York, NY) NY), 2020-06, Vol.9 (6), p.59, Article 59 |
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| creator | Weidner, Philip Söhn, Michaela Schroeder, Torsten Helm, Laura Hauber, Veronika Gutting, Tobias Betge, Johannes Röcken, Christoph Rohrbacher, Florian N. Pattabiraman, Vijaya R. Bode, Jeffrey W. Seger, Rony Saar, Daniel Nunes-Alves, Ariane Wade, Rebecca C. Ebert, Matthias P. A. Burgermeister, Elke |
| description | 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. |
| doi_str_mv | 10.1038/s41389-020-0238-8 |
| format | Article |
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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.</description><identifier>ISSN: 2157-9024</identifier><identifier>EISSN: 2157-9024</identifier><identifier>DOI: 10.1038/s41389-020-0238-8</identifier><identifier>PMID: 32522977</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 13/95 ; 14/35 ; 38/77 ; 42 ; 45 ; 631/154/555 ; 631/337/458/1733 ; 631/67/1504/1885 ; 631/80/86/2364 ; 64 ; 64/60 ; 82 ; 82/58 ; 82/75 ; Apoptosis ; Binding sites ; Carcinogenesis ; Cell Biology ; Cell proliferation ; Diabetes mellitus (non-insulin dependent) ; Extracellular signal-regulated kinase ; Human Genetics ; Internal Medicine ; Kinases ; Life Sciences & Biomedicine ; Medicine ; Medicine & Public Health ; Mimicry ; Oncology ; Peptides ; Phosphorylation ; Post-translation ; Sarcoma ; Science & Technology ; Steroid receptor coactivator 1 ; Synthetic peptides ; Tumor cell lines</subject><ispartof>Oncogenesis (New York, NY), 2020-06, Vol.9 (6), p.59, Article 59</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>7</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000540171600001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c498t-9ef239d3ba9599412f4c66e78ab4f254014d7f280b1c920614ed018040e2edac3</citedby><cites>FETCH-LOGICAL-c498t-9ef239d3ba9599412f4c66e78ab4f254014d7f280b1c920614ed018040e2edac3</cites><orcidid>0000-0002-5488-4732 ; 0000-0001-5197-4591 ; 0000-0001-5951-8670 ; 0000-0001-9549-1866</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286916/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286916/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2115,27929,27930,28253,41125,42194,51581,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32522977$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weidner, Philip</creatorcontrib><creatorcontrib>Söhn, Michaela</creatorcontrib><creatorcontrib>Schroeder, Torsten</creatorcontrib><creatorcontrib>Helm, Laura</creatorcontrib><creatorcontrib>Hauber, Veronika</creatorcontrib><creatorcontrib>Gutting, Tobias</creatorcontrib><creatorcontrib>Betge, Johannes</creatorcontrib><creatorcontrib>Röcken, Christoph</creatorcontrib><creatorcontrib>Rohrbacher, Florian N.</creatorcontrib><creatorcontrib>Pattabiraman, Vijaya R.</creatorcontrib><creatorcontrib>Bode, Jeffrey W.</creatorcontrib><creatorcontrib>Seger, Rony</creatorcontrib><creatorcontrib>Saar, Daniel</creatorcontrib><creatorcontrib>Nunes-Alves, Ariane</creatorcontrib><creatorcontrib>Wade, Rebecca C.</creatorcontrib><creatorcontrib>Ebert, Matthias P. A.</creatorcontrib><creatorcontrib>Burgermeister, Elke</creatorcontrib><title>Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma</title><title>Oncogenesis (New York, NY)</title><addtitle>Oncogenesis</addtitle><addtitle>ONCOGENESIS</addtitle><addtitle>Oncogenesis</addtitle><description>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.</description><subject>13/109</subject><subject>13/95</subject><subject>14/35</subject><subject>38/77</subject><subject>42</subject><subject>45</subject><subject>631/154/555</subject><subject>631/337/458/1733</subject><subject>631/67/1504/1885</subject><subject>631/80/86/2364</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/58</subject><subject>82/75</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Carcinogenesis</subject><subject>Cell Biology</subject><subject>Cell proliferation</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Extracellular signal-regulated kinase</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Life Sciences & Biomedicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mimicry</subject><subject>Oncology</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Post-translation</subject><subject>Sarcoma</subject><subject>Science & Technology</subject><subject>Steroid receptor coactivator 1</subject><subject>Synthetic peptides</subject><subject>Tumor cell lines</subject><issn>2157-9024</issn><issn>2157-9024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>AOWDO</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkU1rFjEUhQdRbKn9AW5kwKWMJpl8bgR58Qta3NhFVyGTufOaMpOMSaa1_94M077WhcVASLh5zuHenKp6idFbjFr5LlHcStUggspuZSOfVMcEM9EoROjTB_ej6jSlK1QW45gz9rw6agkjRAlxXF2e34a8dMtoovNNhNFk6Os5hgzO16I2NrvrUkv1DDH8cilMsD6PboBocojNPdHXESzMa2lvpsm8qJ4NZkxweneeVBefPn7ffWnOvn3-uvtw1liqZG4UDKRVfdsZxZSimAzUcg5Cmo4OhFGEaS8GIlGHrSKIYwo9whJRBAR6Y9uT6v3mOy_dBL0Fn6MZ9RzdZOKtDsbpv1-8-6H34VoLIrnCvBi8vjOI4ecCKeursERfetaESkEYYxw9TmGCqWrR6oU3ysaQUoTh0AdGeo1Nb7HpEpteY9OyaF49HOCguA-pAHIDbqALQ7IOvIUDtuZafklgvkaMdy6b7ILfhcXnIn3z_9JCk41OhfB7iH9m_Hf7vwFlNsRw</recordid><startdate>20200610</startdate><enddate>20200610</enddate><creator>Weidner, Philip</creator><creator>Söhn, Michaela</creator><creator>Schroeder, Torsten</creator><creator>Helm, Laura</creator><creator>Hauber, Veronika</creator><creator>Gutting, Tobias</creator><creator>Betge, Johannes</creator><creator>Röcken, Christoph</creator><creator>Rohrbacher, Florian N.</creator><creator>Pattabiraman, Vijaya R.</creator><creator>Bode, Jeffrey W.</creator><creator>Seger, Rony</creator><creator>Saar, Daniel</creator><creator>Nunes-Alves, Ariane</creator><creator>Wade, Rebecca C.</creator><creator>Ebert, Matthias P. 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A.</au><au>Burgermeister, Elke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma</atitle><jtitle>Oncogenesis (New York, NY)</jtitle><stitle>Oncogenesis</stitle><stitle>ONCOGENESIS</stitle><addtitle>Oncogenesis</addtitle><date>2020-06-10</date><risdate>2020</risdate><volume>9</volume><issue>6</issue><spage>59</spage><pages>59-</pages><artnum>59</artnum><issn>2157-9024</issn><eissn>2157-9024</eissn><abstract>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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32522977</pmid><doi>10.1038/s41389-020-0238-8</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-5488-4732</orcidid><orcidid>https://orcid.org/0000-0001-5197-4591</orcidid><orcidid>https://orcid.org/0000-0001-5951-8670</orcidid><orcidid>https://orcid.org/0000-0001-9549-1866</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/109 13/95 14/35 38/77 42 45 631/154/555 631/337/458/1733 631/67/1504/1885 631/80/86/2364 64 64/60 82 82/58 82/75 Apoptosis Binding sites Carcinogenesis Cell Biology Cell proliferation Diabetes mellitus (non-insulin dependent) Extracellular signal-regulated kinase Human Genetics Internal Medicine Kinases Life Sciences & Biomedicine Medicine Medicine & Public Health Mimicry Oncology Peptides Phosphorylation Post-translation Sarcoma Science & Technology Steroid receptor coactivator 1 Synthetic peptides Tumor cell lines |
| title | Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-15T16%3A50%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Myotubularin-related%20protein%207%20activates%20peroxisome%20proliferator-activated%20receptor-gamma&rft.jtitle=Oncogenesis%20(New%20York,%20NY)&rft.au=Weidner,%20Philip&rft.date=2020-06-10&rft.volume=9&rft.issue=6&rft.spage=59&rft.pages=59-&rft.artnum=59&rft.issn=2157-9024&rft.eissn=2157-9024&rft_id=info:doi/10.1038/s41389-020-0238-8&rft_dat=%3Cproquest_webof%3E2412149306%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2412149306&rft_id=info:pmid/32522977&rfr_iscdi=true |