Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR

New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2011-07, Vol.6 (7), p.e22862
Main Authors: Yore, Mark M, Kettenbach, Arminja N, Sporn, Michael B, Gerber, Scott A, Liby, Karen T
Format: Article
Language:English
Subjects:
Acids
Analysis
Antifungal agents
Apoptosis
Binding
Binding proteins
Biology
Biotinylation
Cell culture
Chemistry
Chromatography, Liquid
Chronic illnesses
Colorectal cancer
Computational Biology
Cotton, Norris
Diabetes
Drugs
Estrogen receptors
Estrogens
Growth factors
HEK293 Cells
Homology
Humans
Imidazoles - chemistry
Imidazoles - metabolism
Insulin
Janus kinase
Kidney diseases
Mass Spectrometry
Medical schools
Medical treatment
Medicine
Nitriles
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - chemistry
Oleanolic Acid - metabolism
Oxidative stress
Pharmacology
Phosphatases
Polyclonal antibodies
Prevention
Prostate cancer
Protein Binding
Protein purification
Proteins
Proteomics
Proteomics - methods
PTEN protein
Rapamycin
Reproducibility of Results
Retinoic acid
Retinoic acid receptors
Rodents
Signal transduction
Signaling
Tensin
TOR protein
TOR Serine-Threonine Kinases - metabolism
Transcription factors
Transducers
Triterpenoids
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653
cites cdi_FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653
container_end_page
container_issue 7
container_start_page e22862
container_title PloS one
container_volume 6
creator Yore, Mark M
Kettenbach, Arminja N
Sporn, Michael B
Gerber, Scott A
Liby, Karen T
description New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.
doi_str_mv 10.1371/journal.pone.0022862
format article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1305756775</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A476883853</galeid><doaj_id>oai_doaj_org_article_a7c38a4aacf542828461f6e36dcceef4</doaj_id><sourcerecordid>A476883853</sourcerecordid><originalsourceid>FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653</originalsourceid><addsrcrecordid>eNqNkuFr1DAYxosobjv9D0QLwsQPdyZNmqRfhDGcHgxO5vRrSNO31xy95pak6v33pl43rrIPUkhD3t_7JHnyJMkrjBaYcPxhY3vXqXaxsx0sEMoywbInySkuSDZnGSJPj-YnyZn3G4RyIhh7npxkWGBBET5Nrr46G8BujU5VVNt741Pf2F9x3HehgRALtoVY6yANzgRwO-isqdLSdJVPg023t6ubF8mzWrUeXo7_WfL96tPt5Zf59erz8vLieq55zsNclyWtSsU511gUjFBdVDnOcqIwKwhmXAgNZY0olEoRRShkvBAlVFRwwllOZsmbg-6utV6OFniJCcp5zjgfiOWBqKzayJ0zW-X20ioj_y5Yt5bKxVu1IBXXRCiqlK5zmolMUIZrBoRVWgPUNGp9HHfryy1UGrrgVDsRnVY608i1_SkJprSgIgq8GwWcvevBB7k1XkPbRjdt76UQmHI0ODFL3v5DPn65kVqreH7T1TZuqwdNeUE5E4KInERq8QgVvwriO8e41CauTxreTxoiE-B3WKvee7n8dvP_7OrHlD0_YhtQbWi8bftgbOenID2A2lnvHdQPHmMkh7TfuyGHtMsx7bHt9fH7PDTdx5v8AaIL-jo</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1305756775</pqid></control><display><type>article</type><title>Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR</title><source>Publicly Available Content Database</source><source>PubMed Central</source><creator>Yore, Mark M ; Kettenbach, Arminja N ; Sporn, Michael B ; Gerber, Scott A ; Liby, Karen T</creator><contributor>Vij, Neeraj</contributor><creatorcontrib>Yore, Mark M ; Kettenbach, Arminja N ; Sporn, Michael B ; Gerber, Scott A ; Liby, Karen T ; Vij, Neeraj</creatorcontrib><description>New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0022862</identifier><identifier>PMID: 21818401</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Analysis ; Antifungal agents ; Apoptosis ; Binding ; Binding proteins ; Biology ; Biotinylation ; Cell culture ; Chemistry ; Chromatography, Liquid ; Chronic illnesses ; Colorectal cancer ; Computational Biology ; Cotton, Norris ; Diabetes ; Drugs ; Estrogen receptors ; Estrogens ; Growth factors ; HEK293 Cells ; Homology ; Humans ; Imidazoles - chemistry ; Imidazoles - metabolism ; Insulin ; Janus kinase ; Kidney diseases ; Mass Spectrometry ; Medical schools ; Medical treatment ; Medicine ; Nitriles ; Oleanolic Acid - analogs &amp; derivatives ; Oleanolic Acid - chemistry ; Oleanolic Acid - metabolism ; Oxidative stress ; Pharmacology ; Phosphatases ; Polyclonal antibodies ; Prevention ; Prostate cancer ; Protein Binding ; Protein purification ; Proteins ; Proteomics ; Proteomics - methods ; PTEN protein ; Rapamycin ; Reproducibility of Results ; Retinoic acid ; Retinoic acid receptors ; Rodents ; Signal transduction ; Signaling ; Tensin ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Transcription factors ; Transducers ; Triterpenoids</subject><ispartof>PloS one, 2011-07, Vol.6 (7), p.e22862</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Yore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Yore et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653</citedby><cites>FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1305756775/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1305756775?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,25734,27905,27906,36993,36994,44571,53772,53774,74875</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21818401$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Vij, Neeraj</contributor><creatorcontrib>Yore, Mark M</creatorcontrib><creatorcontrib>Kettenbach, Arminja N</creatorcontrib><creatorcontrib>Sporn, Michael B</creatorcontrib><creatorcontrib>Gerber, Scott A</creatorcontrib><creatorcontrib>Liby, Karen T</creatorcontrib><title>Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.</description><subject>Acids</subject><subject>Analysis</subject><subject>Antifungal agents</subject><subject>Apoptosis</subject><subject>Binding</subject><subject>Binding proteins</subject><subject>Biology</subject><subject>Biotinylation</subject><subject>Cell culture</subject><subject>Chemistry</subject><subject>Chromatography, Liquid</subject><subject>Chronic illnesses</subject><subject>Colorectal cancer</subject><subject>Computational Biology</subject><subject>Cotton, Norris</subject><subject>Diabetes</subject><subject>Drugs</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Growth factors</subject><subject>HEK293 Cells</subject><subject>Homology</subject><subject>Humans</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - metabolism</subject><subject>Insulin</subject><subject>Janus kinase</subject><subject>Kidney diseases</subject><subject>Mass Spectrometry</subject><subject>Medical schools</subject><subject>Medical treatment</subject><subject>Medicine</subject><subject>Nitriles</subject><subject>Oleanolic Acid - analogs &amp; derivatives</subject><subject>Oleanolic Acid - chemistry</subject><subject>Oleanolic Acid - metabolism</subject><subject>Oxidative stress</subject><subject>Pharmacology</subject><subject>Phosphatases</subject><subject>Polyclonal antibodies</subject><subject>Prevention</subject><subject>Prostate cancer</subject><subject>Protein Binding</subject><subject>Protein purification</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Proteomics - methods</subject><subject>PTEN protein</subject><subject>Rapamycin</subject><subject>Reproducibility of Results</subject><subject>Retinoic acid</subject><subject>Retinoic acid receptors</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Tensin</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Transcription factors</subject><subject>Transducers</subject><subject>Triterpenoids</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNkuFr1DAYxosobjv9D0QLwsQPdyZNmqRfhDGcHgxO5vRrSNO31xy95pak6v33pl43rrIPUkhD3t_7JHnyJMkrjBaYcPxhY3vXqXaxsx0sEMoywbInySkuSDZnGSJPj-YnyZn3G4RyIhh7npxkWGBBET5Nrr46G8BujU5VVNt741Pf2F9x3HehgRALtoVY6yANzgRwO-isqdLSdJVPg023t6ubF8mzWrUeXo7_WfL96tPt5Zf59erz8vLieq55zsNclyWtSsU511gUjFBdVDnOcqIwKwhmXAgNZY0olEoRRShkvBAlVFRwwllOZsmbg-6utV6OFniJCcp5zjgfiOWBqKzayJ0zW-X20ioj_y5Yt5bKxVu1IBXXRCiqlK5zmolMUIZrBoRVWgPUNGp9HHfryy1UGrrgVDsRnVY608i1_SkJprSgIgq8GwWcvevBB7k1XkPbRjdt76UQmHI0ODFL3v5DPn65kVqreH7T1TZuqwdNeUE5E4KInERq8QgVvwriO8e41CauTxreTxoiE-B3WKvee7n8dvP_7OrHlD0_YhtQbWi8bftgbOenID2A2lnvHdQPHmMkh7TfuyGHtMsx7bHt9fH7PDTdx5v8AaIL-jo</recordid><startdate>20110727</startdate><enddate>20110727</enddate><creator>Yore, Mark M</creator><creator>Kettenbach, Arminja N</creator><creator>Sporn, Michael B</creator><creator>Gerber, Scott A</creator><creator>Liby, Karen T</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110727</creationdate><title>Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR</title><author>Yore, Mark M ; Kettenbach, Arminja N ; Sporn, Michael B ; Gerber, Scott A ; Liby, Karen T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acids</topic><topic>Analysis</topic><topic>Antifungal agents</topic><topic>Apoptosis</topic><topic>Binding</topic><topic>Binding proteins</topic><topic>Biology</topic><topic>Biotinylation</topic><topic>Cell culture</topic><topic>Chemistry</topic><topic>Chromatography, Liquid</topic><topic>Chronic illnesses</topic><topic>Colorectal cancer</topic><topic>Computational Biology</topic><topic>Cotton, Norris</topic><topic>Diabetes</topic><topic>Drugs</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Growth factors</topic><topic>HEK293 Cells</topic><topic>Homology</topic><topic>Humans</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - metabolism</topic><topic>Insulin</topic><topic>Janus kinase</topic><topic>Kidney diseases</topic><topic>Mass Spectrometry</topic><topic>Medical schools</topic><topic>Medical treatment</topic><topic>Medicine</topic><topic>Nitriles</topic><topic>Oleanolic Acid - analogs &amp; derivatives</topic><topic>Oleanolic Acid - chemistry</topic><topic>Oleanolic Acid - metabolism</topic><topic>Oxidative stress</topic><topic>Pharmacology</topic><topic>Phosphatases</topic><topic>Polyclonal antibodies</topic><topic>Prevention</topic><topic>Prostate cancer</topic><topic>Protein Binding</topic><topic>Protein purification</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Proteomics - methods</topic><topic>PTEN protein</topic><topic>Rapamycin</topic><topic>Reproducibility of Results</topic><topic>Retinoic acid</topic><topic>Retinoic acid receptors</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Tensin</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Transcription factors</topic><topic>Transducers</topic><topic>Triterpenoids</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yore, Mark M</creatorcontrib><creatorcontrib>Kettenbach, Arminja N</creatorcontrib><creatorcontrib>Sporn, Michael B</creatorcontrib><creatorcontrib>Gerber, Scott A</creatorcontrib><creatorcontrib>Liby, Karen T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints In Context: Health and Medicine</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Complete (ProQuest Database)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Databases</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>https://resources.nclive.org/materials</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest advanced technologies &amp; aerospace journals</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yore, Mark M</au><au>Kettenbach, Arminja N</au><au>Sporn, Michael B</au><au>Gerber, Scott A</au><au>Liby, Karen T</au><au>Vij, Neeraj</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-07-27</date><risdate>2011</risdate><volume>6</volume><issue>7</issue><spage>e22862</spage><pages>e22862-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21818401</pmid><doi>10.1371/journal.pone.0022862</doi><tpages>e22862</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1932-6203
ispartof PloS one, 2011-07, Vol.6 (7), p.e22862
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1305756775
source Publicly Available Content Database; PubMed Central
subjects Acids
Analysis
Antifungal agents
Apoptosis
Binding
Binding proteins
Biology
Biotinylation
Cell culture
Chemistry
Chromatography, Liquid
Chronic illnesses
Colorectal cancer
Computational Biology
Cotton, Norris
Diabetes
Drugs
Estrogen receptors
Estrogens
Growth factors
HEK293 Cells
Homology
Humans
Imidazoles - chemistry
Imidazoles - metabolism
Insulin
Janus kinase
Kidney diseases
Mass Spectrometry
Medical schools
Medical treatment
Medicine
Nitriles
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - chemistry
Oleanolic Acid - metabolism
Oxidative stress
Pharmacology
Phosphatases
Polyclonal antibodies
Prevention
Prostate cancer
Protein Binding
Protein purification
Proteins
Proteomics
Proteomics - methods
PTEN protein
Rapamycin
Reproducibility of Results
Retinoic acid
Retinoic acid receptors
Rodents
Signal transduction
Signaling
Tensin
TOR protein
TOR Serine-Threonine Kinases - metabolism
Transcription factors
Transducers
Triterpenoids
title Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T15%3A00%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Proteomic%20analysis%20shows%20synthetic%20oleanane%20triterpenoid%20binds%20to%20mTOR&rft.jtitle=PloS%20one&rft.au=Yore,%20Mark%20M&rft.date=2011-07-27&rft.volume=6&rft.issue=7&rft.spage=e22862&rft.pages=e22862-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0022862&rft_dat=%3Cgale_plos_%3EA476883853%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c757t-cbb4dba777c189634c9d51253a169316788cebf04ebaa3a34e2798bed48737653%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1305756775&rft_id=info:pmid/21818401&rft_galeid=A476883853&rfr_iscdi=true