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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner</title><author><name sortKey="Kalender, Adem" sort="Kalender, Adem" uniqKey="Kalender A" first="Adem" last="Kalender">Adem Kalender</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Selvaraj, Anand" sort="Selvaraj, Anand" uniqKey="Selvaraj A" first="Anand" last="Selvaraj">Anand Selvaraj</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Kim, So Young" sort="Kim, So Young" uniqKey="Kim S" first="So Young" last="Kim">So Young Kim</name><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Dana-Farber Cancer Institute, Department of Medical Oncology 44 Binney Street, D1537, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Gulati, Pawan" sort="Gulati, Pawan" uniqKey="Gulati P" first="Pawan" last="Gulati">Pawan Gulati</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation></author><author><name sortKey="Le, Sophie Br" sort="Le, Sophie Br" uniqKey="Le S" first="Sophie Br" last="Lé">Sophie Br Lé</name><affiliation><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff></affiliation></author><author><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name><affiliation><nlm:aff id="A5"> Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">INSERM, U567, Paris-75014, France</nlm:aff></affiliation></author><author><name sortKey="Kemp, Bruce" sort="Kemp, Bruce" uniqKey="Kemp B" first="Bruce" last="Kemp">Bruce Kemp</name><affiliation><nlm:aff id="A7"> St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia</nlm:aff></affiliation></author><author><name sortKey="Bardeesy, Nabeel" sort="Bardeesy, Nabeel" uniqKey="Bardeesy N" first="Nabeel" last="Bardeesy">Nabeel Bardeesy</name><affiliation><nlm:aff id="A8"> Massachusetts General Hospital, Center for Cancer Research, Simches Bldg, CPZN 4200, 185 Cambridge Street, Boston, MA 02114</nlm:aff></affiliation></author><author><name sortKey="Dennis, Patrick" sort="Dennis, Patrick" uniqKey="Dennis P" first="Patrick" last="Dennis">Patrick Dennis</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation></author><author><name sortKey="Schlager, John J" sort="Schlager, John J" uniqKey="Schlager J" first="John J." last="Schlager">John J. Schlager</name><affiliation><nlm:aff id="A9"> Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton OH 45433</nlm:aff></affiliation></author><author><name sortKey="Marette, Andre" sort="Marette, Andre" uniqKey="Marette A" first="André" last="Marette">André Marette</name><affiliation><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff></affiliation></author><author><name sortKey="Kozma, Sara C" sort="Kozma, Sara C" uniqKey="Kozma S" first="Sara C." last="Kozma">Sara C. Kozma</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Thomas, George" sort="Thomas, George" uniqKey="Thomas G" first="George" last="Thomas">George Thomas</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20444419</idno><idno type="pmc">3081779</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081779</idno><idno type="RBID">PMC:3081779</idno><idno type="doi">10.1016/j.cmet.2010.03.014</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">001434</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001434</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner</title><author><name sortKey="Kalender, Adem" sort="Kalender, Adem" uniqKey="Kalender A" first="Adem" last="Kalender">Adem Kalender</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Selvaraj, Anand" sort="Selvaraj, Anand" uniqKey="Selvaraj A" first="Anand" last="Selvaraj">Anand Selvaraj</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Kim, So Young" sort="Kim, So Young" uniqKey="Kim S" first="So Young" last="Kim">So Young Kim</name><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Dana-Farber Cancer Institute, Department of Medical Oncology 44 Binney Street, D1537, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Gulati, Pawan" sort="Gulati, Pawan" uniqKey="Gulati P" first="Pawan" last="Gulati">Pawan Gulati</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation></author><author><name sortKey="Le, Sophie Br" sort="Le, Sophie Br" uniqKey="Le S" first="Sophie Br" last="Lé">Sophie Br Lé</name><affiliation><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff></affiliation></author><author><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name><affiliation><nlm:aff id="A5"> Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">INSERM, U567, Paris-75014, France</nlm:aff></affiliation></author><author><name sortKey="Kemp, Bruce" sort="Kemp, Bruce" uniqKey="Kemp B" first="Bruce" last="Kemp">Bruce Kemp</name><affiliation><nlm:aff id="A7"> St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia</nlm:aff></affiliation></author><author><name sortKey="Bardeesy, Nabeel" sort="Bardeesy, Nabeel" uniqKey="Bardeesy N" first="Nabeel" last="Bardeesy">Nabeel Bardeesy</name><affiliation><nlm:aff id="A8"> Massachusetts General Hospital, Center for Cancer Research, Simches Bldg, CPZN 4200, 185 Cambridge Street, Boston, MA 02114</nlm:aff></affiliation></author><author><name sortKey="Dennis, Patrick" sort="Dennis, Patrick" uniqKey="Dennis P" first="Patrick" last="Dennis">Patrick Dennis</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation></author><author><name sortKey="Schlager, John J" sort="Schlager, John J" uniqKey="Schlager J" first="John J." last="Schlager">John J. Schlager</name><affiliation><nlm:aff id="A9"> Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton OH 45433</nlm:aff></affiliation></author><author><name sortKey="Marette, Andre" sort="Marette, Andre" uniqKey="Marette A" first="André" last="Marette">André Marette</name><affiliation><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff></affiliation></author><author><name sortKey="Kozma, Sara C" sort="Kozma, Sara C" uniqKey="Kozma S" first="Sara C." last="Kozma">Sara C. Kozma</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Thomas, George" sort="Thomas, George" uniqKey="Thomas G" first="George" last="Thomas">George Thomas</name><affiliation><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff></affiliation></author></analytic><series><title level="j">Cell metabolism</title><idno type="ISSN">1550-4131</idno><idno type="eISSN">1932-7420</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the anti-diabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2, but also in the absence of AMPK. Consistent with these observations, in two distinct pre-clinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.</p></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101233170</journal-id><journal-id journal-id-type="pubmed-jr-id">32527</journal-id><journal-id journal-id-type="nlm-ta">Cell Metab</journal-id><journal-title>Cell metabolism</journal-title><issn pub-type="ppub">1550-4131</issn><issn pub-type="epub">1932-7420</issn></journal-meta><article-meta><article-id pub-id-type="pmid">20444419</article-id><article-id pub-id-type="pmc">3081779</article-id><article-id pub-id-type="doi">10.1016/j.cmet.2010.03.014</article-id><article-id pub-id-type="manuscript">NIHMS194488</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kalender</surname><given-names>Adem</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="A2" ref-type="aff">2</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Selvaraj</surname><given-names>Anand</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="A2" ref-type="aff">2</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>So Young</given-names></name><xref rid="A2" ref-type="aff">2</xref><xref rid="A3" ref-type="aff">3</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Gulati</surname><given-names>Pawan</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>lé</surname><given-names>Sophie Br</given-names></name><xref rid="A4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Viollet</surname><given-names>Benoit</given-names></name><xref rid="A5" ref-type="aff">5</xref><xref rid="A6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Kemp</surname><given-names>Bruce</given-names></name><xref rid="A7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Bardeesy</surname><given-names>Nabeel</given-names></name><xref rid="A8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Dennis</surname><given-names>Patrick</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Schlager</surname><given-names>John J.</given-names></name><xref rid="A9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Marette</surname><given-names>André</given-names></name><xref rid="A4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Kozma</surname><given-names>Sara C.</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="A2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>George</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="A2" ref-type="aff">2</xref><xref rid="FN1" ref-type="author-notes">§</xref></contrib></contrib-group><aff id="A1"><label>1</label> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</aff><aff id="A2"><label>2</label> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</aff><aff id="A3"><label>3</label> Dana-Farber Cancer Institute, Department of Medical Oncology 44 Binney Street, D1537, Boston, MA 02115</aff><aff id="A4"><label>4</label> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</aff><aff id="A5"><label>5</label> Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France</aff><aff id="A6"><label>6</label>INSERM, U567, Paris-75014, France</aff><aff id="A7"><label>7</label> St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia</aff><aff id="A8"><label>8</label> Massachusetts General Hospital, Center for Cancer Research, Simches Bldg, CPZN 4200, 185 Cambridge Street, Boston, MA 02114</aff><aff id="A9"><label>9</label> Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton OH 45433</aff><author-notes><corresp id="FN1"><label>§</label>To whom correspondence should be addressed: <email>thomasg4@uc.edu</email> Phone: 513-558-7100 Fax: 513-558-5061</corresp><fn id="FN2" fn-type="equal"><label>*</label><p>These authors contributed equally to the work</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>19</day><month>4</month><year>2010</year></pub-date><pub-date pub-type="ppub"><day>5</day><month>5</month><year>2010</year></pub-date><pub-date pub-type="pmc-release"><day>5</day><month>5</month><year>2011</year></pub-date><volume>11</volume><issue>5</issue><fpage>390</fpage><lpage>401</lpage><abstract><p id="P1">Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the anti-diabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2, but also in the absence of AMPK. Consistent with these observations, in two distinct pre-clinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.</p></abstract><contract-num rid="CA1">U01 CA141464-01
||CA</contract-num><contract-num rid="DK1">R01 DK078019-02
||DK</contract-num><contract-num rid="DK1">R01 DK073802-04
||DK</contract-num><contract-sponsor id="CA1">National Cancer Institute : NCI</contract-sponsor><contract-sponsor id="DK1">National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK</contract-sponsor></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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