mTOR-S6K1 pathway mediates cytoophidium assembly
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摘要
CTP synthase(CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin(mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1(mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6 K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6 K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing m TOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells.Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.
CTP synthase(CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin(mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1(mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6 K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6 K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing m TOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells.Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.
CTP synthase(CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin(mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1(mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6 K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6 K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing m TOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells.Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.
引文
Aughey,G.N.,Grice,S.J.,Liu,J.L.,2016.The interplay between Myc and CTP synthase in Drosophila.PLoS Genet.12,e1005867.
Aughey,G.N.,Grice,S.J.,Shen,Q.J.,Xu,Y.,Chang,C.C.,Azzam,G.,Wang,P.Y.,Freeman-Mills,L.,Pai,L.M.,Sung,L.Y.,Yan,J.,Liu,J.L.,2014.Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism.Biol.Open 3,1045e1056.
Azzam,G.,Liu,J.L.,2013.Only one isoform of Drosophila melanogaster CTP synthase forms the cytoophidium.PLoS Genet.9,e1003256.
Barry,R.M.,Bitbol,A.F.,Lorestani,A.,Charles,E.J.,Habrian,C.H.,Hansen,J.M.,Li,H.J.,Baldwin,E.P.,Wingreen,N.S.,Kollman,J.M.,Gitai,Z.,2014.Large-scale filament formation inhibits the activity of CTP synthetase.eLife 3,e03638.
Ben-Sahra,I.,Howell,J.J.,Asara,J.M.,Manning,B.D.,2013.Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1.Science 339,1323e1328.
Ben-Sahra,I.,Hoxhaj,G.,Ricoult,S.J.H.,Asara,J.M.,Manning,B.D.,2016.mTORC1induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle.Science 351,728e733.
Carcamo,W.C.,Satoh,M.,Kasahara,H.,Terada,N.,Hamazaki,T.,Chan,J.Y.,Yao,B.,Tamayo,S.,Covini,G.,von Muhlen,C.A.,Chan,E.K.,2011.Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells.PLo S One 6,e29690.
Chang,C.C.,Jeng,Y.M.,Peng,M.,Keppeke,G.D.,Sung,L.Y.,Liu,J.L.,2017.CTP synthase forms the cytoophidium in human hepatocellular carcinoma.Exp.Cell Res.361,292e299.
Chang,Y.F.,Martin,S.S.,Baldwin,E.P.,Carman,G.M.,2007.Phosphorylation of human CTP synthetase 1 by protein kinase C:identification of Ser(462)and Thr(455)as major sites of phosphorylation.J.Biol.Chem.282,17613e17622.
Chen,K.,Zhang,J.,Tastan,O.Y.,Deussen,Z.A.,Siswick,M.Y.,Liu,J.L.,2011.Glutamine analogs promote cytoophidium assembly in human and Drosophila cells.J.Genet.Genomics.38,391e402.
Choi,M.G.,Park,T.S.,Carman,G.M.,2003.Phosphorylation of Saccharomyces cerevisiae CTP synthetase at Ser424 by protein kinases A and C regulates phosphatidylcholine synthesis by the CDP-choline pathway.J.Biol.Chem.278,23610e23616.
Earhart,R.H.,Amato,D.J.,Chang,A.Y.,Borden,E.C.,Shiraki,M.,Dowd,M.E.,Comis,R.L.,Davis,T.E.,Smith,T.J.,1990.Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas.Invest.N.Drugs 8,113e119.
Ellims,P.H.,Gan,T.E.,Medley,G.,1983.Cytidine triphosphate synthetase activity in lymphoproliferative disorders.Cancer Res.43,1432e1435.
Falkson,G.,Cnaan,A.,Simson,I.W.,Dayal,Y.,Falkson,H.,Smith,T.J.,Haller,D.G.,1990.A randomized phase II study of acivicin and 4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study.Am.J.Clin.Oncol.13,510e515.
Fingar,D.C.,Salama,S.,Tsou,C.,Harlow,E.,Blenis,J.,2002.Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.Genes Dev.16,1472e1487.
Grabiner,B.C.,Nardi,V.,Birsoy,K.,Possemato,R.,Shen,K.,Sinha,S.,Jordan,A.,Beck,A.H.,Sabatini,D.M.,2014.A diverse array of cancer-associated MTORmutations are hyperactivating and can predict rapamycin sensitivity.Cancer Discov.4,554e563.
Han,G.S.,Sreenivas,A.,Choi,M.G.,Chang,Y.F.,Martin,S.S.,Baldwin,E.P.,Carman,G.M.,2005.Expression of human CTP synthetase in Saccharomyces cerevisiae reveals phosphorylation by protein kinase A.J.Biol.Chem.280,38328e38336.
Higgins,M.J.,Graves,P.R.,Graves,L.M.,2007.Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3.J.Biol.Chem.282,29493e29503.
Huang,M.,Graves,L.M.,2003.De novo synthesis of pyrimidine nucleotides;emerging interfaces with signal transduction pathways.Cell.Mol.Life Sci.60,321e336.
Huang,Y.,Wang,J.J.,Ghosh,S.,Liu,J.L.,2017.Critical roles of CTP synthase N-terminal in cytoophidium assembly.Exp.Cell Res.354,122e133.
Ingerson-Mahar,M.,Briegel,A.,Werner,J.N.,Jensen,G.J.,Gitai,Z.,2010.The metabolic enzyme CTP synthase forms cytoskeletal filaments.Nat.Cell Biol.12,739e746.
Julien,L.A.,Carriere,A.,Moreau,J.,Roux,P.P.,2010.mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling.Mol.Cell.Biol.30,908e921.
Kizaki,H.,Williams,J.C.,Morris,H.P.,Weber,G.,1980.Increased cytidine 5'-triphosphate synthetase activity in rat and human tumors.Cancer Res.40,3921e3927.
Levitzki,A.,Koshland Jr.,D.E.,1971.Cytidine triphosphate synthetase.Covalent intermediates and mechanisms of action.Biochemistry 10,3365e3371.
Liu,J.L.,2010.Intracellular compartmentation of CTP synthase in Drosophila.J.Genet.Genomics.37,281e296.
Liu,J.L.,2016.The cytoophidium and its kind:filamentation and compartmentation of metabolic enzymes.Annu.Rev.Cell Dev.Biol.32,349e372.
Lloyd,A.C.,2013.The regulation of cell size.Cell 154,1194e1205.
Lynch,E.M.,Hicks,D.R.,Shepherd,M.,Endrizzi,J.A.,Maker,A.,Hansen,J.M.,Barry,R.M.,Gitai,Z.,Baldwin,E.P.,Kollman,J.M.,2017.Human CTP synthase filament structure reveals the active enzyme conformation.Nat.Struct.Mol.Biol.24,507e514.
Lynch,G.,Kemeny,N.,Casper,E.,1982.Phase II evaluation of DON(6-diazo-5-oxo-L-norleucine)in patients with advanced colorectal carcinoma.Am.J.Clin.Oncol.5,541e543.
Maroun,J.A.,Stewart,D.J.,Verma,S.,Evans,W.K.,Eisenhauer,E.,1990.Phase I study of acivicin and cisplatin in non-small-cell lung cancer.A National Cancer Institute of Canada study.Am.J.Clin.Oncol.13,401e404.
Noree,C.,Monfort,E.,Shiau,A.K.,Wilhelm,J.E.,2014.Common regulatory control of CTP synthase enzyme activity and filament formation.Mol.Biol.Cell 25,2282e2290.
Noree,C.,Sato,B.K.,Broyer,R.M.,Wilhelm,J.E.,2010.Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster.J.Cell Biol.190,541e551.
Park,T.S.,O'Brien,D.J.,Carman,G.M.,2003.Phosphorylation of CTP synthetase on Ser36,Ser330,Ser354,and Ser454 regulates the levels of CTP and phosphatidylcholine synthesis in Saccharomyces cerevisiae.J.Biol.Chem.278,20785e20794.
Park,T.S.,Ostrander,D.B.,Pappas,A.,Carman,G.M.,1999.Identification of Ser424 as the protein kinase A phosphorylation site in CTP synthetase from Saccharomyces cerevisiae.Biochemistry 38,8839e8848.
Robitaille,A.M.,Christen,S.,Shimobayashi,M.,Cornu,M.,Fava,L.L.,Moes,S.,Prescianotto-Baschong,C.,Sauer,U.,Jenoe,P.,Hall,M.N.,2013.Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis.Science 339,1320e1323.
Rubin,J.,Sorensen,S.,Schutt,A.J.,van Hazel,G.A.,O'Connell,M.J.,Moertel,C.G.,1983.A phase II study of 6-diazo-5-oxo-L-norleucine(DON,NSC-7365)in advanced large bowel carcinoma.Am.J.Clin.Oncol.6,325e326.
Sarbassov,D.D.,Ali,S.M.,Sengupta,S.,Sheen,J.H.,Hsu,P.P.,Bagley,A.F.,Markhard,A.L.,Sabatini,D.M.,2006.Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.Mol.Cell 22,159e168.
Sarbassov,D.D.,Guertin,D.A.,Ali,S.M.,Sabatini,D.M.,2005.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science 307,1098e1101.
Sato,T.,Nakashima,A.,Guo,L.,Coffman,K.,Tamanoi,F.,2010.Single amino-acid changes that confer constitutive activation of m TOR are discovered in human cancer.Oncogene 29,2746e2752.
Saxton,R.A.,Sabatini,D.M.,2017.mTOR signaling in growth,metabolism,and disease.Cell 169,361e371.
Schmidt,T.T.,Reyes,G.,Gries,K.,Ceylan,C.U.,Sharma,S.,Meurer,M.,Knop,M.,Chabes,A.,Hombauer,H.,2017.Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis.Proc.Natl.Acad.Sci.U.S.A.114,E4442e E4451.
Strochlic,T.I.,Stavrides,K.P.,Thomas,S.V.,Nicolas,E.,O'Reilly,A.M.,Peterson,J.R.,2014.Ack kinase regulates CTP synthase filaments during Drosophila oogenesis.EMBO Rep.15,1184e1191.
Traut,T.W.,1994.Physiological concentrations of purines and pyrimidines.Mol.Cell.Biochem.140,1e22.
Treins,C.,Warne,P.H.,Magnuson,M.A.,Pende,M.,Downward,J.,2010.Rictor is a novel target of p70 S6 kinase-1.Oncogene 29,1003e1016.
Valvezan,A.J.,Turner,M.,Belaid,A.,Lam,H.C.,Miller,S.K.,McNamara,M.C.,Baglini,C.,Housden,B.E.,Perrimon,N.,Kwiatkowski,D.J.,Asara,J.M.,Henske,E.P.,Manning,B.D.,2017.m TORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability.Cancer Cell32,624e638 e625.
van den Berg,A.A.,van Lenthe,H.,Busch,S.,de Korte,D.,Roos,D.,van Kuilenburg,A.B.,van Gennip,A.H.,1993.Evidence for transformation-related increase in CTP synthetase activity in situ in human lymphoblastic leukemia.Eur.J.Biochem.216,161e167.
Wang,P.Y.,Lin,W.C.,Tsai,Y.C.,Cheng,M.L.,Lin,Y.H.,Tseng,S.H.,Chakraborty,A.,Pai,L.M.,2015.Regulation of CTP synthase filament formation during DNAendoreplication in Drosophila.Genetics 201,1511e1523.
Weber,G.,Lui,M.S.,Takeda,E.,Denton,J.E.,1980.Enzymology of human colon tumors.Life Sci.27,793e799.
Williams,J.C.,Kizaki,H.,Weber,G.,Morris,H.P.,1978.Increased CTP synthetase activity in cancer cells.Nature 271,71e73.
Willoughby,L.F.,Schlosser,T.,Manning,S.A.,Parisot,J.P.,Street,I.P.,Richardson,H.E.,Humbert,P.O.,Brumby,A.M.,2013.An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery.Dis.Model.Mech.6,521e529.
Zhang,H.,Stallock,J.P.,Ng,J.C.,Reinhard,C.,Neufeld,T.P.,2000.Regulation of cellular growth by the Drosophila target of rapamycin dTOR.Genes Dev.14,2712e2724.
Aughey,G.N.,Grice,S.J.,Shen,Q.J.,Xu,Y.,Chang,C.C.,Azzam,G.,Wang,P.Y.,Freeman-Mills,L.,Pai,L.M.,Sung,L.Y.,Yan,J.,Liu,J.L.,2014.Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism.Biol.Open 3,1045e1056.
Azzam,G.,Liu,J.L.,2013.Only one isoform of Drosophila melanogaster CTP synthase forms the cytoophidium.PLoS Genet.9,e1003256.
Barry,R.M.,Bitbol,A.F.,Lorestani,A.,Charles,E.J.,Habrian,C.H.,Hansen,J.M.,Li,H.J.,Baldwin,E.P.,Wingreen,N.S.,Kollman,J.M.,Gitai,Z.,2014.Large-scale filament formation inhibits the activity of CTP synthetase.eLife 3,e03638.
Ben-Sahra,I.,Howell,J.J.,Asara,J.M.,Manning,B.D.,2013.Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1.Science 339,1323e1328.
Ben-Sahra,I.,Hoxhaj,G.,Ricoult,S.J.H.,Asara,J.M.,Manning,B.D.,2016.mTORC1induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle.Science 351,728e733.
Carcamo,W.C.,Satoh,M.,Kasahara,H.,Terada,N.,Hamazaki,T.,Chan,J.Y.,Yao,B.,Tamayo,S.,Covini,G.,von Muhlen,C.A.,Chan,E.K.,2011.Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells.PLo S One 6,e29690.
Chang,C.C.,Jeng,Y.M.,Peng,M.,Keppeke,G.D.,Sung,L.Y.,Liu,J.L.,2017.CTP synthase forms the cytoophidium in human hepatocellular carcinoma.Exp.Cell Res.361,292e299.
Chang,Y.F.,Martin,S.S.,Baldwin,E.P.,Carman,G.M.,2007.Phosphorylation of human CTP synthetase 1 by protein kinase C:identification of Ser(462)and Thr(455)as major sites of phosphorylation.J.Biol.Chem.282,17613e17622.
Chen,K.,Zhang,J.,Tastan,O.Y.,Deussen,Z.A.,Siswick,M.Y.,Liu,J.L.,2011.Glutamine analogs promote cytoophidium assembly in human and Drosophila cells.J.Genet.Genomics.38,391e402.
Choi,M.G.,Park,T.S.,Carman,G.M.,2003.Phosphorylation of Saccharomyces cerevisiae CTP synthetase at Ser424 by protein kinases A and C regulates phosphatidylcholine synthesis by the CDP-choline pathway.J.Biol.Chem.278,23610e23616.
Earhart,R.H.,Amato,D.J.,Chang,A.Y.,Borden,E.C.,Shiraki,M.,Dowd,M.E.,Comis,R.L.,Davis,T.E.,Smith,T.J.,1990.Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas.Invest.N.Drugs 8,113e119.
Ellims,P.H.,Gan,T.E.,Medley,G.,1983.Cytidine triphosphate synthetase activity in lymphoproliferative disorders.Cancer Res.43,1432e1435.
Falkson,G.,Cnaan,A.,Simson,I.W.,Dayal,Y.,Falkson,H.,Smith,T.J.,Haller,D.G.,1990.A randomized phase II study of acivicin and 4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study.Am.J.Clin.Oncol.13,510e515.
Fingar,D.C.,Salama,S.,Tsou,C.,Harlow,E.,Blenis,J.,2002.Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.Genes Dev.16,1472e1487.
Grabiner,B.C.,Nardi,V.,Birsoy,K.,Possemato,R.,Shen,K.,Sinha,S.,Jordan,A.,Beck,A.H.,Sabatini,D.M.,2014.A diverse array of cancer-associated MTORmutations are hyperactivating and can predict rapamycin sensitivity.Cancer Discov.4,554e563.
Han,G.S.,Sreenivas,A.,Choi,M.G.,Chang,Y.F.,Martin,S.S.,Baldwin,E.P.,Carman,G.M.,2005.Expression of human CTP synthetase in Saccharomyces cerevisiae reveals phosphorylation by protein kinase A.J.Biol.Chem.280,38328e38336.
Higgins,M.J.,Graves,P.R.,Graves,L.M.,2007.Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3.J.Biol.Chem.282,29493e29503.
Huang,M.,Graves,L.M.,2003.De novo synthesis of pyrimidine nucleotides;emerging interfaces with signal transduction pathways.Cell.Mol.Life Sci.60,321e336.
Huang,Y.,Wang,J.J.,Ghosh,S.,Liu,J.L.,2017.Critical roles of CTP synthase N-terminal in cytoophidium assembly.Exp.Cell Res.354,122e133.
Ingerson-Mahar,M.,Briegel,A.,Werner,J.N.,Jensen,G.J.,Gitai,Z.,2010.The metabolic enzyme CTP synthase forms cytoskeletal filaments.Nat.Cell Biol.12,739e746.
Julien,L.A.,Carriere,A.,Moreau,J.,Roux,P.P.,2010.mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling.Mol.Cell.Biol.30,908e921.
Kizaki,H.,Williams,J.C.,Morris,H.P.,Weber,G.,1980.Increased cytidine 5'-triphosphate synthetase activity in rat and human tumors.Cancer Res.40,3921e3927.
Levitzki,A.,Koshland Jr.,D.E.,1971.Cytidine triphosphate synthetase.Covalent intermediates and mechanisms of action.Biochemistry 10,3365e3371.
Liu,J.L.,2010.Intracellular compartmentation of CTP synthase in Drosophila.J.Genet.Genomics.37,281e296.
Liu,J.L.,2016.The cytoophidium and its kind:filamentation and compartmentation of metabolic enzymes.Annu.Rev.Cell Dev.Biol.32,349e372.
Lloyd,A.C.,2013.The regulation of cell size.Cell 154,1194e1205.
Lynch,E.M.,Hicks,D.R.,Shepherd,M.,Endrizzi,J.A.,Maker,A.,Hansen,J.M.,Barry,R.M.,Gitai,Z.,Baldwin,E.P.,Kollman,J.M.,2017.Human CTP synthase filament structure reveals the active enzyme conformation.Nat.Struct.Mol.Biol.24,507e514.
Lynch,G.,Kemeny,N.,Casper,E.,1982.Phase II evaluation of DON(6-diazo-5-oxo-L-norleucine)in patients with advanced colorectal carcinoma.Am.J.Clin.Oncol.5,541e543.
Maroun,J.A.,Stewart,D.J.,Verma,S.,Evans,W.K.,Eisenhauer,E.,1990.Phase I study of acivicin and cisplatin in non-small-cell lung cancer.A National Cancer Institute of Canada study.Am.J.Clin.Oncol.13,401e404.
Noree,C.,Monfort,E.,Shiau,A.K.,Wilhelm,J.E.,2014.Common regulatory control of CTP synthase enzyme activity and filament formation.Mol.Biol.Cell 25,2282e2290.
Noree,C.,Sato,B.K.,Broyer,R.M.,Wilhelm,J.E.,2010.Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster.J.Cell Biol.190,541e551.
Park,T.S.,O'Brien,D.J.,Carman,G.M.,2003.Phosphorylation of CTP synthetase on Ser36,Ser330,Ser354,and Ser454 regulates the levels of CTP and phosphatidylcholine synthesis in Saccharomyces cerevisiae.J.Biol.Chem.278,20785e20794.
Park,T.S.,Ostrander,D.B.,Pappas,A.,Carman,G.M.,1999.Identification of Ser424 as the protein kinase A phosphorylation site in CTP synthetase from Saccharomyces cerevisiae.Biochemistry 38,8839e8848.
Robitaille,A.M.,Christen,S.,Shimobayashi,M.,Cornu,M.,Fava,L.L.,Moes,S.,Prescianotto-Baschong,C.,Sauer,U.,Jenoe,P.,Hall,M.N.,2013.Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis.Science 339,1320e1323.
Rubin,J.,Sorensen,S.,Schutt,A.J.,van Hazel,G.A.,O'Connell,M.J.,Moertel,C.G.,1983.A phase II study of 6-diazo-5-oxo-L-norleucine(DON,NSC-7365)in advanced large bowel carcinoma.Am.J.Clin.Oncol.6,325e326.
Sarbassov,D.D.,Ali,S.M.,Sengupta,S.,Sheen,J.H.,Hsu,P.P.,Bagley,A.F.,Markhard,A.L.,Sabatini,D.M.,2006.Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.Mol.Cell 22,159e168.
Sarbassov,D.D.,Guertin,D.A.,Ali,S.M.,Sabatini,D.M.,2005.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science 307,1098e1101.
Sato,T.,Nakashima,A.,Guo,L.,Coffman,K.,Tamanoi,F.,2010.Single amino-acid changes that confer constitutive activation of m TOR are discovered in human cancer.Oncogene 29,2746e2752.
Saxton,R.A.,Sabatini,D.M.,2017.mTOR signaling in growth,metabolism,and disease.Cell 169,361e371.
Schmidt,T.T.,Reyes,G.,Gries,K.,Ceylan,C.U.,Sharma,S.,Meurer,M.,Knop,M.,Chabes,A.,Hombauer,H.,2017.Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis.Proc.Natl.Acad.Sci.U.S.A.114,E4442e E4451.
Strochlic,T.I.,Stavrides,K.P.,Thomas,S.V.,Nicolas,E.,O'Reilly,A.M.,Peterson,J.R.,2014.Ack kinase regulates CTP synthase filaments during Drosophila oogenesis.EMBO Rep.15,1184e1191.
Traut,T.W.,1994.Physiological concentrations of purines and pyrimidines.Mol.Cell.Biochem.140,1e22.
Treins,C.,Warne,P.H.,Magnuson,M.A.,Pende,M.,Downward,J.,2010.Rictor is a novel target of p70 S6 kinase-1.Oncogene 29,1003e1016.
Valvezan,A.J.,Turner,M.,Belaid,A.,Lam,H.C.,Miller,S.K.,McNamara,M.C.,Baglini,C.,Housden,B.E.,Perrimon,N.,Kwiatkowski,D.J.,Asara,J.M.,Henske,E.P.,Manning,B.D.,2017.m TORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability.Cancer Cell32,624e638 e625.
van den Berg,A.A.,van Lenthe,H.,Busch,S.,de Korte,D.,Roos,D.,van Kuilenburg,A.B.,van Gennip,A.H.,1993.Evidence for transformation-related increase in CTP synthetase activity in situ in human lymphoblastic leukemia.Eur.J.Biochem.216,161e167.
Wang,P.Y.,Lin,W.C.,Tsai,Y.C.,Cheng,M.L.,Lin,Y.H.,Tseng,S.H.,Chakraborty,A.,Pai,L.M.,2015.Regulation of CTP synthase filament formation during DNAendoreplication in Drosophila.Genetics 201,1511e1523.
Weber,G.,Lui,M.S.,Takeda,E.,Denton,J.E.,1980.Enzymology of human colon tumors.Life Sci.27,793e799.
Williams,J.C.,Kizaki,H.,Weber,G.,Morris,H.P.,1978.Increased CTP synthetase activity in cancer cells.Nature 271,71e73.
Willoughby,L.F.,Schlosser,T.,Manning,S.A.,Parisot,J.P.,Street,I.P.,Richardson,H.E.,Humbert,P.O.,Brumby,A.M.,2013.An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery.Dis.Model.Mech.6,521e529.
Zhang,H.,Stallock,J.P.,Ng,J.C.,Reinhard,C.,Neufeld,T.P.,2000.Regulation of cellular growth by the Drosophila target of rapamycin dTOR.Genes Dev.14,2712e2724.
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