@article{RN6092,
   author = {Akgül, S. and Li, Y. and Zheng, S. and Kool, M. and Treisman, D. M. and Li, C. and Wang, Y. and Gröbner, S. and Ikenoue, T. and Shen, Y. and Camelo-Piragua, S. and Tomasek, G. and Stark, S. and Guduguntla, V. and Gusella, J. F. and Guan, K. L. and Pfister, S. M. and Verhaak, R. G. W. and Zhu, Y.},
   title = {Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma},
   journal = {Cell Rep},
   volume = {24},
   number = {2},
   pages = {463-478.e5},
   note = {2211-1247
Akgül, Seçkin
Li, Yinghua
Zheng, Siyuan
Kool, Marcel
Treisman, Daniel M
Li, Chaoyang
Wang, Yuan
Gröbner, Susanne
Ikenoue, Tsuneo
Shen, Yiping
Camelo-Piragua, Sandra
Tomasek, Gerald
Stark, Sebastian
Guduguntla, Vinay
Gusella, James F
Guan, Kun-Liang
Pfister, Stefan M
Verhaak, Roel G W
Zhu, Yuan
P01 CA085878/CA/NCI NIH HHS/United States
R01 NS053900/NS/NINDS NIH HHS/United States
R01 NS073762/NS/NINDS NIH HHS/United States
R35 CA196878/CA/NCI NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
2018/07/12
Cell Rep. 2018 Jul 10;24(2):463-478.e5. doi: 10.1016/j.celrep.2018.06.050.},
   abstract = {Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.},
   keywords = {Adult
Animals
Basic Helix-Loop-Helix Transcription Factors/metabolism
Carcinogenesis/pathology
Cell Differentiation
Cell Proliferation
Child
Genome, Human
Glioma/genetics/*metabolism/pathology
Hedgehog Proteins/*metabolism
Humans
Mechanistic Target of Rapamycin Complex 2/*metabolism
Medulloblastoma/genetics/*metabolism/pathology
Mice
Mutation/genetics
Protein Binding
Proteolysis
Proto-Oncogene Proteins c-akt/metabolism
Rapamycin-Insensitive Companion of mTOR Protein/*metabolism
*Signal Transduction
Treatment Outcome
Tumor Suppressor Protein p53/genetics
Akt
Pi3k
Pten
Rictor
glioblastoma
mTORC2
mammalian target of rapamycin complex 2
medulloblastoma
p53
phosphatidylinositol 3-kinase pathway},
   DOI = {10.1016/j.celrep.2018.06.050},
   year = {2018},
   type = {Journal Article}
}

{"_id":"b5yGE6WpPpqPTpA3m","bibbaseid":"akgl-li-zheng-kool-treisman-li-wang-grbner-etal-opposingtumorpromotingandsuppressivefunctionsofrictormtorc2signalinginadultgliomaandpediatricshhmedulloblastoma-2018","author_short":["Akgül, S.","Li, Y.","Zheng, S.","Kool, M.","Treisman, D. M.","Li, C.","Wang, Y.","Gröbner, S.","Ikenoue, T.","Shen, Y.","Camelo-Piragua, S.","Tomasek, G.","Stark, S.","Guduguntla, V.","Gusella, J. F.","Guan, K. L.","Pfister, S. M.","Verhaak, R. G. W.","Zhu, Y."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Akgül"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Li"],"firstnames":["Y."],"suffixes":[]},{"propositions":[],"lastnames":["Zheng"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Kool"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Treisman"],"firstnames":["D.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Li"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Wang"],"firstnames":["Y."],"suffixes":[]},{"propositions":[],"lastnames":["Gröbner"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Ikenoue"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Shen"],"firstnames":["Y."],"suffixes":[]},{"propositions":[],"lastnames":["Camelo-Piragua"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Tomasek"],"firstnames":["G."],"suffixes":[]},{"propositions":[],"lastnames":["Stark"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Guduguntla"],"firstnames":["V."],"suffixes":[]},{"propositions":[],"lastnames":["Gusella"],"firstnames":["J.","F."],"suffixes":[]},{"propositions":[],"lastnames":["Guan"],"firstnames":["K.","L."],"suffixes":[]},{"propositions":[],"lastnames":["Pfister"],"firstnames":["S.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Verhaak"],"firstnames":["R.","G.","W."],"suffixes":[]},{"propositions":[],"lastnames":["Zhu"],"firstnames":["Y."],"suffixes":[]}],"title":"Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma","journal":"Cell Rep","volume":"24","number":"2","pages":"463-478.e5","note":"2211-1247 Akgül, Seçkin Li, Yinghua Zheng, Siyuan Kool, Marcel Treisman, Daniel M Li, Chaoyang Wang, Yuan Gröbner, Susanne Ikenoue, Tsuneo Shen, Yiping Camelo-Piragua, Sandra Tomasek, Gerald Stark, Sebastian Guduguntla, Vinay Gusella, James F Guan, Kun-Liang Pfister, Stefan M Verhaak, Roel G W Zhu, Yuan P01 CA085878/CA/NCI NIH HHS/United States R01 NS053900/NS/NINDS NIH HHS/United States R01 NS073762/NS/NINDS NIH HHS/United States R35 CA196878/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States 2018/07/12 Cell Rep. 2018 Jul 10;24(2):463-478.e5. doi: 10.1016/j.celrep.2018.06.050.","abstract":"Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.","keywords":"Adult Animals Basic Helix-Loop-Helix Transcription Factors/metabolism Carcinogenesis/pathology Cell Differentiation Cell Proliferation Child Genome, Human Glioma/genetics/*metabolism/pathology Hedgehog Proteins/*metabolism Humans Mechanistic Target of Rapamycin Complex 2/*metabolism Medulloblastoma/genetics/*metabolism/pathology Mice Mutation/genetics Protein Binding Proteolysis Proto-Oncogene Proteins c-akt/metabolism Rapamycin-Insensitive Companion of mTOR Protein/*metabolism *Signal Transduction Treatment Outcome Tumor Suppressor Protein p53/genetics Akt Pi3k Pten Rictor glioblastoma mTORC2 mammalian target of rapamycin complex 2 medulloblastoma p53 phosphatidylinositol 3-kinase pathway","doi":"10.1016/j.celrep.2018.06.050","year":"2018","bibtex":"@article{RN6092,\n author = {Akgül, S. and Li, Y. and Zheng, S. and Kool, M. and Treisman, D. M. and Li, C. and Wang, Y. and Gröbner, S. and Ikenoue, T. and Shen, Y. and Camelo-Piragua, S. and Tomasek, G. and Stark, S. and Guduguntla, V. and Gusella, J. F. and Guan, K. L. and Pfister, S. M. and Verhaak, R. G. W. and Zhu, Y.},\n title = {Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma},\n journal = {Cell Rep},\n volume = {24},\n number = {2},\n pages = {463-478.e5},\n note = {2211-1247\nAkgül, Seçkin\nLi, Yinghua\nZheng, Siyuan\nKool, Marcel\nTreisman, Daniel M\nLi, Chaoyang\nWang, Yuan\nGröbner, Susanne\nIkenoue, Tsuneo\nShen, Yiping\nCamelo-Piragua, Sandra\nTomasek, Gerald\nStark, Sebastian\nGuduguntla, Vinay\nGusella, James F\nGuan, Kun-Liang\nPfister, Stefan M\nVerhaak, Roel G W\nZhu, Yuan\nP01 CA085878/CA/NCI NIH HHS/United States\nR01 NS053900/NS/NINDS NIH HHS/United States\nR01 NS073762/NS/NINDS NIH HHS/United States\nR35 CA196878/CA/NCI NIH HHS/United States\nJournal Article\nResearch Support, N.I.H., Extramural\nResearch Support, Non-U.S. Gov't\nUnited States\n2018/07/12\nCell Rep. 2018 Jul 10;24(2):463-478.e5. doi: 10.1016/j.celrep.2018.06.050.},\n abstract = {Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.},\n keywords = {Adult\nAnimals\nBasic Helix-Loop-Helix Transcription Factors/metabolism\nCarcinogenesis/pathology\nCell Differentiation\nCell Proliferation\nChild\nGenome, Human\nGlioma/genetics/*metabolism/pathology\nHedgehog Proteins/*metabolism\nHumans\nMechanistic Target of Rapamycin Complex 2/*metabolism\nMedulloblastoma/genetics/*metabolism/pathology\nMice\nMutation/genetics\nProtein Binding\nProteolysis\nProto-Oncogene Proteins c-akt/metabolism\nRapamycin-Insensitive Companion of mTOR Protein/*metabolism\n*Signal Transduction\nTreatment Outcome\nTumor Suppressor Protein p53/genetics\nAkt\nPi3k\nPten\nRictor\nglioblastoma\nmTORC2\nmammalian target of rapamycin complex 2\nmedulloblastoma\np53\nphosphatidylinositol 3-kinase pathway},\n DOI = {10.1016/j.celrep.2018.06.050},\n year = {2018},\n type = {Journal Article}\n}\n\n","author_short":["Akgül, S.","Li, Y.","Zheng, S.","Kool, M.","Treisman, D. 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