Metabolic circuits in neural stem cells

Cellular and Molecular Life Sciences

Volumn 71, Issue 21, 2014, Pages 4221-4241

  Kim, Do Yeon ^a   Rhee, Inmoo ^a,b   Paik, Jihye ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b Gachon University College of Medicine   (South Korea)

Author keywords

Differentiation; Metabolism; Neural stem progenitor cells; Self renewal

Indexed keywords

CARBON; GLUCOSE; GLUTAMINE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; LIPID; MAMMALIAN TARGET OF RAPAMYCIN; MYC PROTEIN; PENTOSE PHOSPHATE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE B; PROTEIN P53; PROTEIN TYROSINE KINASE; SIRTUIN; TRANSCRIPTION FACTOR FOXO;

CARBON METABOLISM; CELL ASSAY; CELL FATE; CELL FUNCTION; CELL HYPOXIA; CELL MATURATION; CELL METABOLISM; CELL RENEWAL; CELL SURVIVAL; EPIGENETICS; GLYCOLYSIS; HUMAN; INFLAMMATION; LIPID METABOLISM; METABOLIC REGULATION; MICROENVIRONMENT; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NONHUMAN; PHASE TRANSITION; PROTEIN DETERMINATION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; ANOXIA; BRAIN; CELL LINEAGE; CHEMISTRY; COGNITION; COGNITIVE DEFECT; CYTOLOGY; DEGENERATIVE DISEASE; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; METABOLISM; PHYSIOLOGY; REGENERATION;

ANIMALS; ANOXIA; BRAIN; CELL LINEAGE; COGNITION; COGNITION DISORDERS; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATION; LIPIDS; NEURAL STEM CELLS; NEURODEGENERATIVE DISEASES; NEUROGENESIS; REGENERATION;

EID: 84922069609     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-014-1686-0     Document Type: Review

References (213)

1. Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Belmonte JC (2013) Mitochondrial regulation in pluripotent stem cells. Cell Metab 18(3):325-332. doi: 10.1016/j.cmet.2013.06.005
2. Shyh-Chang N, Daley GQ, Cantley LC (2013) Stem cell metabolism in tissue development and aging. Development 140(12):2535-2547. doi: 10.1242/dev.091777
3. Ochocki JD, Simon MC (2013) Nutrient-sensing pathways and metabolic regulation in stem cells. J Cell Bio 203(1):23-33. doi: 10.1083/jcb.201303110
4. Knobloch M, Braun SM, Zurkirchen L, von Schoultz C, Zamboni N, Arauzo-Bravo MJ, Kovacs WJ, Karalay O, Suter U, Machado RA, Roccio M, Lutolf MP, Semenkovich CF, Jessberger S (2013) Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493(7431):226-230. doi: 10.1038/nature11689
5. Sidman RL, Miale IL, Feder N (1959) Cell proliferation and migration in the primitive ependymal zone: an autoradiographic study of histogenesis in the nervous system. Exp Neurol 1:322-333
6. Altman J (1962) Are new neurons formed in the brains of adult mammals? Science 135(3509):1127-1128
7. Altman J (1963) Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anatomical Rec 145:573-591
8. Altman J, Das GD (1967) Postnatal neurogenesis in the guinea-pig. Nature 214(5093):1098-1101
9. Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433-1438
10. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645-660. doi: 10.1016/j.cell.2008.01.033
11. Ma DK, Bonaguidi MA, Ming GL, Song H (2009) Adult neural stem cells in the mammalian central nervous system. Cell Res 19(6):672-682. doi: 10.1038/cr.2009.56
12. Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S, Kageyama R (2008) Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11(10):1153-1161. doi: 10.1038/nn.2185
13. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisen J (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153(6):1219-1227. doi: 10.1016/j.cell.2013.05.002
14. Carlen M, Cassidy RM, Brismar H, Smith GA, Enquist LW, Frisen J (2002) Functional integration of adult-born neurons. Current Biol 12(7):606-608
15. Duan X, Kang E, Liu CY, Ming GL, Song H (2008) Development of neural stem cell in the adult brain. Curr Opin Neurobiol 18(1):108-115. doi: 10.1016/j.conb.2008.04.001
16. Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27(8):447-452. doi: 10.1016/j.tins.2004.05.013
17. Garcia-Verdugo JM, Doetsch F, Wichterle H, Lim DA, Alvarez-Buylla A (1998) Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 36(2):234-248
18. Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK, Roysam B, Temple S (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3(3):289-300. doi: 10.1016/j.stem.2008.07.026
19. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisen J (2014) Neurogenesis in the striatum of the adult human brain. Cell 156(5):1072-1083. doi: 10.1016/j.cell.2014.01.044
20. Fuentealba LC, Obernier K, Alvarez-Buylla A (2012) Adult neural stem cells bridge their niche. Cell Stem Cell 10(6):698-708. doi: 10.1016/j.stem.2012.05.012
21. Erecinska M, Silver IA (2001) Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 128(3):263-276
22. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7(2):150-161. doi: 10.1016/j.stem.2010.07.007
23. Harms KM, Li L, Cunningham LA (2010) Murine neural stem/progenitor cells protect neurons against ischemia by HIF-1alpha-regulated VEGF signaling. PLoS One 5(3):e9767. doi: 10.1371/journal.pone.0009767
24. Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD, Panchision DM (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25(9):2291-2301. doi: 10.1634/stemcells.2006-0609
25. Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, Wold B, McKay R (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20(19):7377-7383
26. Felfly H, Zambon AC, Xue J, Muotri A, Zhou D, Snyder EY, Haddad GG (2011) Severe Hypoxia: consequences to neural stem cells and neurons. J Neurol Res 1 (5). doi: 10.4021/jnr70w
27. Morrison SJ, Csete M, Groves AK, Melega W, Wold B, Anderson DJ (2000) Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. J Neurosci 20(19):7370-7376
28. Candelario KM, Shuttleworth CW, Cunningham LA (2013) Neural stem/progenitor cells display a low requirement for oxidative metabolism independent of hypoxia inducible factor-1alpha expression. J Neurochem 125(3):420-429. doi: 10.1111/jnc.12204
29. Mazumdar J, O'Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS, Simon MC (2010) O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12(10):1007-1013. doi: 10.1038/ncb2102
30. Ingraham CA, Park GC, Makarenkova HP, Crossin KL (2011) Matrix metalloproteinase (MMP)-9 induced by Wnt signaling increases the proliferation and migration of embryonic neural stem cells at low O2 levels. J Biol Chem 286(20):17649-17657. doi: 10.1074/jbc.M111.229427
31. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770-776
32. de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA (1997) Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 124(6):1139-1148
33. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442(7104):823-826. doi: 10.1038/nature04940
34. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9(5):617-628. doi: 10.1016/j.devcel.2005.09.010
35. Zheng X, Linke S, Dias JM, Zheng X, Gradin K, Wallis TP, Hamilton BR, Gustafsson M, Ruas JL, Wilkins S, Bilton RL, Brismar K, Whitelaw ML, Pereira T, Gorman JJ, Ericson J, Peet DJ, Lendahl U, Poellinger L (2008) Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc Natl Acad Sci USA 105(9):3368-3373. doi: 10.1073/pnas.0711591105
36. Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297(5580):365-369. doi: 10.1126/science.1074192
37. Kaidi A, Williams AC, Paraskeva C (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9(2):210-217. doi: 10.1038/ncb1534
38. Pistollato F, Chen HL, Schwartz PH, Basso G, Panchision DM (2007) Oxygen tension controls the expansion of human CNS precursors and the generation of astrocytes and oligodendrocytes. Mol Cell Neurosci 35(3):424-435. doi: 10.1016/j.mcn.2007.04.003
39. Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, Labosky PA, Simon MC, Keith B (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20(5):557-570. doi: 10.1101/gad.1399906
40. Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher AG (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8(5):532-538. doi: 10.1038/ncb1403
41. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315-326. doi: 10.1016/j.cell.2006.02.041
42. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760-1765. doi: 10.1126/science.1088417
43. Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486-492
44. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100(23):13632-13637. doi: 10.1073/pnas.2234031100
45. Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M, Aiso S, Kato R, Asai M (1995) Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci 15(3 Pt 1):1961-1970
46. Ji R, Tian S, Lu HJ, Lu Q, Zheng Y, Wang X, Ding J, Li Q (2013) TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. J Immunol 191(12):6165-6177. doi: 10.4049/jimmunol.1302229
47. Taga T, Fukuda S (2005) Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 28(3):249-256. doi: 10.1385/CRIAI:28:3:249
48. Namihira M, Nakashima K (2013) Mechanisms of astrocytogenesis in the mammalian brain. Curr Opin Neurobiol 23(6):921-927. doi: 10.1016/j.conb.2013.06.002
49. Li X, Newbern JM, Wu Y, Morgan-Smith M, Zhong J, Charron J, Snider WD (2012) MEK is a key regulator of gliogenesis in the developing brain. Neuron 75(6):1035-1050. doi: 10.1016/j.neuron.2012.08.031
50. Folmes CD, Dzeja PP, Nelson TJ, Terzic A (2012) Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11(5):596-606. doi: 10.1016/j.stem.2012.10.002
51. Folmes CD, Park S, Terzic A (2013) Lipid metabolism greases the stem cell engine. Cell Metab 17(2):153-155. doi: 10.1016/j.cmet.2013.01.010
52. Agathocleous M, Love NK, Randlett O, Harris JJ, Liu J, Murray AJ, Harris WA (2012) Metabolic differentiation in the embryonic retina. Nat Cell Biol 14(8):859-864. doi: 10.1038/ncb2531
53. Lonergan T, Brenner C, Bavister B (2006) Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Physiol 208(1):149-153. doi: 10.1002/jcp.20641
54. Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, Popescu R, Della Donna L, Evers P, Dekmezian C, Reue K, Christofk H, Mischel PS, Pajonk F (2011) Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci USA 108(38):16062-16067. doi: 10.1073/pnas.1106704108
55. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029-1033. doi: 10.1126/science.1160809
56. Chung S, Dzeja PP, Faustino RS, Perez-Terzic C, Behfar A, Terzic A (2007) Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Clin Prac Cardiovasc Med 4(Suppl 1):S60-S67. doi: 10.1038/ncpcardio0766
57. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, Ikeda Y, Perez-Terzic C, Terzic A (2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14(2):264-271. doi: 10.1016/j.cmet.2011.06.011
58. Panopoulos AD, Izpisua Belmonte JC (2011) Anaerobicizing into pluripotency. Cell Metab 14(2):143-144. doi: 10.1016/j.cmet.2011.07.003
59. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105-111. doi: 10.1038/35102167
60. Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411(6835):349-354. doi: 10.1038/35077219
61. Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, Jaeger C, Kammerer B, Winter L, Wiche G, Dalgaard K, Selvaraj M, Gaster M, Lee-Young RS, Febbraio MA, Knauf C, Cani PD, Aberger F, Penninger JM, Pospisilik JA, Esterbauer H (2012) Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151(2):414-426. doi: 10.1016/j.cell.2012.09.021
62. Landor SK, Mutvei AP, Mamaeva V, Jin S, Busk M, Borra R, Gronroos TJ, Kronqvist P, Lendahl U, Sahlgren CM (2011) Hypo- and hyperactivated Notch signaling induce q glycolytic switch through distinct mechanisms. Proc Natl Acad Sci USA 108(46):18814-18819. doi: 10.1073/pnas.1104943108
63. Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F (2013) WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab 17(5):745-755. doi: 10.1016/j.cmet.2013.03.017
64. Birket MJ, Orr AL, Gerencser AA, Madden DT, Vitelli C, Swistowski A, Brand MD, Zeng X (2011) A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. J Cell Sci 124(Pt 3):348-358. doi: 10.1242/jcs.072272
65. Guppy M, Greiner E, Brand K (1993) The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem 212(1):95-99
66. Maurer MH, Geomor HK, Burgers HF, Schelshorn DW, Kuschinsky W (2006) Adult neural stem cells express glucose transporters GLUT1 and GLUT3 and regulate GLUT3 expression. FEBS Lett 580(18):4430-4434. doi: 10.1016/j.febslet.2006.07.012
67. Gershon TR, Crowther AJ, Tikunov A, Garcia I, Annis R, Yuan H, Miller CR, Macdonald J, Olson J, Deshmukh M (2013) Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab 1(1):2
68. Suh SW, Fan Y, Hong SM, Liu Z, Matsumori Y, Weinstein PR, Swanson RA, Liu J (2005) Hypoglycemia induces transient neurogenesis and subsequent progenitor cell loss in the rat hippocampus. Diabetes 54(2):500-509
69. Alvarez EO, Beauquis J, Revsin Y, Banzan AM, Roig P, De Nicola AF, Saravia F (2009) Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes. Behav Brain Res 198(1):224-230. doi: 10.1016/j.bbr.2008.11.001
70. Fu J, Tay SS, Ling EA, Dheen ST (2007) Aldose reductase is implicated in high glucose-induced oxidative stress in mouse embryonic neural stem cells. J Neurochem 103(4):1654-1665. doi: 10.1111/j.1471-4159.2007.04880.x
71. Horecker BL, Mehler AH (1955) Carbohydrate metabolism. Annu Rev Biochem 24:207-274. doi: 10.1146/annurev.bi.24.070155.001231
72. Doiron B, Cuif MH, Chen R, Kahn A (1996) Transcriptional glucose signaling through the glucose response element is mediated by the pentose phosphate pathway. J Biol Chem 271(10):5321-5324
73. Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB (2010) The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 24(24):2784-2799. doi: 10.1101/gad.1985910
74. Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334(6060):1278-1283
75. Gruning NM, Rinnerthaler M, Bluemlein K, Mulleder M, Wamelink MM, Lehrach H, Jakobs C, Breitenbach M, Ralser M (2011) Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab 14(3):415-427. doi: 10.1016/j.cmet.2011.06.017
76. Yeo H, Lyssiotis CA, Zhang Y, Ying H, Asara JM, Cantley LC, Paik JH (2013) FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells. The EMBO J 32(19):2589-2602. doi: 10.1038/emboj.2013.186
77. Zhao Y, Pan X, Zhao J, Wang Y, Peng Y, Zhong C (2009) Decreased transketolase activity contributes to impaired hippocampal neurogenesis induced by thiamine deficiency. J Neurochem 111(2):537-546. doi: 10.1111/j.1471-4159.2009.06341.x
78. Bergstrom J, Furst P, Noree LO, Vinnars E (1974) Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol 36(6):693-697
79. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104(49):19345-19350. doi: 10.1073/pnas.0709747104
80. Hensley CT, Wasti AT, DeBerardinis RJ (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Investig 123(9):3678-3684. doi: 10.1172/JCI69600
81. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101-105. doi: 10.1038/nature12040
82. Mates JM, Perez-Gomez C, Nunez de Castro I, Asenjo M, Marquez J (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34(5):439-458
83. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521-534. doi: 10.1016/j.cell.2008.11.044
84. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762-765. doi: 10.1038/nature07823
85. Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13(8):572-583. doi: 10.1038/nrc3557
86. Tibbetts AS, Appling DR (2010) Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr 30:57-81. doi: 10.1146/annurev.nutr.012809.104810
87. Kruman II, Mouton PR, Emokpae R Jr, Cutler RG, Mattson MP (2005) Folate deficiency inhibits proliferation of adult hippocampal progenitors. NeuroReport 16(10):1055-1059
88. Zhang X, Liu H, Cong G, Tian Z, Ren D, Wilson JX, Huang G (2008) Effects of folate on notch signaling and cell proliferation in neural stem cells of neonatal rats in vitro. J Nutr Sci Vitaminol 54(5):353-356
89. Liu H, Cao J, Zhang H, Qin S, Yu M, Zhang X, Wang X, Gao Y, Wilson JX, Huang G (2013) Folic acid stimulates proliferation of transplanted neural stem cells after focal cerebral ischemia in rats. J Nutr Biochem 24(11):1817-1822. doi: 10.1016/j.jnutbio.2013.04.002
90. Luo S, Zhang X, Yu M, Yan H, Liu H, Wilson JX, Huang G (2013) Folic acid acts through DNA methyltransferases to induce the differentiation of neural stem cells into neurons. Cell Biochem Biophys 66(3):559-566. doi: 10.1007/s12013-012-9503-6
91. Li W, Yu M, Luo S, Liu H, Gao Y, Wilson JX, Huang G (2013) DNA methyltransferase mediates dose-dependent stimulation of neural stem cell proliferation by folate. J Nutr Biochem 24(7):1295-1301. doi: 10.1016/j.jnutbio.2012.11.001
92. Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA (2010) DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463(7280):563-567. doi: 10.1038/nature08683
93. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer JJ, Zhu H, Asara JM, Daley GQ, Cantley LC (2013) Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339(6116):222-226. doi: 10.1126/science.1226603
94. Zhu Q, Mariash A, Margosian MR, Gopinath S, Fareed MT, Anderson GW, Mariash CN (2001) Spot 14 gene deletion increases hepatic de novo lipogenesis. Endocrinology 142(10):4363-4370. doi: 10.1210/endo.142.10.8431
95. Moncur JT, Park JP, Memoli VA, Mohandas TK, Kinlaw WB (1998) The "Spot 14" gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: implications for control of tumor metabolism. Proc Natl Acad Sci USA 95(12):6989-6994
96. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, Schafer ZT, Evans RM, Suda T, Lee CH, Pandolfi PP (2012) A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 18(9):1350-1358. doi: 10.1038/nm.2882
97. Saito K, Dubreuil V, Arai Y, Wilsch-Brauninger M, Schwudke D, Saher G, Miyata T, Breier G, Thiele C, Shevchenko A, Nave KA, Huttner WB (2009) Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proc Natl Acad Sci USA 106(20):8350-8355. doi: 10.1073/pnas.0903541106
98. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, Clemenson GD Jr, Suh H, Couillard-Despres S, Aigner L, Gage FH, Jessberger S (2012) Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 32(10):3376-3387. doi: 10.1523/JNEUROSCI.4248-11.2012
99. Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3(3):279-288. doi: 10.1016/j.stem.2008.07.025
100. Panchision DM (2009) The role of oxygen in regulating neural stem cells in development and disease. J Cell Physiol 220(3):562-568. doi: 10.1002/jcp.21812
101. Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF, van der Kooy D (1999) Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Develop Biol 208(1):166-188. doi: 10.1006/dbio.1998.9192
102. Arsenijevic Y, Weiss S, Schneider B, Aebischer P (2001) Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. J Neurosci 21(18):7194-7202
103. O'Kusky JR, Ye P, D'Ercole AJ (2000) Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 20(22):8435-8442
104. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS (2000) Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 20(8):2896-2903
105. Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI (2011) Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 8(1):59-71. doi: 10.1016/j.stem.2010.11.028
106. Groszer M, Erickson R, Scripture-Adams DD, Dougherty JD, Le Belle J, Zack JA, Geschwind DH, Liu X, Kornblum HI, Wu H (2006) PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci USA 103(1):111-116. doi: 10.1073/pnas.0509939103
107. Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X, Wu H (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294(5549):2186-2189. doi: 10.1126/science.1065518
108. Watatani K, Hirabayashi Y, Itoh Y, Gotoh Y (2012) PDK1 regulates the generation of oligodendrocyte precursor cells at an early stage of mouse telencephalic development. Genes Cells 17(4):326-335. doi: 10.1111/j.1365-2443.2012.01591.x
109. Oishi K, Watatani K, Itoh Y, Okano H, Guillemot F, Nakajima K, Gotoh Y (2009) Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1. Proc Natl Acad Sci USA 106(31):13064-13069. doi: 10.1073/pnas.0808400106
110. Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, Michaelis T, Frahm J, Hemmings BA (2005) Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132(13):2943-2954. doi: 10.1242/dev.01864
111. Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, Snider WD (2009) GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 12(11):1390-1397. doi: 10.1038/nn.2408
112. Robey RB, Hay N (2009) Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19(1):25-31. doi: 10.1016/j.semcancer.2008.11.010
113. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64(11):3892-3899. doi: 10.1158/0008-5472.CAN-03-2904
114. Robey RB, Hay N (2006) Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25(34):4683-4696. doi: 10.1038/sj.onc.1209595
115. Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak TW, Wang X (2010) The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143(5):711-724. doi: 10.1016/j.cell.2010.10.010
116. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24(50):7410-7425. doi: 10.1038/sj.onc.1209086
117. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128(2):309-323. doi: 10.1016/j.cell.2006.12.029
118. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128(2):325-339. doi: 10.1016/j.cell.2007.01.003
119. Zhang X, Yalcin S, Lee DF, Yeh TY, Lee SM, Su J, Mungamuri SK, Rimmele P, Kennedy M, Sellers R, Landthaler M, Tuschl T, Chi NW, Lemischka I, Keller G, Ghaffari S (2011) FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol 13(9):1092-1099. doi: 10.1038/ncb2293
120. Vilchez D, Boyer L, Lutz M, Merkwirth C, Morantte I, Tse C, Spencer B, Page L, Masliah E, Berggren WT, Gage FH, Dillin A (2013) FOXO4 is necessary for neural differentiation of human embryonic stem cells. Aging Cell 12(3):518-522. doi: 10.1111/acel.12067
121. Goertz MJ, Wu Z, Gallardo TD, Hamra FK, Castrillon DH (2011) Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis. J Clin Investig 121(9):3456-3466. doi: 10.1172/JCI57984
122. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama KI, Harada M, Motoyama N, Suda T, Hirao A (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1(1):101-112. doi: 10.1016/j.stem.2007.02.001
123. Kang JY, Nan X, Jin MS, Youn SJ, Ryu YH, Mah S, Han SH, Lee H, Paik SG, Lee JO (2009) Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity 31(6):873-884. doi: 10.1016/j.immuni.2009.09.018
124. Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD, Butte AJ, Brunet A (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5(5):527-539. doi: 10.1016/j.stem.2009.09.014
125. van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen LP, Groot Koerkamp MJ, Braat AK, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ (2012) Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nature Cell Biol 14(8):829-837. doi: 10.1038/ncb2536
126. Vazquez P, Arroba AI, Cecconi F, de la Rosa EJ, Boya P, de Pablo F (2012) Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy 8(2):187-199. doi: 10.4161/auto.8.2.18535
127. Wang C, Liang CC, Bian ZC, Zhu Y, Guan JL (2013) FIP200 is required for maintenance and differentiation of postnatal neural stem cells. Nat Neurosci 16(5):532-542. doi: 10.1038/nn.3365
128. Magri L, Cambiaghi M, Cominelli M, Alfaro-Cervello C, Cursi M, Pala M, Bulfone A, Garcia-Verdugo JM, Leocani L, Minicucci F, Poliani PL, Galli R (2011) Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 9(5):447-462. doi: 10.1016/j.stem.2011.09.008
129. Anderl S, Freeland M, Kwiatkowski DJ, Goto J (2011) Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet 20(23):4597-4604. doi: 10.1093/hmg/ddr393
130. Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ (2011) Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci USA 108(45):E1070-E1079. doi: 10.1073/pnas.1106454108
131. Zhou J, Shrikhande G, Xu J, McKay RM, Burns DK, Johnson JE, Parada LF (2011) Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 25(15):1595-1600. doi: 10.1101/gad.16750211
132. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9-22. doi: 10.1016/j.ccr.2007.05.008
133. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153(4):840-854. doi: 10.1016/j.cell.2013.04.023
134. Ricoult SJ, Manning BD (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO reports 14(3):242-251. doi: 10.1038/embor.2013.5
135. Lamming DW, Sabatini DM (2013) A Central role for mTOR in lipid homeostasis. Cell Metabol 18(4):465-469. doi: 10.1016/j.cmet.2013.08.002
136. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM (2011) The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. Proc Natl Acad Sci USA 108(37):15201-15206. doi: 10.1073/pnas.1103746108
137. Morrisett JD, Abdel-Fattah G, Hoogeveen R, Mitchell E, Ballantyne CM, Pownall HJ, Opekun AR, Jaffe JS, Oppermann S, Kahan BD (2002) Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 43(8):1170-1180
138. Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Investig 123(9):3664-3671. doi: 10.1172/JCI67230
139. Simon MC, Keith B (2008) The role of oxygen availability in embryonic development and stem cell function nature reviews. Mol Cell Biol 9(4):285-296. doi: 10.1038/nrm2354
140. Adelman DM, Maltepe E, Simon MC (1999) Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev 13(19):2478-2483
141. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7(3):391-402. doi: 10.1016/j.stem.2010.06.020
142. Jang YY, Sharkis SJ (2007) A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110(8):3056-3063. doi: 10.1182/blood-2007-05-087759
143. Zhu XH, Yan HC, Zhang J, Qu HD, Qiu XS, Chen L, Li SJ, Cao X, Bean JC, Chen LH, Qin XH, Liu JH, Bai XC, Mei L, Gao TM (2010) Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adult rats. J Neurosci 30(38):12653-12663. doi: 10.1523/JNEUROSCI.6414-09.2010
144. Tsai YW, Yang YR, Wang PS, Wang RY (2011) Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats. PLoS One 6(8):e24001. doi: 10.1371/journal.pone.0024001
145. Zhu LL, Zhao T, Li HS, Zhao H, Wu LY, Ding AS, Fan WH, Fan M (2005) Neurogenesis in the adult rat brain after intermittent hypoxia. Brain Res 1-2:1-6. doi: 10.1016/j.brainres.2005.04.075
146. Chen X, Tian Y, Yao L, Zhang J, Liu Y (2010) Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience 165(3):705-714. doi: 10.1016/j.neuroscience.2009.11.007
147. Zhu LL, Wu LY, Yew DT, Fan M (2005) Effects of hypoxia on the proliferation and differentiation of NSCs. Mol Neurobiol 31(1-3):231-242. doi: 10.1385/MN:31:1-3:231
148. Mu J, Krafft PR, Zhang JH (2011) Hyperbaric oxygen therapy promotes neurogenesis: where do we stand? Med Gas Res 1(1):14. doi: 10.1186/2045-9912-1-14
149. Milosevic J, Adler I, Manaenko A, Schwarz SC, Walkinshaw G, Arend M, Flippin LA, Storch A, Schwarz J (2009) Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells. Neurotox Res 15(4):367-380. doi: 10.1007/s12640-009-9043-z
150. Yeung SJ, Pan J, Lee MH (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. CMLS 65(24):3981-3999. doi: 10.1007/s00018-008-8224-x
151. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A (2001) Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 276(12):9519-9525. doi: 10.1074/jbc.M010144200
152. Riddle SR, Ahmad A, Ahmad S, Deeb SS, Malkki M, Schneider BK, Allen CB, White CW (2000) Hypoxia induces hexokinase II gene expression in human lung cell line A549. Am J Physiol Lung Cell Mol Physiol 278(2):L407-L416
153. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, Schneider JW, Zhang CC, Sadek HA (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7(3):380-390. doi: 10.1016/j.stem.2010.07.011
154. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481(7381):380-384. doi: 10.1038/nature10602
155. Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19(2):285-292. doi: 10.1016/j.cmet.2013.11.022
156. Haigis MC, Guarente LP (2006) Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev 20(21):2913-2921. doi: 10.1101/gad.1467506
157. Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460(7255):587-591. doi: 10.1038/nature08197
158. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434(7029):113-118. doi: 10.1038/nature03354
159. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105(9):3374-3379. doi: 10.1073/pnas.0712145105
160. Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140(2):280-293. doi: 10.1016/j.cell.2009.12.041
161. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC (2011) SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 19(3):416-428. doi: 10.1016/j.ccr.2011.02.014
162. Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, Verdin EM, Kahn CR (2011) Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci USA 108(35):14608-14613. doi: 10.1073/pnas.1111308108
163. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143(5):802-812. doi: 10.1016/j.cell.2010.10.002
164. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12(6):662-667. doi: 10.1016/j.cmet.2010.11.015
165. Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, Zhang D, Scadden DT, Chen D (2013) SIRT3 reverses aging-associated degeneration. Cell Rep 3(2):319-327. doi: 10.1016/j.celrep.2013.01.005
166. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126(5):941-954. doi: 10.1016/j.cell.2006.06.057
167. Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV Jr, Weissman S, Verdin E, Schwer B (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Molecular Cell Biol 27(24):8807-8814. doi: 10.1128/MCB.01636-07
168. Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382(3):790-801. doi: 10.1016/j.jmb.2008.07.048
169. Saharan S, Jhaveri DJ, Bartlett PF (2013) SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus. J Neurosci Res 91(5):642-659. doi: 10.1002/jnr.23199
170. Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, Ninnemann O, Siegert E, Bendix I, Brustle O, Nitsch R, Zipp F, Aktas O (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nature Cell Biol 10(4):385-394. doi: 10.1038/ncb1700
171. Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S, Sato M, Horio Y (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci USA 105(40):15599-15604. doi: 10.1073/pnas.0800612105
172. Rafalski VA, Ho PP, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LM, Ibrahim A, Baker SJ, Barres BA, Steinman L, Brunet A (2013) Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature Cell Biol 15(6):614-624. doi: 10.1038/ncb2735
173. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13(4):225-238. doi: 10.1038/nrm3293
174. Baudino TA, McKay C, Pendeville-Samain H, Nilsson JA, Maclean KH, White EL, Davis AC, Ihle JN, Cleveland JL (2002) c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev 16(19):2530-2543. doi: 10.1101/gad.1024602
175. van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG (2005) MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nature Gene 37(5):465-467. doi: 10.1038/ng1546
176. Hirvonen H, Makela TP, Sandberg M, Kalimo H, Vuorio E, Alitalo K (1990) Expression of the myc proto-oncogenes in developing human fetal brain. Oncogene 5(12):1787-1797
177. Kerosuo L, Piltti K, Fox H, Angers-Loustau A, Hayry V, Eilers M, Sariola H, Wartiovaara K (2008) Myc increases self-renewal in neural progenitor cells through Miz-1. J Cell Sci 121(Pt 23):3941-3950. doi: 10.1242/jcs.024802
178. Knoepfler PS, Cheng PF, Eisenman RN (2002) N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev 16(20):2699-2712. doi: 10.1101/gad.1021202
179. Wey A, Knoepfler PS (2010) c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain. Oncotarget 1(2):120-130
180. Wey A, Martinez Cerdeno V, Pleasure D, Knoepfler PS (2010) c- and N-myc regulate neural precursor cell fate, cell cycle, and metabolism to direct cerebellar development. Cerebellum 9(4):537-547
181. Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, Pasche AC, Knabenhans C, Macdonald HR, Trumpp A (2004) c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18(22):2747-2763. doi: 10.1101/gad.313104
182. Moumen M, Chiche A, Deugnier MA, Petit V, Gandarillas A, Glukhova MA, Faraldo MM (2012) The proto-oncogene Myc is essential for mammary stem cell function. Stem Cells 30(6):1246-1254. doi: 10.1002/stem.1090
183. Zinin N, Adameyko I, Wilhelm M, Fritz N, Uhlen P, Ernfors P, Henriksson MA (2014) MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division. EMBO Rep 15(4):383-391. doi: 10.1002/embr.201337424
184. Dang CV (2013) MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harbor perspectives in medicine 3 (8). doi: 10.1101/cshperspect.a014217
185. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105(48):18782-18787. doi: 10.1073/pnas.0810199105
186. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22-35. doi: 10.1016/j.cell.2012.03.003
187. Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O'Donnell KA, Dang CV (2004) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24(13):5923-5936. doi: 10.1128/MCB.24.13.5923-5936.2004
188. David CJ, Chen M, Assanah M, Canoll P, Manley JL (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463(7279):364-368. doi: 10.1038/nature08697
189. Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS (2013) mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 18(5):726-739. doi: 10.1016/j.cmet.2013.09.013
190. van Lookeren Campagne M, Gill R (1998) Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Waf1/Cip1, p27Kip1, p57Kip2, p16Ink4a, cyclin G1, and the proto-oncogene Bax. J Comp Neurol 397(2):181-198
191. Murase S, Poser SW, Joseph J, McKay RD (2011) p53 controls neuronal death in the CA3 region of the newborn mouse hippocampus. Eur J Neurosci 34(3):374-381. doi: 10.1111/j.1460-9568.2011.07758.x
192. Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133(2):363-369. doi: 10.1242/dev.02208
193. Kippin TE, Martens DJ, van der Kooy D (2005) p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev 19(6):756-767. doi: 10.1101/gad.1272305
194. Forsberg K, Wuttke A, Quadrato G, Chumakov PM, Wizenmann A, Di Giovanni S (2013) The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling. J Neurosci 33(36):14318-14330. doi: 10.1523/JNEUROSCI.1056-13.2013
195. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107-120. doi: 10.1016/j.cell.2006.05.036
196. Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28(19):3015-3026. doi: 10.1038/emboj.2009.242
197. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W (2012) Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149(6):1269-1283. doi: 10.1016/j.cell.2012.04.026
198. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM (2005) The antioxidant function of the p53 tumor suppressor. Nat Med 11(12):1306-1313. doi: 10.1038/nm1320
199. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312(5780):1650-1653. doi: 10.1126/science.1126863
200. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA 107(16):7461-7466. doi: 10.1073/pnas.1002459107
201. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 107(16):7455-7460. doi: 10.1073/pnas.1001006107
202. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW (2001) Regulation of PTEN transcription by p53. Molecular Cell 8(2):317-325
203. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. New Eng J Med 360(8):765-773. doi: 10.1056/NEJMoa0808710
204. Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D, Pieri L, Finke CM, Kilpivaara O, Wadleigh M, Mai M, McClure RF, Gilliland DG, Levine RL, Pardanani A, Vannucchi AM (2010) IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 24(7):1302-1309. doi: 10.1038/leu.2010.113
205. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274):739-744
206. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6):553-567. doi: 10.1016/j.ccr.2010.11.015
207. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, Kaelin WG Jr (2013) (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339(6127):1621-1625. doi: 10.1126/science.1231677
208. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, Kawamura A (2011) The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 12(5):463-469. doi: 10.1038/embor.2011.43
209. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19(1):17-30. doi: 10.1016/j.ccr.2010.12.014
210. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483(7390):474-478. doi: 10.1038/nature10860
211. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zuniga-Pflucker JC, Mak TW (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488(7413):656-659. doi: 10.1038/nature11323
212. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340(6132):626-630. doi: 10.1126/science.1236062
213. Ben-Shaanan TL, Ben-Hur T, Yanai J (2008) Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Mol Psychiatry 13(2):222-231. doi: 10.1038/sj.mp.4002084