Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation

eLife

Volumn 5, Issue MARCH2016, 2016, Pages

  Blake, Sophia M ^a,g   Stricker, Stefan H ^b,h   Halavach, Hanna ^a   Poetsch, Anna R ^a,c,d   Cresswell, George ^a   Kelly, Gavin ^a   Kanu, Nnennaya ^a,b   Marino, Silvia ^e   Luscombe, Nicholas M ^a,c,d   Pollard, Steven M ^b,i   Behrens, Axel ^a,f  

^a THE FRANCIS CRICK INSTITUTE   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d OKINAWA INSTITUTE OF SCIENCE AND TECHNOLOGY GRADUATE UNIVERSITY   (Japan)

^e QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^f KING'S COLLEGE LONDON   (United Kingdom)

^g BOEHRINGER INGELHEIM RCV GMBH AND CO KG   (Austria)

^h INSTITUTE OF EPIDEMIOLOGY   (Germany)

ⁱ UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; PROTEIN P53; ATM PROTEIN, MOUSE; ATMIN PROTEIN, MOUSE; TRANSCRIPTION FACTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CARCINOGENESIS; CELL PROLIFERATION; COPY NUMBER VARIATION; DNA DAMAGE; GENE DELETION; GENE MUTATION; GENETIC TRANSFECTION; GLIOBLASTOMA; HISTOLOGY; HYPOXIA; IMMUNOPRECIPITATION; LUCIFERASE ASSAY; MICROARRAY ANALYSIS; MOUSE; NONHUMAN; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SENSITIVITY ANALYSIS; SIGNAL TRANSDUCTION; WESTERN BLOTTING; ANIMAL; DEFICIENCY; DISEASE MODEL; GENE INACTIVATION; GENETICS; HUMAN; METABOLISM; PATHOLOGY;

ANIMALS; ATAXIA TELANGIECTASIA MUTATED PROTEINS; DISEASE MODELS, ANIMAL; GENE KNOCKOUT TECHNIQUES; GLIOBLASTOMA; HUMANS; MICE; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84961907974     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.08711     Document Type: Article

References (61)

1. Andrae J, Gallini R, Betsholtz C. 2008. Role of platelet-derived growth factors in physiology and medicine. Genes & Development 22:1276–1312. doi: 10.1101/gad.1653708
2. Bakkenist CJ, Kastan MB. 2003. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506. doi: 10.1038/nature01368
3. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A. 1996. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86:159–171. doi: 10.1016/S0092-8674(00)80086-0
4. Bartkova J, Hořejší Z, Koed K, Krämer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Ørntoft T, Lukas J, Bartek J. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–870. doi: 10.1038/nature03482
5. Basu B, Yap TA, Molife LR, de Bono JS. 2012. Targeting the DNA damage response in oncology. Current Opinion in Oncology 24:316–324. doi: 10.1097/CCO.0b013e32835280c6
6. Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NMB, Lau A, Newell DR, Curtin NJ. 2013. Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer. Molecular Cancer Therapeutics 12:959–967. doi: 10.1158/1535-7163.MCT-12-0707
7. Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NCK, Tokarz M, Adams BR, Wagner AF, Khalil A, Gilfor D, Golding SE, Deb S, Temesi DG, Lau A, O’Connor MJ, Choe KS, Parada LF, Lim SK, Mukhopadhyay ND, Valerie K. 2013. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clinical Cancer Research 19:3189–3200. doi: 10.1158/1078-0432.CCR-12-3408
8. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L.TCGA Research Network. 2013. The somatic genomic landscape of glioblastoma. Cell 155: 462–477. doi: 10.1016/j.cell.2013.09.034
9. Cancer Genome Atlas Research Network. 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068. doi: 10.1038/nature07385
10. Chen J, McKay RM, Parada LF. 2012. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47. doi: 10.1016/j.cell.2012.03.009
11. Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying Q-L, Cattaneo E, Smith A. 2005. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biology 3:e283. doi: 10.1371/journal.pbio.0030283
12. Dabney AR. 2006. ClaNC: point-and-click software for classifying microarrays to nearest centroids. Bioinformatics 22:122–123. doi: 10.1093/bioinformatics/bti756
13. Du P, Kibbe WA, Lin SM. 2008. Lumi: a pipeline for processing illumina microarray. Bioinformatics 24:1547–1548. doi: 10.1093/bioinformatics/btn224
14. Engström PG, Tommei D, Stricker SH, Ender C, Pollard SM, Bertone P. 2012. Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival. Genome Medicine 4:76. doi: 10.1186/gm377
15. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK. 2007. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes & Development 21:2683–2710. doi: 10.1101/gad.1596707
16. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JYH, Zhang J. 2004. Bioconductor: open software development for computational biology and bioinformatics. Genome Biology 5:R80. doi: 10.1186/gb-2004-5-10-r80
17. Gilbertson RJ, Rich JN. 2007. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nature Reviews Cancer 7:733–736. doi: 10.1038/nrc2246
18. Goggolidou P, L. Stevens, Agueci F, Keynton J, Wheway G, Grimes DT, Patel SH, Hilton H, Morthorst SK, DiPaolo A, Williams DJ, Sanderson J, Khoronenkova SV, Powles-Glover N, Ermakov A, Esapa CT, Romero R, Dianov GL, Briscoe J, Johnson CA, Pedersen LB, Norris DP. 2014. ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. Development 141:3966–3977. doi: 10.1242/dev.107755
19. Golding SE, Rosenberg E, Adams BR, Wignarajah S, Beckta JM, O’Connor MJ, Valerie K. 2012. Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle 11:1167–1173. doi: 10.4161/cc.11.6.19576
20. Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O’Connor MJ, Povirk LF, van Meter T, Valerie K. 2009. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Molecular Cancer Therapeutics 8:2894–2902. doi: 10.1158/1535-7163.MCT-09-0519
21. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ. 1996. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91. doi: 10.1038/379088a0
22. Hermanson M, Funa K, Koopmann J, Maintz D, Waha A, Westermark B, Heldin CH, Wiestler OD, Louis DN, von Deimling A, Nistér M. 1996. Association of loss of heterozygosity on chromosome 17p with high platelet- derived growth factor alpha receptor expression in human malignant gliomas. Cancer Research 56:164–171.
23. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC. 2004. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Research 64:9152–9159. doi: 10.1158/0008-5472.CAN-04-2727
24. Homsi J, Daud AI. 2007. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control 14:285–294.
25. Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A. 2006. PDGFRa-positive b cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51:187–199. doi: 10.1016/j.neuron.2006.06.012
26. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJM, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF. 2014. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193. doi: 10.1126/science.1239947
27. Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A. 2001. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genetics 29: 418–425. doi: 10.1038/ng747
28. Jurado S, Conlan LA, Baker EK, Ng J-L, Tenis N, Hoch NC, Gleeson K, Smeets M, Izon D, Heierhorst J. 2012a. ATM substrate Chk2-interacting Zn2+ finger (aSCIZ) is a bi-functional transcriptional activator and feedback sensor in the regulation of dynein light chain (dYNLL1) expression. Journal of Biological Chemistry 287:3156–3164. doi: 10.1074/jbc.M111.306019
29. Jurado S, Gleeson K, O’Donnell K, Izon DJ, Walkley CR, Strasser A, Tarlinton DM, Heierhorst J. 2012b. The zinc-finger protein ASCIZ regulates b cell development via DYNLL1 and bim. The Journal of Experimental Medicine 209:1629–1639. doi: 10.1084/jem.20120785
30. Kanu N, Behrens A. 2007. ATMIN defines an NBS1-independent pathway of ATM signalling. The EMBO Journal 26:2933–2941. doi: 10.1038/sj.emboj.7601733
31. Kanu N, Penicud K, Hristova M, Wong B, Irvine E, Plattner F, Raivich G, Behrens A. 2010. The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. Journal of Biological Chemistry 285:38534–38542. doi: 10.1074/jbc.M110.145896
32. Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O’Reilly T, Buchdunger E, Black PM, Stiles CD. 2000. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Research 60:5143–5150.
33. Liu T, Laurell C, Selivanova G, Lundeberg J, Nilsson P, Wiman KG. 2007. Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis. Cell Death and Differentiation 14:411–421. doi: 10.1038/sj.cdd.4402022
34. Locke MEO, Milojevic M, Eitutis ST, Patel N, Wishart AE, Daley M, Hill KA. 2015. Genomic copy number variation in mus musculus. BMC Genomics 16. doi: 10.1186/s12864-015-1713-z
35. Loizou JI, Sancho R, Kanu N, Bolland DJ, Yang F, Rada C, Corcoran AE, Behrens A. 2011. ATMIN is required for maintenance of genomic stability and suppression of b cell lymphoma. Cancer Cell 19:587–600. doi: 10.1016/j.ccr.2011.03.022
36. Lord CJ, Ashworth A. 2012. The DNA damage response and cancer therapy. Nature 481:287–294. doi: 10.1038/nature10760
37. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA. 2001. Malignant glioma: genetics and biology of a grave matter. Genes & Development 15:1311–1333. doi: 10.1101/gad.891601
38. Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJA, Smirnov IV, Reis GF, Phillips JJ, Barnes MJ, Idbaih A, Alentorn A, Kloezeman JJ, Lamfers MLM, Bollen AW, Taylor BS, Molinaro AM, Olshen AB, Chang SM, Song JS, Costello JF. 2015. DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumors. Cancer Cell 28:307–317. doi: 10.1016/j.ccell.2015.07.012
39. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P. 2004. Genetic pathways to glioblastoma: a population-based study. Cancer Research 64:6892–6899. doi: 10.1158/0008-5472.CAN-04-1337
40. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M. 2007. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Human Mutation 28:622–629. doi: 10.1002/humu.20495
41. Pollard SM, Conti L, Sun Y, Goffredo D, Smith A. 2006. Adherent neural stem (nS) cells from fetal and adult forebrain. Cerebral Cortex 16:i112–i120. doi: 10.1093/cercor/bhj167
42. Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, Squire JA, Smith A, Dirks P. 2009. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4:568–580. doi: 10.1016/j.stem.2009.03.014
43. Quinlan AR, Hall IM. 2010. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842. doi: 10.1093/bioinformatics/btq033
44. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS. 2004. Phase II trial of gefitinib in recurrent glioblastoma. Journal of Clinical Oncology 22:133–142. doi: 10.1200/JCO.2004.08.110
45. Sancho R, Blake SM, Tendeng C, Clurman BE, Lewis J, Behrens A. 2013. Fbw7 repression by Hes5 creates a feedback loop that modulates notch-mediated intestinal and neural stem cell fate decisions. PLoS Biology 11: e1001586. doi: 10.1371/journal.pbio.1001586
46. Shiloh Y, Ziv Y. 2013. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology 14:197–210. doi: 10.1038/nrm3546
47. Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC. 2010. Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell 18: 619–629. doi: 10.1016/j.ccr.2010.10.034
48. Stricker SH, Feber A, Engstrom PG, Caren H, Kurian KM, Takashima Y, Watts C, Way M, Dirks P, Bertone P, Smith A, Beck S, Pollard SM. 2013. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes & Development 27:654–669. doi: 10.1101/gad.212662.112
49. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO.European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy GroupsNational Cancer Institute of Canada Clinical Trials Group. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 352:987–996. doi: 10.1056/NEJMoa043330
50. Suvasini R, Shruti B, Thota B, Shinde SV, Friedmann-Morvinski D, Nawaz Z, Prasanna KV, Thennarasu K, Hegde AS, Arivazhagan A, Chandramouli BA, Santosh V, Somasundaram K. 2011. Insulin growth factor-2 binding protein 3 (iGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-Kinase/Mitogen-activated protein kinase (pI3K/MAPK) pathways by modulating IGF-2. Journal of Biological Chemistry 286: 25882–25890. doi: 10.1074/jbc.M110.178012
51. Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schu¨ tz G. 1999. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genetics 23:99–103. doi: 10.1038/12703
52. van de Wiel MA, Kim KI, Vosse SJ, van Wieringen WN, Wilting SM, Ylstra B. 2007. CGHcall: calling aberrations for array CGH tumor profiles. Bioinformatics 23:892–894. doi: 10.1093/bioinformatics/btm030
53. Velimezi G, Liontos M, Vougas K, Roumeliotis T, Bartkova J, Sideridou M, Dereli-Oz A, Kocylowski M, Pateras IS, Evangelou K, Kotsinas A, Orsolic I, Bursac S, Cokaric-Brdovcak M, Zoumpourlis V, Kletsas D, Papafotiou G, Klinakis A, Volarevic S, Gu W, Bartek J, Halazonetis TD, Gorgoulis VG. 2013. Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer. Nature Cell Biology 15:967–977. doi: 10.1038/ncb2795
54. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN. Cancer Genome Atlas Research Network. 2010. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110. doi: 10.1016/j.ccr.2009.12.020
55. Vousden KH, Lane DP. 2007. P53 in health and disease. Nature Reviews Molecular Cell Biology 8:275–283. doi: 10.1038/nrm2147
56. Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, Lee EY-HP, Zhu Y. 2009. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15:514–526. doi: 10.1016/j.ccr.2009.04.001
57. Wen PY, Kesari S. 2008. Malignant gliomas in adults. New England Journal of Medicine 359:492–507. doi: 10.1056/NEJMra0708126
58. Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD. 2006. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: north american brain tumor consortium study 99-08. Clinical Cancer Research 12:4899–4907. doi: 10.1158/1078-0432.CCR-06-0773
59. Westphal CH, Rowan S, Schmaltz C, Elson A, Fisher DE, Leder P. 1997. Atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genetics 16:397–401. doi: 10.1038/ng0897-397
60. Zhang T, Cronshaw J, Kanu N, Snijders AP, Behrens A. 2014. UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function. Proceedings of the National Academy of Sciences of the United States of America 111:12091–12096. doi: 10.1073/pnas.1400230111
61. Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen A-J, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, DePinho RA. 2008. P53 and pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455:1129–1133. doi: 10.1038/nature07443