Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Feletti, Alberto (2013) The role of mitotic slippage, USP1-regulated apoptosis, and multiple treatments in the action of temozolomide in glioblastoma multiforme. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF
7Mb

Abstract (inglese)

Background. Temozolomide (TMZ) is a methylating drug that is commonly used in the treatment of glioma. Although many features are still unclear, its general mechanism of action is well described. TMZ induces O6-methylguanine (O6MeG) lesions in DNA, which, in the absence of repair by O6-methylguanine methyltransferase (MGMT), mispair with thymine and start a futile cycle of repair-resynthesis events. The resultant DNA double-strand breaks (DSBs) activate the components of G2 checkpoint, and cells with a 4N DNA content accumulate and remain arrested at the G2/M boundary for several days. Cell death subsequently occurs by senescence, necrosis, or mitotic catastrophe, while apoptosis has been ruled out in many studies. Moreover, the effect of multiple TMZ treatments on G2 arrest and apoptosis induction is not clear. Repair of methylating drug-induced DNA lesions requires monoubiquitination of PCNA and FANCD2. Loss of either protein or inhibition of their monoubiquitination increases drug toxicity. USP1 is a hydrolase that removes monoubiquitin from PCNA and FANCD2, and can potentially play a role in TMZ mechanism of action.
Materials and methods. U87, U251 (TMZ-sensitive, low MGMT), and GBM8 (TMZ-resistant, high MGMT) cell lines were used for experiments. The treatment was scheduled with 100μM TMZ for 3 hours for 1, 2, or 3 consecutive days. Cell cycle progression was studied with both FACS-based analysis and a novel time-lapse microscopic real-time analysis using FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator), and apoptosis was measured with FACS-based Annexin V-PI analysis. To address the possible role of USP1 in TMZ action, we examined expression of USP1 at the mRNA levels in expression microarray databases derived from primary GBM. We also used siRNA targeting USP1 to modulate USP1 expression, and studied the effect of USP1 downregulation on TMZ-induced G2 arrest, cell death, and clonogenicity.
Results. Compared to single treatment, multiple TMZ treatments cause a significant reduction of clonogenicity in TMZ-sensitive cells and induce a significant increase of apoptosis, particularly in a late stage. However, multiple treatments don’t have any major effect on cell cycle profile. Time-lapse microscopic analysis with FUCCI system showed that TMZ-sensitive glioma cells arrest at the G2 checkpoint for less than 48 hours and, in the presence of an activated G2 checkpoint, they replicate their DNA without cellular division, re-enter the cell cycle at the next G1 phase, and repeat the cycle, ultimately giving rise to polyploid cells. siRNA-mediated suppression of USP1 had no effect on cell cycle progression or the extent of temozolomide-induced G2 arrest. However, while USP1 knockdown alone had minimal effect on cell death, it increased temozolomide-induced loss of clonagenicity both in TMZ-sensitive and TMZ-resistant cells. Further examination of the mechanism of cell death suggested that while control cells, control cells exposed to TMZ, or USP1-suppressed cells rarely underwent apoptotic cell death, temozolomide-treated cells in which USP1 levels were suppressed underwent high rates of apoptosis.
Conclusions. The present studies show that TMZ can induce apoptosis in TMZ-sensitive glioma cells, which is visible after 3 days but significant after 7 days. Multiple TMZ treatments don’t affect cell cycle profile, but significantly increase apoptosis. Moreover, time-lapse studies suggest a novel mechanism of action for TMZ, alternative to the one commonly accepted. These results have significant implications for the development of TMZ resistance. Furthermore, rather than sensitizing cells to DNA damaging agents, USP1 appears to suppress latent apoptotic pathways and to protect cells from temozolomide-induced apoptosis. These results identify a new function for USP1 and suggest that suppression of USP1 and/or USP1 controlled pathway may be a means to enhance the cytotoxic potential of temozolomide and to sensitize TMZ-resistant GBM cells

Abstract (italiano)

Introduzione. La temozolomide (TMZ) è un farmaco alchilante frequentemente utilizzato nella chemioterapia dei gliomi. Nonostante molti aspetti siano ancora enigmatici, il suo meccanismo di azione generale è ben noto. La TMZ induce metilazione della guanina nel DNA (O6MeG) che, in assenza di riparazione ad opera di O6-methylguanine methyltransferase (MGMT), si appaia con una timina innescando un ciclo futile di riparazione e risintesi. Ne risultano rotture del DNA a doppio filamento (DSBs) che attivano i componenti del checkpoint in G2, e le cellule con DNA 4N si accumulano e arrestano in G2 per parecchi giorni. Le cellule muoiono poi per senescenza, necrosi, o catastrofe mitotica, mentre l’apoptosi è stata a lungo negata. Inoltre non è chiaro l’effetto di somministrazioni multiple di TMZ sull’arresto in G2/M e sull’induzione di apoptosi. La riparazione delle lesioni al DNA causate dai farmaci alchilanti richiede la monoubiquitinazione di PCNA e FANCD2; la perdita di una delle due proteine o l’inibizione della loro monoubiquitinazione potenzia la tossicità indotta dagli agenti metilanti. USP1 è una idrolasi in grado di rimuovere la monoubiquitina da PCNA e FANCD2, e per questo può essere un regolatore della risposta alla TMZ.
Materiali e metodi. Sono state utilizzate le linee cellulari U87, U251 (TMZ-sensibili, bassi livelli di MGMT) e GBM8 (TMZ-resistenti, alti livelli di MGMT). Il protocollo di trattamento prevede 1, 2 o 3 dosi di TMZ 100μM per 3 ore. La progressione nel ciclo cellulare è stata studiata sia con FACS sia con una nuova tecnica di microscopia time-lapse in tempo reale (FUCCI, Fluorescent Ubiquitination-based Cell Cycle Indicator), mentre l’apoptosi è stata verificata al citofluorimetro con il metodo dell’annessina V-Propidio Ioduro. Per verificare il possibile ruolo di USP1 nell’azione della TMZ, dopo aver esaminato su databases di mRNA microarray l’espressione di USP1 nei glioblastomi, le cellule sono state transfettate con RNA a interferenza contro USP1 o di controllo. È quindi stato studiato l’effetto della soppressione dei livelli di USP1 sull’arresto in G2/M, la morte cellulare e la clonogenicità indotte dalla TMZ.
Risultati. Trattamenti multipli con TMZ riducono la clonogenicità delle cellule di glioma sensibili al farmaco in maniera significativamente superiore rispetto al trattamento singolo, non modificano l’entità dell’arresto in G2, mentre inducono un significativo aumento dell’apoptosi in particolare in fase tardiva. L’analisi in time-lapse con il sistema FUCCI ha mostrato che le cellule sensibili alla TMZ subiscono un arresto in G2 inferiore alle 48 ore. Inoltre, in presenza di attivazione del checkpoint in G2, replicano il DNA ma non si dividono, rientrando nel ciclo cellulare in G1 e dando origine a cellule poliploidi. La soppressione dei livelli di USP1 da sola ha effetti minimi sulla progressione del ciclo cellulare e sulla morte cellulare sia nelle cellule sensibili che in quelle resistenti alla TMZ. Allo stesso modo, la soppressione dei livelli di USP1 non altera l’entità dell’arresto in G2/M indotto dalla TMZ. Tuttavia il knockdown di USP1 sorprendentemente incrementa la perdita di clonogenicità indotta dalla TMZ sia nelle cellule sensibili che in quelle resistenti. A differenza delle cellule di controllo in cui USP1 è stato soppresso, o di quelle con normale espressione di USP1 e trattate con TMZ, le cellule USP1-knockdown trattate con TMZ subiscono un’alta percentuale di morte per apoptosi.
Conclusioni. I risultati dei nostri studi hanno mostrato che il trattamento delle cellule di glioma con TMZ può indurre apoptosi, e che questa è evidenziabile già dopo 3 giorni, sebbene diventi significativa solo tardivamente. Trattamenti multipli non modificano l’entità dell’arresto in G2, ma aumentano significativamente l’apoptosi. Inoltre gli studi di time-lapse permettono di proporre un nuovo meccanismo di azione per la TMZ, diverso da quello finora comunemente accettato, con significative implicazioni sullo sviluppo della resistenza al farmaco. La deubiquitinasi USP1, piuttosto che impedire l’attivazione di PCNA e FANCD2 e inibire in questo modo la riparazione del danno al DNA indotto dagli agenti metilanti, come indirettamente suggerito da studi precedenti, sembra invece sopprimere vie apoptotiche latenti e proteggere le cellule dall’apoptosi indotta dalla TMZ. La soppressione di USP1 o delle vie controllate da USP1 può rappresentare un modo per incrementare il potenziale citotossico della TMZ e per sensibilizzare GBM prima resistenti

Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Pegoraro, Elena
Correlatore:Pieper, Russell O.
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:28 Gennaio 2013
Anno di Pubblicazione:28 Gennaio 2013
Informazioni aggiuntive:Ricerca svolta in collaborazione con The Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
Parole chiave (italiano / inglese):Temozolomide / Temozolomide; USP1 / USP1; Apoptosi / Apoptosis; Arresto in G2 / G2 arrest; Ciclo cellulare / Cell cycle; FUCCI / FUCCI; Salto della mitosi / Mitotic slippage; resistenza alla TMZ / TMZ resistance; agenti alchilanti / Methylating agents; Chemioterapia / Chemotherapy; Rottura del doppio filamento del DNA / DNA double strand breaks; Checkpoint in G2 / G2 checkpoint
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/27 Neurochirurgia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:5627
Depositato il:15 Ott 2013 09:25
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1) Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A 1996;93:13629-34. Cerca con Google

2) Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 2004;18:1958-1963. Cerca con Google

3) Bashir T, Pagano M. Don't skip the G1 phase: how APC/CCdh1 keeps SCFSKP2 in check. Cell Cycle. 2004 Jul;3(7):850-2. Cerca con Google

4) Bergink S, Jentsch S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature 2009;458:461-7. Cerca con Google

5) Bignami M, O'Driscoll M, Aquilina G, Karran P. Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating agents. Mutat Res 2000;462:71-82. Cerca con Google

6) Bobola MS, Berger MS, Ellenbogen RG, Roberts TS, Geyer JR, Silber JR. O6-Methylguanine-DNA methyltransferase in pediatric primary brain tumors: relation to patient and tumor characteristics. Clin Cancer Res 2001;7:613-619. Cerca con Google

7) Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 2006;18:185-91. Cerca con Google

8) Brada M, Judson I, Beale P, Moore S, Reidenberg P, Statkevich P, Dugan M, Batra V, Cutler D. Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 1999;81:1022-30. Cerca con Google

9) Bu Y, Yang Z, Li Q, Song F. Silencing of polo-like kinase (Plk) 1 via siRNA causes inhibition of growth and induction of apoptosis in human esophageal cancer cells. Oncology 2008;74:198-206. Cerca con Google

10) Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol 2003;30(Suppl 19):10-14. Cerca con Google

11) Caporali S, Falcinelli S, Starace G, Russo MT, Bonmassar E, Jiricny J, D'Atri S. DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Mol Pharmacol 2004;66:478-91. Cerca con Google

12) Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004;23:2825-37. Cerca con Google

13) Chalmers AJ, Ruff EM, Martindale C, Lovegrove N, Short SC. Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent. Int J Radiat Oncol Biol Phys 2009;75:1511-9. Cerca con Google

14) Chen J, Dexheimer TS, Ai Y, Liang Q, Villamil MA, Inglese J, Maloney DJ, Jadhav A, Simeonov A, Zhuang Z. Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem Biol 2011;18:1390-400. Cerca con Google

15) Chen JM, Zhang YP, Wang C, Sun Y, Fujimoto J, Ikenaga M. O6-methylguanine-DNA methyltransferase activity in human tumors. Carcinogenesis 1992;13:1503-1507. Cerca con Google

16) Chu R, Terrano DT, Chambers TC. Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis by phosphorylation of Mcl-1, promoting its degradation and freeing Bak from sequestration. Biochem Pharmacol 2012;83:199-206. Cerca con Google

17) Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704-710. Cerca con Google

18) Davoli T, de Lange T. The causes and consequences of polyploidy in normal development and cancer. Annu Rev Cell Dev Biol 2011;27:585-610. Cerca con Google

19) Davoli T, Denchi EL, de Lange T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 2010;141:81-93. Cerca con Google

20) De Angelis LM. Brain tumors. N Engl J Med 2001;344:114-123. Cerca con Google

21) De Angelis LM, Loeffler JS, Adam N. Mamelak AN. Primary and Metastatic Brain Tumors. In Pazdur R, Coia LR, Hoskins WJ, and Wagman LD. Cancer Management: A Multidisciplinary Approach, 2007; 10th Edition. Cerca con Google

22) Denny BJ, Wheelhouse RT, Stevens MF, Tsang LL, Slack JA. NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 1994;33:9045-9051. Cerca con Google

23) Dresemann G. Temozolomide in malignant glioma. Onco Targets Ther 2010;3:139-46. Cerca con Google

24) Duckett DR, Drummond JT, Murchie AI, Reardon JT, Sancar A, Lilley DM, Modrich P. Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci U S A 1996;93:6443-7. Cerca con Google

25) Dunkern T, Roos W, Kaina B. Apoptosis induced by MNNG in human TK6 lymphoblastoid cells is p53 and Fas/CD95/Apo-1 related. Mutat Res 2003;544:167-172. Cerca con Google

26) Elder RT, Yu M, Chen M, Zhu X, Yanagida M, Zhao Y. HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25. Virology 2001;287:359-70. Cerca con Google

27) Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793-797. Cerca con Google

28) Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 2001;61:4689-4692. Cerca con Google

29) Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992;69:119-28. Cerca con Google

30) Friedman HS, Dolan ME, Pegg AE, Marcelli S, Keir S, Catino JJ, Bigner DD, Schold SC Jr. Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res 1995;55:2853-7. Cerca con Google

31) Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res 2000;6:2585-97. Cerca con Google

32) Friedman HS, McLendon RE, Kerby T, Dugan M, Bigner SH, Henry AJ, Ashley DM, Krischer J, Lovell S, Rasheed K, Marchev F, Seman AJ, Cokgor I, Rich J, Stewart E, Colvin OM, Provenzale JM, Bigner DD, Haglund MM, Friedman AH, Modrich PL. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998;16:3851-7. Cerca con Google

33) Ganem NJ, Storchova Z, Pellman D. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 2007;17:157-62. Cerca con Google

34) Gene Expression Omnibus: http://www.ncbi.nlm.nih.gov/geo/ Vai! Cerca con Google

35) Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 2002;20:2388-99. Cerca con Google

36) Günther W, Pawlak E, Damasceno R, Arnold H, Terzis AJ. Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids. Br J Cancer 2003;88:463-469. Cerca con Google

37) Guo Z, Kumagai A, Wang SX, Dunphy WG. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev 2000;14:2745-56. Cerca con Google

38) Hampson R, Humbert O, Macpherson P, Aquilina G, Karran P. Mismatch repair defects and O6-methylguanine-DNA methyltransferase expression in acquired resistance to methylating agents in human cells. J Biol Chem 1997;272:28596-28606. Cerca con Google

39) Hibbert RG, Sixma TK. Intrinsic flexibility of ubiquitin on proliferating cell nuclear antigen (PCNA) in translesion synthesis. J Biol Chem 2012;287:39216-23. Cerca con Google

40) Hickman MJ, Samson LD. Apoptotic signaling in response to a single type of DNA lesion, O(6)-methylguanine. Mol Cell 2004;14:105-116. Cerca con Google

41) Hirose Y, Berger MS, Pieper RO. p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 2001;61:1957-1963. Cerca con Google

42) Hirose Y, Berger MS, Pieper RO. Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer Res 2001;61:5843-5849. Cerca con Google

43) Hirose Y, Kreklau EL, Erickson LC, Berger MS, Pieper RO. Delayed repletion of O6-methylguanine-DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity. J Neurosurg 2003;98:591-8. Cerca con Google

44) Houtgraaf JH, Versmissen J, van der Giessen WJ. A concise review of DNA damage checkpoints and repair in mammalian cells. Cardiovasc Revasc Med 2006;7:165-72. Cerca con Google

45) Huang TT, D'Andrea AD. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol 2006;7:323-334. Cerca con Google

46) Hyun SY, Rosen EM, Jang YJ. Novel DNA damage checkpoint in mitosis: Mitotic DNA damage induces re-replication without cell division in various cancer cells. Biochem Biophys Res Commun 2012;423:593-9. Cerca con Google

47) Joshi S, Braithwaite AW, Robinson PJ, Chircop M. Dynamin inhibitors induce caspase-mediated apoptosis following cytokinesis failure in human cancer cells and this is blocked by Bcl-2 overexpression. Mol Cancer 2011;10:78. Cerca con Google

48) Kannouche PL, Wing J, Lehmann AR. Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell 2004;14:491-500. Cerca con Google

49) Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004;11:448-457. Cerca con Google

50) Karran P, Bignami M. DNA damage tolerance, mismatch repair and genome instability. Bioessays 1994;16:833-839. Cerca con Google

51) Karran P, Marinus MG. Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 1982;296:868-9. Cerca con Google

52) Katayama K, Fujita N, Tsuruo T. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol 2005;25:5725-37. Cerca con Google

53) Kennedy RD, D'Andrea AD. The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes Dev 2005;19:2925-2940. Cerca con Google

54) Kim SY, Ferrell JE Jr. Substrate competition as a source of ultrasensitivity in the inactivation of Wee1. Cell 2007;128:1133-45. Cerca con Google

55) Kondo T, Kobayashi M, Tanaka J, Yokoyama A, Suzuki S, Kato N, Onozawa M, Chiba K, Hashino S, Imamura M, Minami Y, Minamino N, Asaka M. Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex. J Biol Chem. 2004 Jun 25;279(26):27315-9. Cerca con Google

56) Lantos PL, VandenBerg SR, Kleihues P. Tumours of the Nervous System. In: Greenfield’s Neuropathology, Graham DI, Lantod PL (eds), 6th ed. Arnold: London. 1996; pp. 583-879. Cerca con Google

57) Lee HJ, Hwang HI, Jang YJ. Mitotic DNA damage response: Polo-like kinase-1 is dephosphorylated through ATM-Chk1 pathway. Cell Cycle 2010;9:2389-98. Cerca con Google

58) Li M, Zhang P. The function of APC/CCdh1 in cell cycle and beyond. Cell Div. 2009 Jan 19;4:2. Cerca con Google

59) Li X, Zhao Q, Liao R, Sun P, Wu X. The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. J Biol Chem. 2003 Aug 15;278(33):30854-8. Cerca con Google

60) Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, Van Tilborg AA, Zwinderman AH, Geerts D, Kaspers GJ, Peter Vandertop W, Cloos J, Tannous BA, Wesseling P, Aten JA, Noske DP, Van Noorden CJ, Würdinger T. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell 2010;18:244-57. Cerca con Google

61) Moldovan GL, D'Andrea AD. How the fanconi anemia pathway guards the genome. Annu Rev Genet 2009;43:223-249. Cerca con Google

62) Murai J, Yang K, Dejsuphong D, Hirota K, Takeda S, D’Andrea AD. The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Mol Cell Biol 2011;31:2462-9. Cerca con Google

63) Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD, Wang ZQ, Jasin M. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc Natl Acad Sci U S A 2005;102:1110-1115. Cerca con Google

64) Natsumeda M, Aoki H, Miyahara H, Yajima N, Uzuka T, Toyoshima Y, Kakita A, Takahashi H, Fujii Y. Induction of autophagy in temozolomide treated malignant gliomas. Neuropathology. 2011 Oct;31(5):486-93. Cerca con Google

65) Neidle S, Thurston DE. Chemical approaches to the discovery and development of cancer therapies. Nat Rev Cancer 2005;5:285-296. Cerca con Google

66) Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 1992;65:287-91. Cerca con Google

67) Niimi A, Brown S, Sabbioneda S, Kannouche PL, Scott A, Yasui A, Green CM, Lehmann AR. Regulation of proliferating cell nuclear antigen ubiquitination in mammalian cells. Proc Natl Acad Sci U S A 2008;105:16125-16130. Cerca con Google

68) Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D'Andrea AD, Bernards R. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 2005;17:331-339. Cerca con Google

69) Nishitani H, Lygerou Z, Nishimoto T. Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region. J Biol Chem 2004;279:30807-16. Cerca con Google

70) Ochs K, Kaina B. Apoptosis induced by DNA damage O6-methylguanine is Bcl-2 and caspase-9/3 regulated and Fas/caspase-8 independent. Cancer Res 2000;60:5815-5824. Cerca con Google

71) O'Connell MJ, Raleigh JM, Verkade HM, Nurse P. Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J 1997;16:545-54. Cerca con Google

72) Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, Ohzeki M, Takata M, Sale JE, Patel KJ. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell 2007;28:798-809. Cerca con Google

73) Oncomine: https://www.oncomine.org/resource/login.html Vai! Cerca con Google

74) Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, García-Lopez JL, Piquer J, Safont MJ, Balaña C, Sanchez-Cespedes M, García-Villanueva M, Arribas L, Esteller M. CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 2004;10:4933-8. Cerca con Google

75) Pegg AE. Repair of O6-alkylguanine by alkyltransferases. Mutat Res 2000;462:83-100. Cerca con Google

76) Pieper RO. Understanding and manipulating O6-methylguanine-DNA methyltransferase expression. Pharmacol Ther 1997;74:285-97. Cerca con Google

77) Plowman J, Waud WR, Koutsoukos AD, Rubinstein LV, Moore TD, Grever MR. Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 1994;54:3793-9. Cerca con Google

78) Preuss I, Eberhagen I, Haas S, Eibl RH, Kaufmann M, von Minckwitz G, Kaina B. O6-methylguanine-DNA methyltransferase activity in breast and brain tumors. Int J Cancer 1995;61:321-326. Cerca con Google

79) Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, Kaina B. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007;26:186-197. Cerca con Google

80) Roos W, Baumgartner M, Kaina B. Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Oncogene 2004;23:359-367. Cerca con Google

81) Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, Kashiwagi S, Fukami K, Miyata T, Miyoshi H, Imamura T, Ogawa M, Masai H, Miyawaki A. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 2008;132:487-498. Cerca con Google

82) Sakaue-Sawano A, Ohtawa K, Hama H, Kawano M, Ogawa M, Miyawaki A. Tracing the silhouette of individual cells in S/G2/M phases with fluorescence. Chem Biol 2008;15:1243-1248. Cerca con Google

83) Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery 2008;62:753-64. Cerca con Google

84) Shan B, Lee WH. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol 1994;14:8166-73. Cerca con Google

85) Shi L, Nishioka WK, Th'ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Science 1994;263:1143-5. Cerca con Google

86) Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS. O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 1999;5:807-814. Cerca con Google

87) Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987;47:5846-52. Cerca con Google

88) Storchova Z, Kuffer C. The consequences of tetraploidy and aneuploidy. J Cell Sci;121(Pt 23):3859-66. Cerca con Google

89) 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. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996. Cerca con Google

90) Suzuki K, Kodama S, Watanabe M. Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. J Biol Chem 1999;274:25571-5. Cerca con Google

91) Tada S. Cdt1 and geminin: role during cell cycle progression and DNA damage in higher eukaryotes. Front Biosci. 2007 Jan 1;12:1629-41. Cerca con Google

92) The Stanford Tissue Microarray Database TMAD: http://tma.stanford.edu Vai! Cerca con Google

93) Thompson DA, Desai MM, Murray AW. Ploidy controls the success of mutators and nature of mutations during budding yeast evolution. Curr Biol 2006;16:1581-90. Cerca con Google

94) Tsang LL, Quarterman CP, Gescher A, Slack JA. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother Pharmacol 1991;27:342-346. Cerca con Google

95) Unsal-Kaçmaz K, Makhov AM, Griffith JD, Sancar A. Preferential binding of ATR protein to UV-damaged DNA. Proc Natl Acad Sci U S A 2002;99:6673-8. Cerca con Google

96) Van Horn RD, Chu S, Fan L, Yin T, Du J, Beckmann R, Mader M, Zhu G, Toth J, Blanchard K, Ye XS. Cdk1 activity is required for mitotic activation of aurora A during G2/M transition of human cells. J Biol Chem 2010;285:21849-57. Cerca con Google

97) van Vugt MA, Brás A, Medema RH. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol Cell 2004;15:799-811. Cerca con Google

98) Villamil MA, Chen J, Liang Q, Zhuang Z. A noncanonical cysteine protease USP1 is activated through active site modulation by USP1-associated factor 1. Biochemistry 2012;51:2829-39. Cerca con Google

99) Vodermaier HC. APC/C and SCF: controlling each other and the cell cycle. Curr Biol 2004;14:R787-96. Cerca con Google

100) Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. Proc Natl Acad Sci U S A 2004;101:4419-24. Cerca con Google

101) Xouri G, Dimaki M, Bastiaens PI, Lygerou Z. Cdt1 interactions in the licensing process: a model for dynamic spatiotemporal control of licensing. Cell Cycle. 2007 Jul 1;6(13):1549-52. Cerca con Google

102) Yamamoto K, Ishiai M, Matsushita N, Arakawa H, Lamerdin JE, Buerstedde JM, Tanimoto M, Harada M, Thompson LH, Takata M. Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells. Mol Cell Biol 2003;23:5421-5430. Cerca con Google

103) Zhu LH, Bi W, Liu XD, Li JF, Wu YY, Du BY, Tan YH. Induction of apoptosis by evodiamine involves both activation of mitotic arrest and mitotic slippage. Oncol Rep 2011;26:1447-55. Cerca con Google

104) Zhuang Z, Johnson RE, Haracska L, Prakash L, Prakash S, Benkovic SJ. Regulation of polymerase exchange between Poleta and Poldelta by monoubiquitination of PCNA and the movement of DNA polymerase holoenzyme. Proc Natl Acad Sci U S A 2008;105:5361-6. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record