title: The Arf/p53 protein module, which induces apoptosis, down-regulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs.
abstract: BACKGROUND
  It is unclear how DNA-damaging agents target cancer cells over normal somatic cells.
  
  
  RESULTS
  Arf/p53-dependent down-regulation of H2AX enables normal cells to survive after DNA damage.
  
  
  CONCLUSIONS
  Transformed cells, which harbor mutations in either Arf or p53, are more sensitive to DNA-damaging agents.
  
  
  CONCLUSIONS
  Cellular transformation renders cells more susceptible to some DNA-damaging agents. Anti-cancer drugs generally target cancer cells rather than normal somatic cells. However, the factors that determine this differential sensitivity are poorly understood. Here we show that Arf/p53-dependent down-regulation of H2AX induced the selective survival of normal cells after drug treatment, resulting in the preferential targeting of cancer cells. Treatment with camptothecin, a topoisomerase I inhibitor, caused normal cells to down-regulate H2AX and become quiescent, a process mediated by both Arf and p53. In contrast, transformed cells that harbor mutations in either Arf or p53 do not down-regulate H2AX and are more sensitive to drugs unless they have developed drug resistance. Such transformation-associated changes in H2AX expression rendered cancer cells more susceptible to drug-induced damage (by two orders of magnitude). Thus, the expression of H2AX and γH2AX (phosphorylated form of H2AX at Ser-139) is a critical factor that determines drug sensitivity and should be considered when administering chemotherapy.
authors.affiliation: Division of Genome Stability Research, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Atsumi
authors.forename: Aki
authors.initials: A
authors.lastname: Inase
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Osawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakasai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Teraoka
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Masamoto
authors.initials: M
authors.lastname: Kanno
authors.forename: Fumio
authors.initials: F
authors.lastname: Tashiro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D048430:Cell Shape; D002478:Cells, Cultured; D016922:Cellular Senescence; D002945:Cisplatin / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D002945:Cisplatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004317:Doxorubicin; D006657:Histones; D006918:Hydroxyurea; D010616:Phenanthrenes; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; C417743:Cdkn2a protein, mouse; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C499321:Parp1 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: ARF; Arf/p53 Module; Camptothecin; Cancer Chemotherapy; Cancer Therapy; Cell Biology; DNA Damage Response; H2AX; p53; γH2AX
references.citation: Nat Rev Cancer. 2006 Oct;6(10):789-802
references.pmid: 16990856
references.citation: Nat Rev Mol Cell Biol. 2000 Dec;1(3):179-86
references.pmid: 11252893
references.citation: Nature. 2004 Nov 18;432(7015):307-15
references.pmid: 15549092
references.citation: Nat Struct Mol Biol. 2012 Mar 04;19(4):417-23
references.pmid: 22388737
references.citation: Apoptosis. 2009 Apr;14(4):597-606
references.pmid: 19259822
references.citation: Cancer Res. 2008 Aug 1;68(15):6031-4
references.pmid: 18676821
references.citation: EMBO J. 2006 Mar 22;25(6):1305-14
references.pmid: 16498404
references.citation: Nat Clin Pract Oncol. 2005 Jun;2(6):305-14
references.pmid: 16264988
references.citation: Nature. 2007 Jul 19;448(7151):375-9
references.pmid: 17637672
references.citation: Chem Biol. 2010 May 28;17(5):421-33
references.pmid: 20534341
references.citation: Mol Cell Biol. 2005 Oct;25(20):8925-37
references.pmid: 16199871
references.citation: Nat Rev Cancer. 2012 Mar 22;12(4):237-51
references.pmid: 22437869
references.citation: Nat Rev Cancer. 2008 Dec;8(12):957-67
references.pmid: 19005492
references.citation: J Cell Biol. 1963 May;17:299-313
references.pmid: 13985244
references.citation: Nat Clin Pract Oncol. 2005 Nov;2(11):578-87
references.pmid: 16270098
references.citation: J Clin Oncol. 2003 Dec 1;21(23 Suppl):239s-245s
references.pmid: 14645403
references.citation: Cell Cycle. 2004 Feb;3(2):149-53
references.pmid: 14712078
references.citation: Nat Clin Pract Oncol. 2008 Aug;5(8):455-65
references.pmid: 18542119
references.citation: Cell Death Differ. 2003 Apr;10(4):431-42
references.pmid: 12719720
references.citation: Nature. 2000 Nov 23;408(6811):433-9
references.pmid: 11100718
references.citation: Cell Cycle. 2007 Jan 15;6(2):166-70
references.pmid: 17264673
references.citation: Nucleic Acids Res. 2011 May;39(9):3607-20
references.pmid: 21227924
references.citation: Nat Rev Cancer. 2003 Mar;3(3):155-68
references.pmid: 12612651
references.citation: Crit Rev Oncog. 1998;9(1):83-98
references.pmid: 9754449
references.citation: Toxicol Appl Pharmacol. 2008 Nov 1;232(3):487-97
references.pmid: 18721824
references.citation: Int J Mol Sci. 2012;13(5):6492-506
references.pmid: 22754379
references.citation: Cell. 1997 Nov 28;91(5):649-59
references.pmid: 9393858
references.citation: Nat Rev Cancer. 2007 Aug;7(8):573-84
references.pmid: 17625587
references.citation: Mol Cell. 2006 May 19;22(4):501-10
references.pmid: 16713580
references.citation: Cell. 2012 Jun 8;149(6):1269-83
references.pmid: 22682249
references.citation: Cancer Lett. 2007 Oct 18;256(1):25-8
references.pmid: 17561341
references.citation: PLoS One. 2011;6(8):e23432
references.pmid: 21858116
references.citation: J Biol Chem. 2012 Oct 26;287(44):36777-91
references.pmid: 22961983
references.citation: Cell. 2000 Nov 22;103(5):691-4
references.pmid: 11114324
references.citation: Clin Cancer Res. 2010 Sep 15;16(18):4532-42
references.pmid: 20823146
references.citation: Cell. 2011 May 13;145(4):571-83
references.pmid: 21565614
references.citation: J Cell Biol. 2008 Dec 29;183(7):1203-12
references.pmid: 19103807
references.citation: PLoS One. 2010 Jan 21;5(1):e8821
references.pmid: 20098673
references.citation: Nat Clin Pract Oncol. 2005 Jul;2(7):364-9
references.pmid: 16075796
references.citation: Genes Dev. 2006 Dec 1;20(23):3238-43
references.pmid: 17158742
references.citation: Nucleic Acids Res. 2008 Oct;36(17):5678-94
references.pmid: 18772227
references.citation: EMBO J. 2004 Jul 7;23(13):2674-83
references.pmid: 15201865