电离辐射对食管癌细胞中H2AX、STAT1表达的影响
|
摘要
目的:检测体外培养食管癌细胞中H2AX、STAT1照射前后mRNA及蛋白水平的变化,探讨H2AX、STAT1表达与放射线的时间剂量效应关系,为放射增敏的基因疗法提供理论依据。
方法:(1)在人食管癌细胞株TE1、TE13和Eca109细胞中,采用逆转录-聚合酶链反应(RT-PCR)检测H2AX和STAT1 mRNA表达,免疫组织化学、western blotting和流式细胞技术(FCM)检测H2AX和STAT1蛋白表达;(2)采用克隆形成实验检测TE13和Eca109食管癌细胞的放射敏感性;(3)食管癌细胞株TE13、Eca109在4Gy照射后0-24h及0-10Gy照射后0.5h,应用western blotting检测γ-H2AX和pSTAT1蛋白表达的变化;(4)应用激光共聚焦显微镜检测Eca109食管癌细胞照射后γ-H2AX和pSTAT1斑点形成情况及不同剂量-时间照射后γ-H2AX斑点的动态变化。
结果:(1) TE1、TE13和Eca109这3株食管癌细胞中,H2AX在mRNA水平和蛋白水平上均有表达,3种食管癌细胞之间H2AX的表达未见明显差异(P>0.05)。STAT1在TE13和Eca109食管癌细胞中采用免疫组织化学未检测到,但是应用逆转录-聚合酶链反应(RT-PCR)、western blotting和流式细胞技术(FCM)检测,显示在3种细胞中均有表达,且之间表达无明显差异(P>0.05);(2)克隆形成实验发现TE13和Eca109细胞接种效率分别为54.62 %和67.68 %,D0值分别为2.35Gy和3.04Gy,SF2值分别为0.752和0.796,提示TE13细胞放射敏感性高于Eca109细胞;(3) Western blotting结果显示,食管癌细胞TE13、Eca109中pSTAT1蛋白在0Gy -10Gy照射后0.5h及4Gy照射后0-24h,表达均没有明显变化(P>0.05);(4)Western blotting结果显示,食管癌细胞TE13、Eca109在0Gy -10Gy照射后0.5h,随照射剂量增加,γ-H2AX表达量逐渐增加,各剂量组与对照组比较有显著性统计学差异(p<0.05),γ-H2AX蛋白表达量与照射剂量存在正相关关系,2种食管癌细胞TE13、Eca109的确定系数分别为:0.923、0.957;在4Gy照射后0-24h条件下结果表明照射后0.5h,γ-H2AX表达达到峰值,之后随时间延长γ-H2AX表达逐渐下降,至24h基本达到未照射水平,各剂量组与对照组比较有显著性统计学差异(p<0.05);(5)应用激光共聚焦显微镜检测显示,食管癌细胞Eca109在4Gy照射后5min即有γ-H2AX斑点形成,照射后0.5h达最大值,之后斑点数量逐渐减少,至24h斑点基本消失。在0Gy-10Gy照射后0.5h,随照射剂量增加,γ-H2AX斑点数量逐渐增多;而STAT1在照射后未见核内斑点的形成,顺铂药物处理后可观察到STAT1核内斑点的形成,但电离辐射+顺铂共同处理后核内斑点数量无明显变化。
结论:1、H2AX和STAT1在3种食管癌细胞TE1、TE13及Eca109 mRNA水平和蛋白水平上均有表达;2、Eca109细胞放射抗拒性高于TE13细胞;3、放射线作用后对STAT1蛋白的磷酸化及核内斑点未见影响,经顺铂药物处理后可观察到STAT1核内斑点的形成,但是与放射线联合后斑点数量未见变化;4、γ-H2AX蛋白表达及H2AX核内斑点与放射线存在时间剂量效应关系。
Objective: To observe the expression of STAT1 and H2AX mRNA and protein after irradiated in different type of esophageal cancer cells in vitro, in order to test the dose-effects relationship between ionizing radiation intensity and nuclear foci of the STAT1 and H2AX, for providing a base for changing the radio sensitivity of esophageal caicinoma Toad toxinells by gene therapy.
Methods: (1) In three human esophageal carcinoma cell lines of TE1, TE13 and Eca109, expression of STAT1 and H2AX mRNA were detected with reverse transcriptase-polymerase chain reaction (RT-PCR), expression of STAT1 and H2AX protein were measured with immunohistochemistry assay, western blotting and indirect immuno-fluorescence assay respectively. (2)Radiosensitivity was analysized with clonegentic assay in TE13 and Eca109 esophageal caicinoma cells in vitro. (3) Expression of STAT1 and H2AX protein were detected with western blotting after irradiated in TE13 and Eca109 esophageal caicinoma cells in vitro. (4) The location and quantity with nuclear foci of STAT1 and H2AX were detected with Zeiss fluorescence microscope.
Results: (1)Expression of STAT1 and H2AX in TE1, TE13 and Eca109 cells were observed in level of mRNA and protein, but expression of STAT1 protein were not measured in TE13 and ECA109 with immunohistochemistry assay. (2) D0 value were 2.35Gy and 3.04Gy and SF2 value were 0.752 and 0.796 respectively with clonegenetic assay in TE13 and Eca109 cells, so radiosensitivity is higher in TE13 cells than Eca109 cells. (3)The expression of pSTAT1 protein in TE13 and Eca109 cells were not any changed at 0.5h after irradiated by 0-10Gy, and during 0-24h after irradiated by 4Gy. (4)Level ofγ-H2AX expression was markedly increased at 0.5h after irradiation by 0-10Gy in TE13 and Eca109 cells, and during 0-24h after irradiated by 4Gy. γ-H2AX protein in TE13 and Eca109 cells arrived at peak about 0.5h later, decreased at 1h and recovered to normal level at 24h after radiated by 4Gy. (5) H2AX nuclear foci were clearly present within 5 min after IR. The average number of H2AX-positive foci per cell increased at 0.5h after irradiation by 0-10Gy in TE13 and Eca109 cells, and during 0-24h after irradiated by 4Gy, and peaked 30 min after irradiation. Gradually, the number of H2AX-positive foci decreased to background levels within 24h. The average number of pSTAT1 nuclear foci were not formatted after irradiated, while the pSTAT1 nuclear foci were formatted after treated with cisplatin, but the average number of pSTAT1 nuclear foci was not any changed after irradiation and treated with cisplatin.
Conclusion: (1) Expression of STAT1 and H2AX in different type of esophageal carcinoma cells protein were universally existed in level of mRNA and protein. (2) Radiosensitivity is higher in TE13 cells than Eca109 cells. (3) Irradiation can not affect the expression of STAT1 protein and the number of gene H2AX nuclear foci in esophageal cancer cells. the STAT1 nuclear foci was formatted after treated with cisplatin, but no changes of number of nuclear foci with irradiated. (4) The expression of H2AX protein and the number of gene H2AX nuclear foci have dose-effects relationship between ionizing radiation in esophageal cancer cells.
方法:(1)在人食管癌细胞株TE1、TE13和Eca109细胞中,采用逆转录-聚合酶链反应(RT-PCR)检测H2AX和STAT1 mRNA表达,免疫组织化学、western blotting和流式细胞技术(FCM)检测H2AX和STAT1蛋白表达;(2)采用克隆形成实验检测TE13和Eca109食管癌细胞的放射敏感性;(3)食管癌细胞株TE13、Eca109在4Gy照射后0-24h及0-10Gy照射后0.5h,应用western blotting检测γ-H2AX和pSTAT1蛋白表达的变化;(4)应用激光共聚焦显微镜检测Eca109食管癌细胞照射后γ-H2AX和pSTAT1斑点形成情况及不同剂量-时间照射后γ-H2AX斑点的动态变化。
结果:(1) TE1、TE13和Eca109这3株食管癌细胞中,H2AX在mRNA水平和蛋白水平上均有表达,3种食管癌细胞之间H2AX的表达未见明显差异(P>0.05)。STAT1在TE13和Eca109食管癌细胞中采用免疫组织化学未检测到,但是应用逆转录-聚合酶链反应(RT-PCR)、western blotting和流式细胞技术(FCM)检测,显示在3种细胞中均有表达,且之间表达无明显差异(P>0.05);(2)克隆形成实验发现TE13和Eca109细胞接种效率分别为54.62 %和67.68 %,D0值分别为2.35Gy和3.04Gy,SF2值分别为0.752和0.796,提示TE13细胞放射敏感性高于Eca109细胞;(3) Western blotting结果显示,食管癌细胞TE13、Eca109中pSTAT1蛋白在0Gy -10Gy照射后0.5h及4Gy照射后0-24h,表达均没有明显变化(P>0.05);(4)Western blotting结果显示,食管癌细胞TE13、Eca109在0Gy -10Gy照射后0.5h,随照射剂量增加,γ-H2AX表达量逐渐增加,各剂量组与对照组比较有显著性统计学差异(p<0.05),γ-H2AX蛋白表达量与照射剂量存在正相关关系,2种食管癌细胞TE13、Eca109的确定系数分别为:0.923、0.957;在4Gy照射后0-24h条件下结果表明照射后0.5h,γ-H2AX表达达到峰值,之后随时间延长γ-H2AX表达逐渐下降,至24h基本达到未照射水平,各剂量组与对照组比较有显著性统计学差异(p<0.05);(5)应用激光共聚焦显微镜检测显示,食管癌细胞Eca109在4Gy照射后5min即有γ-H2AX斑点形成,照射后0.5h达最大值,之后斑点数量逐渐减少,至24h斑点基本消失。在0Gy-10Gy照射后0.5h,随照射剂量增加,γ-H2AX斑点数量逐渐增多;而STAT1在照射后未见核内斑点的形成,顺铂药物处理后可观察到STAT1核内斑点的形成,但电离辐射+顺铂共同处理后核内斑点数量无明显变化。
结论:1、H2AX和STAT1在3种食管癌细胞TE1、TE13及Eca109 mRNA水平和蛋白水平上均有表达;2、Eca109细胞放射抗拒性高于TE13细胞;3、放射线作用后对STAT1蛋白的磷酸化及核内斑点未见影响,经顺铂药物处理后可观察到STAT1核内斑点的形成,但是与放射线联合后斑点数量未见变化;4、γ-H2AX蛋白表达及H2AX核内斑点与放射线存在时间剂量效应关系。
Objective: To observe the expression of STAT1 and H2AX mRNA and protein after irradiated in different type of esophageal cancer cells in vitro, in order to test the dose-effects relationship between ionizing radiation intensity and nuclear foci of the STAT1 and H2AX, for providing a base for changing the radio sensitivity of esophageal caicinoma Toad toxinells by gene therapy.
Methods: (1) In three human esophageal carcinoma cell lines of TE1, TE13 and Eca109, expression of STAT1 and H2AX mRNA were detected with reverse transcriptase-polymerase chain reaction (RT-PCR), expression of STAT1 and H2AX protein were measured with immunohistochemistry assay, western blotting and indirect immuno-fluorescence assay respectively. (2)Radiosensitivity was analysized with clonegentic assay in TE13 and Eca109 esophageal caicinoma cells in vitro. (3) Expression of STAT1 and H2AX protein were detected with western blotting after irradiated in TE13 and Eca109 esophageal caicinoma cells in vitro. (4) The location and quantity with nuclear foci of STAT1 and H2AX were detected with Zeiss fluorescence microscope.
Results: (1)Expression of STAT1 and H2AX in TE1, TE13 and Eca109 cells were observed in level of mRNA and protein, but expression of STAT1 protein were not measured in TE13 and ECA109 with immunohistochemistry assay. (2) D0 value were 2.35Gy and 3.04Gy and SF2 value were 0.752 and 0.796 respectively with clonegenetic assay in TE13 and Eca109 cells, so radiosensitivity is higher in TE13 cells than Eca109 cells. (3)The expression of pSTAT1 protein in TE13 and Eca109 cells were not any changed at 0.5h after irradiated by 0-10Gy, and during 0-24h after irradiated by 4Gy. (4)Level ofγ-H2AX expression was markedly increased at 0.5h after irradiation by 0-10Gy in TE13 and Eca109 cells, and during 0-24h after irradiated by 4Gy. γ-H2AX protein in TE13 and Eca109 cells arrived at peak about 0.5h later, decreased at 1h and recovered to normal level at 24h after radiated by 4Gy. (5) H2AX nuclear foci were clearly present within 5 min after IR. The average number of H2AX-positive foci per cell increased at 0.5h after irradiation by 0-10Gy in TE13 and Eca109 cells, and during 0-24h after irradiated by 4Gy, and peaked 30 min after irradiation. Gradually, the number of H2AX-positive foci decreased to background levels within 24h. The average number of pSTAT1 nuclear foci were not formatted after irradiated, while the pSTAT1 nuclear foci were formatted after treated with cisplatin, but the average number of pSTAT1 nuclear foci was not any changed after irradiation and treated with cisplatin.
Conclusion: (1) Expression of STAT1 and H2AX in different type of esophageal carcinoma cells protein were universally existed in level of mRNA and protein. (2) Radiosensitivity is higher in TE13 cells than Eca109 cells. (3) Irradiation can not affect the expression of STAT1 protein and the number of gene H2AX nuclear foci in esophageal cancer cells. the STAT1 nuclear foci was formatted after treated with cisplatin, but no changes of number of nuclear foci with irradiated. (4) The expression of H2AX protein and the number of gene H2AX nuclear foci have dose-effects relationship between ionizing radiation in esophageal cancer cells.
引文
1殷蔚伯.食管癌的放射治疗进展[M].孙燕,赵平.临床肿瘤学进展.北京:中国协和医科大学出版社, 2005:526
2 Brown JM. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies[J], Mol Med Today, 2000, 6(4): 157-162
3 Kastan MB, Bartek J. Cell-cycle checkpoints and cancer[J], Nature , 2004, 432(7015): 316-323
4 Rouse J,Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage, Science, 2002,297(5581):547-551
5 Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on ser-ine 139[J],J Biol Chem, 1998, 273(10): 5858-5868
6 Redon C, Pilch D, Rogakou E, et al. Histone H2A variants H2AX and H2AZ[J], Curr Opin Genet Dev, 2002, 12(2): 162-169
7 WangH, WangM, WangH, et al. Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinaseinhibitors[J], J Cell Physiol, 2005,202(2): 492-502
8 Paull TT, Rogakou EP, Yamazaki V, et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage[J], Curr Biol, 2000, 10 (15): 886-895
9 Ward IM, Chen J. Histone H2AX is phosphorylated in an ATR dependent manner in response to replicational stress[J], J Biol Chem, 2001, 276(51): 47759-47762
10 J.S. Dickey, C.E. Redon, A.J. Nakamura, et al. H2AX: functional roles and potential applications, Chromosoma, 2009,118(6) :683-692.
11 G. Shao, J. Patterson-Fortin, T.E. Messick, et al. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double- strand breaks, Genes Dev, 2009, 23 (6): 740-754
12 B.Wang, K.Hurov, K.Hofmann, et al. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control, Genes Dev, 2009, 23(6): 729-739
13 G.S.Stewart, S.Panier, K.Townsend, et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage, Cell, 2009, 136(3): 420-434
14 Schmitt E, Paquet C, Beauchemin M, et al. DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis[J], J Zhejiang Univ Sci B, 2007, 8(6): 377-397
15 Stewart GS, Wang B, Bignell CR, et al. MDC1 is a mediator of the mammalian DNA damage checkpoint[J], Nature, 2003, 421(6926): 961-966
16 Goldberg M, Stucki M, Falck J, et al. MDC1 is required for the intra- S-phase DNA damage checkpoint[J], Nature,2003,421(6926): 952-956
17 HARTMAN SE, BERTONE P, NATH AK, et al. Global changes in STAT target selection and transcription regulation upon interferon treatments[J], Genes Dev, 2005, 19(24): 2953-2968
18 Shujuan Liang,Haiming Wei,Rui Sun, et al. IFN alpha regulates NK cell cytotoxicity through STAT1 pathway, Cytokine, 2003, 23(6): 190-199
19 Bromber JF,Horvath CM,Wen Z,et a1. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma , Proc Nat Acad Sci USA, 1996, 93(15): 7673-7678
20 YOULYOUZ MARFAK I, GACHARD N, LE CLORENNEC C, et al. Identification of a novel p53 dependent activation pathway of STAT1 by antitumour genotoxic agents [J], Cell Death Differ, 2008, 15 (2): 376-385
21 KIM H S, LEEM S. STAT1 as a key modulator of cell death[J]. Cell Signal, 2007, 19 (3): 454-465
22 Townsend, P.A, Scarbelli, et al. STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis[J], Biol chem., 2004, 279(7): 5811-5820
23 Paul A T, Mark S C, Sean M D, et al. STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage[J], Journal of Cell Science, 2005, 118(8): 1629-1639
24王玉祥,祝淑钗,封巍等. CHK1和CHK2 shRNA转染对食管癌细胞照射后G2期阻滞的影响[J],中华肿瘤杂志, 2006, 28(8): 572-577
25祝淑钗,刘志坤,王玉祥等.电离辐射对食管癌细胞周期及MDC1、53BP1蛋白表达的影响,肿瘤防治研究, 2008, 35(6): 381-385
26 Fernandez-Capetillo O, Chen HT, Celeste I, et al. DNA damage-induced G(2)-M checkpoint activation by histone H2AX and 53BP1, Nat.Cell Biol, 2002, 4(12): 993-997
27 Dimitrova N, de Lange T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev, 2006, 20(23): 3238-3243
28 Peng A, Chen PL. NFBD1, like 53BP1, Is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage, J Biol Chem, 2003, 278(11): 8873-8876
29 Tsuyoshi Ikura, Satoshi Tashiro, Kakino A, et al. DNA Damage- Dependent Acetylation and Ubiquitination of H2AX Enhances Chromatin Dynamics, MOLECULAR AND CELLULAR BIOLOGY, 2007, 27(20): 7028-7040
30 RM Weber-Nordt, C Egen, et al. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus(EBV)-related lymphoma cell lines, Blood, 1996, 88(3): 809-816
31 MacPhail SH, Banath JP, Yu TY, et al. Expression of phosphorylated histone H2AX in cultured cell lines fol-lowing exposure to X-rays [J], Int J Radiat Biol, 2003,79(5): 351-355
32 Duane R Pilch, Olga A Sedelnikova,Christophe Redon, et al. Charact- eristics of gamma-H2AX foci at DNA double-strand breaks sites, Biochem[J], Cell Bio, 2003, 81: 123-129
33 William M Bonner. Low-dose radiation: Thresholds, by stander effects, and adaptive responses[J], PNAS, 2003, 100(9): 4973-4975
34 Liu Shu-Zheng. Nonlinear dose-effect relationship of different parameters in cancer cell lines[J], Critical Reviews in Toxicology, 2005, 35: 595-597
35 Sedelnikova OA,Rogakou EP,Panyutin IG, et al. Quantitative detection of (125) IdU-induced DNA double-strand breaks with gamma H2AX antibody, RadiatRes, 2002, 158(4): 486-492
36 Rothkamn K, Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray dose, Proc Natl Acad Sci USA, 2003, 100(9): 5057-5062
37 Chowdhury D, Keogh M C, Ishii H, et al.γ-H2AX dephosporylation by Protein Phosphatase 2A facilitates DNA double-strand break repair [J], Mol Cell, 2005, 20(5): 801-809
38 Chen HT, Bhandoola A, Difilippantonio MJ, et al. Response to RAG- mediated VDJ cleavage by NBS1 and gamma-H2AX, Science, 2000, 290(5498): 1962-1965
39 Petersen S, Casellas R, Reina-San-Martin B, et al. AID is required to Initiate NBS1/γ-H2AX focus formation and mutations at sites of class Switching, Nature, 2001, 414(6864): 660-665
40 Mahadevaiah SK, Turner JM, Baudat F, et al. Recombinational DNA double-strand breaks in mice precede synapsis, Nat Genet, 2001, 27(3): 271-276
41 Hamer G, Roepers-Gajadien HL, Van Duyn-Goedhart A, et al. DNAdouble-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod, 2003, 68(2): 628-634
42 O.A. Sedelnikova, I.Horikawa, C.Redon, et al. Delayed kinetics of DNA double-strand break processing in normal and pathological aging, Aging Cell, 2008, 7(1): 89-100
43 A.Chebel, S.Bauwens, L.M.Gerland, et al, Telomere uncapping during in vitro T-lymphocyte senescence, Aging Cell, 2009, 8(1): 52-64
44 C.Wang, D.Jurk, M.Maddick, et al. DNA damage response and cellular senescence in tissues of aging mice, Aging Cell, 2009, 8(3): 311-323
45 O.A.Sedelnikova, I.Horikawa, D.B.Zimonjic, et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat Cell Biol, 2004, 6(2): 168-170
46 P.L. Olive. Endogenous DNA breaks:γ-H2AX and the role of telomeres, Aging, 2009, 1(2): 1-3
47 Chen RZ, PetterssonU, Beard C, et al. DNA hypomethylation leads to elevated mutation rates[J], Nature, 1998, 395(6697): 89-93
48崔爽爽,范亚光,孙志娟等,γ-H2AX的辐射剂量效应关系研究,中国辐射卫生, 2010, 19(1): 29-31
49 Gavrilov BA, Firsanov DV, Vezhenkova IV, et al. Detection of phosp -horrylated histone HZAX in differentiated cells after X-ray Irradiation[J], Doklady Biological Sciences, 2007, 414(1): 239-241.
50 TanejaN, DavisM, Choy JS, et al. Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy[J], J Biol Chem, 2004, 279(3): 2273-2280
51 Judit P B, Susan H M, Peggy L O. Radiation sensitivity, H2AX phos -phorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines[J]. Cancer Res, 2004, 64: 7144-7149
52 Yoshida K, Morita T. Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-Off System[J], Cancer Res, 2004, 64 (12): 4131-4136
53 Dmitry K, Susan M M, Judit P B, et al. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays[J], Radiothe Oncol, 2006, 80(2): 223-229
54 W. Bocker, G. Iliakis. Computational Methods for analysis of foci: validation for radiation-induced gamma-H2AX foci in human cells, Radiat. Res, 2006, 165(1): 113-124.
55田梅,潘艳,阮健磊等. 60 Coγ-射线诱导人膀胱癌EJ细胞中磷酸化组蛋白H2AX焦点形成,中国职业医学, 2008, 3(35): 187-190
56任精华,林菊生,刘瑶等.γ-H2AX分析用于检测电离辐射致HepG2细胞DNA双链断裂的研究,中华放射医学与防护杂志, 2007, 27(5): 450-454
57周萍,于琳,赫淑倩等.肝癌细胞γ-H2AX水平与电离辐射敏感性的研究,中华肿瘤防治杂志, 2010, 17(1): 41-44
58孙志娟,范亚光,石大伟等.流式细胞仪检测电离辐射与γ-H2AX剂量效应关系的方法研究,中国工业医学杂志, 2008, 21(6): 364- 367
59 Oscar Fernandez-Capetillo, Alicia Lee, Michel Nussenz-weig, et al. H2AX: the histone guardian of the genome[J], DNA Repair, 2004, 3 (8-9): 959-967
60 Celeste A, Petersen S, Romanienko PJ, et al. Genomic instability in mice lacking histone H2AX[J], Science, 2002, 296(5569): 922-927
61 Celeste A, Difilippantonio S, Difilippantonio MJ, et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility[J], Cell, 2003, 114(3): 371-383
62 Harsha HC, Suresh S, AmanchyR, et al. A manually curated functional annotation of the human X chromosome[J], Nat Genet, 2005, 37(4): 331-332
63 Kao J, Milano M T, Javaheri A, et al.γ-H2AX as a therapeutic target for improving the efficacy of radiation therapy[J], Current Cancer Drug Targets, 2006, 6(3): 197-205
64 Kaneko S, Suzuki N, Koizumi H, et al. Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones, Clin Exp Immunol, 1997,109(1): 185-188
65周钧,钟德许,杨竹林等. STAT1、STAT2、STAT4在原发性肝癌中的表达及意义[J],中华肝胆外科杂志, 2004.10(12): 838-840
66范贤明,张玲,张世波等. STAT1和PCNA在肺癌组织中的表达及其临床意义[J],沪州医学院学报, 2005,28(1): 7-9
67谢庆祥,林吓聪,张闽峰等. STAT1在膀胱癌组织中的表达及临床意义,肿瘤防治研究, 2005,32(7): 78-85
68 KapIan DH, Shankaran V, Dighe AS, et a1.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice, Proc NatI Acad Sci USA, 1998,95(13): 7556-7561
69惠周光,朱晓虹,麦伟源等.氟达拉滨抑制STAT表达对乳头状细胞癌放射敏感性的影响,中华放射肿瘤学杂志, 2008,9(5): 344-348
70 Chang TL, Peng X, Fu XY. J Biol Chem, 2000, 275(14): 102-127
71 HUANG S, BUCANA CD, VAN ARSDALLM, et al. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells[J]. Oncogene, 2002, 21 (16): 2504-2512
72周钧,钟德,华颂文.原发性肝癌中STAT1, STAT2与hMLH1, hMSH2的表达关系,中国普通外科杂志, 2005, 2(14): 100-103
73沈怡, LASSMANN S, HASENBURG A.信号转导和转录活化因子1在上皮性卵巢癌中的表达及其与预后的关系肿瘤,肿瘤, 2009, 29(8): 772-776
74 Paul A, Townsend, Tiziano M, et al. STAT-1 Interacts with p53 to Enhance DNA Damage-induced Apoptosis.THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279(13): 5811-5818
1 FischleW, Wang Y, Allis CD. Histone and chromatin cross-talk [J]. CurrOpin CellBio, 2003, 15(2): 172-183
2 Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on ser-ine 139[J],J Biol Chem, 1998, 273(10): 5858-5868
3 Rothkamm K, Lobrich M. Evidence for a lack of DNA double-strandbreak repair in human cells exposed to very lowX-ray doses[J], Proc NatlAcad Sci USA, 2003, 100(9): 5057-5062
4 Rogakou EP, Nieves-Neira W. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139[J], J Biol Chem, 2000, 275(13): 9390-9395
5 Daniel R, Ramcharan J, Rogakou E, et al. Histone H2AX is phosphorylated at sites of retroviral DNA integration but is dispensable for postintegration repair[J], J Biol Chem, 2004, 279(44): 45810-45814
6 MacPhail SH, Banath JP, Yu TY, et al. Expression of phosphorylated histone H2AX in cultured cell lines following exposure to X-rays[J], Int J Radiat Biol, 2003, 79(5): 351-358
7 Chowdhury D, Keogh M C, Ishii H, et al.γ-H2AX dephosporylation by Protein Phosphatase 2A facilitates DNA double-strand break repair[J], Mol Cell, 2005, 20(5): 801-809
8 Oscar Fernandez-Capetillo, Alicia Lee, Nussenzweig M, et al. H2AX: the histone guardian of the genome[J], DNA Repair, 2004, 3(8-9): 959-967
9 Giacomo Buscem, i Paola Perego, Nives Carenin, et al. Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks[J], Oncogene, 2004, 23(46): 7691-7700
10 Eike Gallmeier, JordanM W inter, Steven C Cunningham, et al. Novel genotoxicity assays identify norethindrone to activate p53 and phosphorylate H2AX[J], Carcinogenesis, 2005, 26 (10): 1811-1820
11 Duane R Pilch, Olga A Sedelnikova, Christophe Redon, et al. Characteristics of gamma-H2AX foci at DNA double-strand breaks sites Biochem[J], CellBio, 2003, 81(3): 123-129
12 William M Bonner. Low-dose radiation: Thresholds, by stander effects, and adaptive responses[J], PNAS, 2003, 100(9): 4973-4975
13 Liu Shu-Zheng. Nonlinear dose-effect relationship of different parameters in cancer cell lines[J], Critical Reviews in Toxicology,2005, 35(6): 595-597
14 Redon C, Pilch D, Rogakou E, et al. Histone H2A variants H2AX and H2AZ[J]. Curr Opin Gene Dev, 2002, 12(2): 162-169
15 Gavrilov BA, Firsanov DV, Vezhenkova IV, et al. Detection of phosphorylated histone HZAX in differentiated cells after X-ray Irradiation[J], Doklady Biological Sciences,2007,414(1):239-241
16 Stewart GS, Wang B, Bignell CR, et al. MDC1 is a mediator of the mammalian DNA damage checkpoint[J], Nature, 2003, 421 (6926): 961-966
17 Lbrich M, Rief N, Kühne M, et al. In vivo formation and repair of DNAdouble-strand breaks after computed tomography examinations [J], PNAS, 2005, 102(25): 8984-8989
18 Rothkamm K, Balroop S, Shekhdar J, et al. Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure[J]. Radiology, 2007, 242 (1):244-251
19崔爽爽,范亚光,孙志娟等,γ-H2AX的辐射剂量效应关系研究,中国辐射卫生, 2010, 19(1): 29-31
20 Qvarnstrom OF, Simonsson M, Johansson KA, et al. DNA double break quantification in skin biopsies[J], Radiother Oncol, 2004, 72(3): 311-317
21 H. Scherthan, L Hieber, Braselmann H, et al. Accumulation of DSBs in c-H2AX domains fuel chromosomal aberrations, Biochemical and Biophysical Research Communications, 2008, 371(4): 694-697
22 Anna Jucha, Aneta Wegierek-Ciuk,Koza Z, et al. FociCounter: A freely available PC programme for quantitative and qualitative analysis of gamma-H2AX foci, Mutation Research, 2010, 696 (1): 16-20
23 Acharya MM, Lan ML, Kan VH, et al. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radical Biology & Medicine, 2010, 49(12): 1846-1855
24 Kai Rothkamm and Simon Horn.γ-H2AX as protein biomarker for radiation exposure, Ann Ist Super Sanita, 2009, 45 (3): 265-271
25田梅,潘艳,阮健磊等.60 Coγ-射线诱导人膀胱癌EJ细胞中磷酸化组蛋白H2AX焦点形成,中国职业医学, 2008, 3(35): 187-190
26任精华,林菊生,刘瑶等.γ-H2AX分析用于检测电离辐射致HepG2细胞DNA双链断裂的研究,中华放射医学与防护杂志, 2007, 27(5): 450-454
27周萍,于琳,赫淑倩等.肝癌细胞γ-H2AX水平与电离辐射敏感性的研究,中华肿瘤防治杂志, 2010 , 17(1): 41-44
28孙志娟,范亚光,石大伟等.流式细胞仪检测电离辐射与γ-H2AX剂量效应关系的方法研究,中国工业医学杂志, 2008, 21(6): 364-367
29于金明,宋现让.放射增敏治疗的靶基因[J].肿瘤防治杂志, 2004, 11(1): 99-102
30 Judit P B, Susan H M, Peggy L O. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines[J], Cancer Res, 2004, 64(19): 7144-7149
31 Yoshida K, Morita T. Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-Off System[J], Cancer Res, 2004, 64(12): 4131-4136
32 Dmitry K, Susan M M, Judit P B, et al. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays[J], Radiothe Oncol, 2006, 80(2): 223-229
33 Olive P L, Banáth J P. Phosphorylation of histone H2AX as a measure of radiosensitivity[J], Int J Radiat Oncol Biol Phys, 2004, 58(2): 331-335
34 TanejaN, DavisM, Choy JS, et al. HistoneH2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy[J]. J BiolChem, 2004, 279(3): 2273-2280
35 Kao J, Milano M T, Javaheri A, et al.γ-H2AX as a therapeutic target for improving the efficacy of radiation therapy[J], Current CancerDrug Targets, 2006, 6(3): 197-205
36 Geng L, Cuneo K C, Fu A, et al. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer[J], Cancer Res, 2006, 66(23): 11298-11304
2 Brown JM. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies[J], Mol Med Today, 2000, 6(4): 157-162
3 Kastan MB, Bartek J. Cell-cycle checkpoints and cancer[J], Nature , 2004, 432(7015): 316-323
4 Rouse J,Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage, Science, 2002,297(5581):547-551
5 Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on ser-ine 139[J],J Biol Chem, 1998, 273(10): 5858-5868
6 Redon C, Pilch D, Rogakou E, et al. Histone H2A variants H2AX and H2AZ[J], Curr Opin Genet Dev, 2002, 12(2): 162-169
7 WangH, WangM, WangH, et al. Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinaseinhibitors[J], J Cell Physiol, 2005,202(2): 492-502
8 Paull TT, Rogakou EP, Yamazaki V, et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage[J], Curr Biol, 2000, 10 (15): 886-895
9 Ward IM, Chen J. Histone H2AX is phosphorylated in an ATR dependent manner in response to replicational stress[J], J Biol Chem, 2001, 276(51): 47759-47762
10 J.S. Dickey, C.E. Redon, A.J. Nakamura, et al. H2AX: functional roles and potential applications, Chromosoma, 2009,118(6) :683-692.
11 G. Shao, J. Patterson-Fortin, T.E. Messick, et al. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double- strand breaks, Genes Dev, 2009, 23 (6): 740-754
12 B.Wang, K.Hurov, K.Hofmann, et al. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control, Genes Dev, 2009, 23(6): 729-739
13 G.S.Stewart, S.Panier, K.Townsend, et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage, Cell, 2009, 136(3): 420-434
14 Schmitt E, Paquet C, Beauchemin M, et al. DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis[J], J Zhejiang Univ Sci B, 2007, 8(6): 377-397
15 Stewart GS, Wang B, Bignell CR, et al. MDC1 is a mediator of the mammalian DNA damage checkpoint[J], Nature, 2003, 421(6926): 961-966
16 Goldberg M, Stucki M, Falck J, et al. MDC1 is required for the intra- S-phase DNA damage checkpoint[J], Nature,2003,421(6926): 952-956
17 HARTMAN SE, BERTONE P, NATH AK, et al. Global changes in STAT target selection and transcription regulation upon interferon treatments[J], Genes Dev, 2005, 19(24): 2953-2968
18 Shujuan Liang,Haiming Wei,Rui Sun, et al. IFN alpha regulates NK cell cytotoxicity through STAT1 pathway, Cytokine, 2003, 23(6): 190-199
19 Bromber JF,Horvath CM,Wen Z,et a1. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma , Proc Nat Acad Sci USA, 1996, 93(15): 7673-7678
20 YOULYOUZ MARFAK I, GACHARD N, LE CLORENNEC C, et al. Identification of a novel p53 dependent activation pathway of STAT1 by antitumour genotoxic agents [J], Cell Death Differ, 2008, 15 (2): 376-385
21 KIM H S, LEEM S. STAT1 as a key modulator of cell death[J]. Cell Signal, 2007, 19 (3): 454-465
22 Townsend, P.A, Scarbelli, et al. STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis[J], Biol chem., 2004, 279(7): 5811-5820
23 Paul A T, Mark S C, Sean M D, et al. STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage[J], Journal of Cell Science, 2005, 118(8): 1629-1639
24王玉祥,祝淑钗,封巍等. CHK1和CHK2 shRNA转染对食管癌细胞照射后G2期阻滞的影响[J],中华肿瘤杂志, 2006, 28(8): 572-577
25祝淑钗,刘志坤,王玉祥等.电离辐射对食管癌细胞周期及MDC1、53BP1蛋白表达的影响,肿瘤防治研究, 2008, 35(6): 381-385
26 Fernandez-Capetillo O, Chen HT, Celeste I, et al. DNA damage-induced G(2)-M checkpoint activation by histone H2AX and 53BP1, Nat.Cell Biol, 2002, 4(12): 993-997
27 Dimitrova N, de Lange T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev, 2006, 20(23): 3238-3243
28 Peng A, Chen PL. NFBD1, like 53BP1, Is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage, J Biol Chem, 2003, 278(11): 8873-8876
29 Tsuyoshi Ikura, Satoshi Tashiro, Kakino A, et al. DNA Damage- Dependent Acetylation and Ubiquitination of H2AX Enhances Chromatin Dynamics, MOLECULAR AND CELLULAR BIOLOGY, 2007, 27(20): 7028-7040
30 RM Weber-Nordt, C Egen, et al. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus(EBV)-related lymphoma cell lines, Blood, 1996, 88(3): 809-816
31 MacPhail SH, Banath JP, Yu TY, et al. Expression of phosphorylated histone H2AX in cultured cell lines fol-lowing exposure to X-rays [J], Int J Radiat Biol, 2003,79(5): 351-355
32 Duane R Pilch, Olga A Sedelnikova,Christophe Redon, et al. Charact- eristics of gamma-H2AX foci at DNA double-strand breaks sites, Biochem[J], Cell Bio, 2003, 81: 123-129
33 William M Bonner. Low-dose radiation: Thresholds, by stander effects, and adaptive responses[J], PNAS, 2003, 100(9): 4973-4975
34 Liu Shu-Zheng. Nonlinear dose-effect relationship of different parameters in cancer cell lines[J], Critical Reviews in Toxicology, 2005, 35: 595-597
35 Sedelnikova OA,Rogakou EP,Panyutin IG, et al. Quantitative detection of (125) IdU-induced DNA double-strand breaks with gamma H2AX antibody, RadiatRes, 2002, 158(4): 486-492
36 Rothkamn K, Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray dose, Proc Natl Acad Sci USA, 2003, 100(9): 5057-5062
37 Chowdhury D, Keogh M C, Ishii H, et al.γ-H2AX dephosporylation by Protein Phosphatase 2A facilitates DNA double-strand break repair [J], Mol Cell, 2005, 20(5): 801-809
38 Chen HT, Bhandoola A, Difilippantonio MJ, et al. Response to RAG- mediated VDJ cleavage by NBS1 and gamma-H2AX, Science, 2000, 290(5498): 1962-1965
39 Petersen S, Casellas R, Reina-San-Martin B, et al. AID is required to Initiate NBS1/γ-H2AX focus formation and mutations at sites of class Switching, Nature, 2001, 414(6864): 660-665
40 Mahadevaiah SK, Turner JM, Baudat F, et al. Recombinational DNA double-strand breaks in mice precede synapsis, Nat Genet, 2001, 27(3): 271-276
41 Hamer G, Roepers-Gajadien HL, Van Duyn-Goedhart A, et al. DNAdouble-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod, 2003, 68(2): 628-634
42 O.A. Sedelnikova, I.Horikawa, C.Redon, et al. Delayed kinetics of DNA double-strand break processing in normal and pathological aging, Aging Cell, 2008, 7(1): 89-100
43 A.Chebel, S.Bauwens, L.M.Gerland, et al, Telomere uncapping during in vitro T-lymphocyte senescence, Aging Cell, 2009, 8(1): 52-64
44 C.Wang, D.Jurk, M.Maddick, et al. DNA damage response and cellular senescence in tissues of aging mice, Aging Cell, 2009, 8(3): 311-323
45 O.A.Sedelnikova, I.Horikawa, D.B.Zimonjic, et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat Cell Biol, 2004, 6(2): 168-170
46 P.L. Olive. Endogenous DNA breaks:γ-H2AX and the role of telomeres, Aging, 2009, 1(2): 1-3
47 Chen RZ, PetterssonU, Beard C, et al. DNA hypomethylation leads to elevated mutation rates[J], Nature, 1998, 395(6697): 89-93
48崔爽爽,范亚光,孙志娟等,γ-H2AX的辐射剂量效应关系研究,中国辐射卫生, 2010, 19(1): 29-31
49 Gavrilov BA, Firsanov DV, Vezhenkova IV, et al. Detection of phosp -horrylated histone HZAX in differentiated cells after X-ray Irradiation[J], Doklady Biological Sciences, 2007, 414(1): 239-241.
50 TanejaN, DavisM, Choy JS, et al. Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy[J], J Biol Chem, 2004, 279(3): 2273-2280
51 Judit P B, Susan H M, Peggy L O. Radiation sensitivity, H2AX phos -phorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines[J]. Cancer Res, 2004, 64: 7144-7149
52 Yoshida K, Morita T. Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-Off System[J], Cancer Res, 2004, 64 (12): 4131-4136
53 Dmitry K, Susan M M, Judit P B, et al. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays[J], Radiothe Oncol, 2006, 80(2): 223-229
54 W. Bocker, G. Iliakis. Computational Methods for analysis of foci: validation for radiation-induced gamma-H2AX foci in human cells, Radiat. Res, 2006, 165(1): 113-124.
55田梅,潘艳,阮健磊等. 60 Coγ-射线诱导人膀胱癌EJ细胞中磷酸化组蛋白H2AX焦点形成,中国职业医学, 2008, 3(35): 187-190
56任精华,林菊生,刘瑶等.γ-H2AX分析用于检测电离辐射致HepG2细胞DNA双链断裂的研究,中华放射医学与防护杂志, 2007, 27(5): 450-454
57周萍,于琳,赫淑倩等.肝癌细胞γ-H2AX水平与电离辐射敏感性的研究,中华肿瘤防治杂志, 2010, 17(1): 41-44
58孙志娟,范亚光,石大伟等.流式细胞仪检测电离辐射与γ-H2AX剂量效应关系的方法研究,中国工业医学杂志, 2008, 21(6): 364- 367
59 Oscar Fernandez-Capetillo, Alicia Lee, Michel Nussenz-weig, et al. H2AX: the histone guardian of the genome[J], DNA Repair, 2004, 3 (8-9): 959-967
60 Celeste A, Petersen S, Romanienko PJ, et al. Genomic instability in mice lacking histone H2AX[J], Science, 2002, 296(5569): 922-927
61 Celeste A, Difilippantonio S, Difilippantonio MJ, et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility[J], Cell, 2003, 114(3): 371-383
62 Harsha HC, Suresh S, AmanchyR, et al. A manually curated functional annotation of the human X chromosome[J], Nat Genet, 2005, 37(4): 331-332
63 Kao J, Milano M T, Javaheri A, et al.γ-H2AX as a therapeutic target for improving the efficacy of radiation therapy[J], Current Cancer Drug Targets, 2006, 6(3): 197-205
64 Kaneko S, Suzuki N, Koizumi H, et al. Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones, Clin Exp Immunol, 1997,109(1): 185-188
65周钧,钟德许,杨竹林等. STAT1、STAT2、STAT4在原发性肝癌中的表达及意义[J],中华肝胆外科杂志, 2004.10(12): 838-840
66范贤明,张玲,张世波等. STAT1和PCNA在肺癌组织中的表达及其临床意义[J],沪州医学院学报, 2005,28(1): 7-9
67谢庆祥,林吓聪,张闽峰等. STAT1在膀胱癌组织中的表达及临床意义,肿瘤防治研究, 2005,32(7): 78-85
68 KapIan DH, Shankaran V, Dighe AS, et a1.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice, Proc NatI Acad Sci USA, 1998,95(13): 7556-7561
69惠周光,朱晓虹,麦伟源等.氟达拉滨抑制STAT表达对乳头状细胞癌放射敏感性的影响,中华放射肿瘤学杂志, 2008,9(5): 344-348
70 Chang TL, Peng X, Fu XY. J Biol Chem, 2000, 275(14): 102-127
71 HUANG S, BUCANA CD, VAN ARSDALLM, et al. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells[J]. Oncogene, 2002, 21 (16): 2504-2512
72周钧,钟德,华颂文.原发性肝癌中STAT1, STAT2与hMLH1, hMSH2的表达关系,中国普通外科杂志, 2005, 2(14): 100-103
73沈怡, LASSMANN S, HASENBURG A.信号转导和转录活化因子1在上皮性卵巢癌中的表达及其与预后的关系肿瘤,肿瘤, 2009, 29(8): 772-776
74 Paul A, Townsend, Tiziano M, et al. STAT-1 Interacts with p53 to Enhance DNA Damage-induced Apoptosis.THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279(13): 5811-5818
1 FischleW, Wang Y, Allis CD. Histone and chromatin cross-talk [J]. CurrOpin CellBio, 2003, 15(2): 172-183
2 Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on ser-ine 139[J],J Biol Chem, 1998, 273(10): 5858-5868
3 Rothkamm K, Lobrich M. Evidence for a lack of DNA double-strandbreak repair in human cells exposed to very lowX-ray doses[J], Proc NatlAcad Sci USA, 2003, 100(9): 5057-5062
4 Rogakou EP, Nieves-Neira W. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139[J], J Biol Chem, 2000, 275(13): 9390-9395
5 Daniel R, Ramcharan J, Rogakou E, et al. Histone H2AX is phosphorylated at sites of retroviral DNA integration but is dispensable for postintegration repair[J], J Biol Chem, 2004, 279(44): 45810-45814
6 MacPhail SH, Banath JP, Yu TY, et al. Expression of phosphorylated histone H2AX in cultured cell lines following exposure to X-rays[J], Int J Radiat Biol, 2003, 79(5): 351-358
7 Chowdhury D, Keogh M C, Ishii H, et al.γ-H2AX dephosporylation by Protein Phosphatase 2A facilitates DNA double-strand break repair[J], Mol Cell, 2005, 20(5): 801-809
8 Oscar Fernandez-Capetillo, Alicia Lee, Nussenzweig M, et al. H2AX: the histone guardian of the genome[J], DNA Repair, 2004, 3(8-9): 959-967
9 Giacomo Buscem, i Paola Perego, Nives Carenin, et al. Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks[J], Oncogene, 2004, 23(46): 7691-7700
10 Eike Gallmeier, JordanM W inter, Steven C Cunningham, et al. Novel genotoxicity assays identify norethindrone to activate p53 and phosphorylate H2AX[J], Carcinogenesis, 2005, 26 (10): 1811-1820
11 Duane R Pilch, Olga A Sedelnikova, Christophe Redon, et al. Characteristics of gamma-H2AX foci at DNA double-strand breaks sites Biochem[J], CellBio, 2003, 81(3): 123-129
12 William M Bonner. Low-dose radiation: Thresholds, by stander effects, and adaptive responses[J], PNAS, 2003, 100(9): 4973-4975
13 Liu Shu-Zheng. Nonlinear dose-effect relationship of different parameters in cancer cell lines[J], Critical Reviews in Toxicology,2005, 35(6): 595-597
14 Redon C, Pilch D, Rogakou E, et al. Histone H2A variants H2AX and H2AZ[J]. Curr Opin Gene Dev, 2002, 12(2): 162-169
15 Gavrilov BA, Firsanov DV, Vezhenkova IV, et al. Detection of phosphorylated histone HZAX in differentiated cells after X-ray Irradiation[J], Doklady Biological Sciences,2007,414(1):239-241
16 Stewart GS, Wang B, Bignell CR, et al. MDC1 is a mediator of the mammalian DNA damage checkpoint[J], Nature, 2003, 421 (6926): 961-966
17 Lbrich M, Rief N, Kühne M, et al. In vivo formation and repair of DNAdouble-strand breaks after computed tomography examinations [J], PNAS, 2005, 102(25): 8984-8989
18 Rothkamm K, Balroop S, Shekhdar J, et al. Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure[J]. Radiology, 2007, 242 (1):244-251
19崔爽爽,范亚光,孙志娟等,γ-H2AX的辐射剂量效应关系研究,中国辐射卫生, 2010, 19(1): 29-31
20 Qvarnstrom OF, Simonsson M, Johansson KA, et al. DNA double break quantification in skin biopsies[J], Radiother Oncol, 2004, 72(3): 311-317
21 H. Scherthan, L Hieber, Braselmann H, et al. Accumulation of DSBs in c-H2AX domains fuel chromosomal aberrations, Biochemical and Biophysical Research Communications, 2008, 371(4): 694-697
22 Anna Jucha, Aneta Wegierek-Ciuk,Koza Z, et al. FociCounter: A freely available PC programme for quantitative and qualitative analysis of gamma-H2AX foci, Mutation Research, 2010, 696 (1): 16-20
23 Acharya MM, Lan ML, Kan VH, et al. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radical Biology & Medicine, 2010, 49(12): 1846-1855
24 Kai Rothkamm and Simon Horn.γ-H2AX as protein biomarker for radiation exposure, Ann Ist Super Sanita, 2009, 45 (3): 265-271
25田梅,潘艳,阮健磊等.60 Coγ-射线诱导人膀胱癌EJ细胞中磷酸化组蛋白H2AX焦点形成,中国职业医学, 2008, 3(35): 187-190
26任精华,林菊生,刘瑶等.γ-H2AX分析用于检测电离辐射致HepG2细胞DNA双链断裂的研究,中华放射医学与防护杂志, 2007, 27(5): 450-454
27周萍,于琳,赫淑倩等.肝癌细胞γ-H2AX水平与电离辐射敏感性的研究,中华肿瘤防治杂志, 2010 , 17(1): 41-44
28孙志娟,范亚光,石大伟等.流式细胞仪检测电离辐射与γ-H2AX剂量效应关系的方法研究,中国工业医学杂志, 2008, 21(6): 364-367
29于金明,宋现让.放射增敏治疗的靶基因[J].肿瘤防治杂志, 2004, 11(1): 99-102
30 Judit P B, Susan H M, Peggy L O. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines[J], Cancer Res, 2004, 64(19): 7144-7149
31 Yoshida K, Morita T. Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-Off System[J], Cancer Res, 2004, 64(12): 4131-4136
32 Dmitry K, Susan M M, Judit P B, et al. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays[J], Radiothe Oncol, 2006, 80(2): 223-229
33 Olive P L, Banáth J P. Phosphorylation of histone H2AX as a measure of radiosensitivity[J], Int J Radiat Oncol Biol Phys, 2004, 58(2): 331-335
34 TanejaN, DavisM, Choy JS, et al. HistoneH2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy[J]. J BiolChem, 2004, 279(3): 2273-2280
35 Kao J, Milano M T, Javaheri A, et al.γ-H2AX as a therapeutic target for improving the efficacy of radiation therapy[J], Current CancerDrug Targets, 2006, 6(3): 197-205
36 Geng L, Cuneo K C, Fu A, et al. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer[J], Cancer Res, 2006, 66(23): 11298-11304