Daxx和E2F1在儿童急性白血病中的表达及其临床意义
摘要
目的:Daxx(death domain associate protein死亡结构域相关蛋白)是一种多功能核蛋白,在细胞凋亡、转录调控、病毒感染等方面发挥重要作用。E2F1( E2 promoter binding factor-1,E2启动子结合因子-1)转录因子,是E2F家族的重要成员,在调节细胞周期进程和调节细胞增殖过程中起关键作用,其过度表达能刺激细胞增殖。本实验通过应用免疫组织化学链霉菌抗生物素蛋白-过氧化物酶连结(streptavidinperosi-dase, SP)方法检测急性白血病患儿骨髓细胞中Daxx和E2F1的表达情况,探讨二者在白血病发病中的作用,为儿童白血病的发生发展机制提供新的思路,为其早期诊断提供理论依据,也为白血病的早期防治提供新靶点。
方法:
1病例及分组:本研究将2008年6月-2009年6月于我院确诊的初诊未治急性白血病患儿40例作为观察组;包括急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)组23例、急性髓细胞性白血病(acute myelocytic leukemia, AML)组17例。ALL组包括L1 3例、L2 20例、无L3病例,其中高危7例,标危16例;AML组包括M2 4例、M3 4例、M4 4例、M53例、M6 1例、M7 1例、无M1病例。另将性别和年龄与观察组相匹配的20例非恶性血液病患儿作为对照组。
2标本采集及处理:分别抽取观察组和对照组每个患儿骨髓液0.2ml,涂片后4℃丙酮固定30分钟,-20℃保存备用,之后应用免疫组化SP法检测Daxx和E2F1的表达。
3统计学分析:应用SPSS13.0统计学软件对所得数据进行卡方检验(或Fisher确切概率法)及相关分析;以P<0.05为差异具有显著性意义
结果:
1 Daxx的表达情况
1.1 Daxx蛋白在观察组患儿中的阳性表达率(40%)明显高于对照组(10%),两者间的差异具有显著性(χ2=5.71,P<0.05)。
1.2 Daxx蛋白在AML组患儿中的阳性表达率(58.8%)高于ALL组(26.1%),两者间的差异具有显著性(χ2=4.365,P<0.05)。
1.3 Daxx在ALL- L1组患儿中的阳性表达率(33.3%)与ALL- L2组(25%)相比,两者间的差异无显著性(P=1, P>0.05)。
1.4 Daxx在ALL高危组的阳性表达率(57.1%)明显高于标危组(12.5%),两者间的差异具有显著性(P=0.045,P<0.05)。Daxx在ALL高危组的阳性表达率与对照组(10%)相比,两者间的差异具有显著性(P=0.024,P<0.05);Daxx在ALL标危组的阳性表达率与对照组相比,两者间的差异无显著性(P=1.0,P>0.05)。
1.5 Daxx在17例AML组各亚型组中的阳性例数依次为3例、3例、2例、2例、0例、0例。阳性率依次为75%、75%、50%、66.67%、0%、0%。因M6、M7各仅有1例且无阳性表达,故将M2、M3、M4、M5各组间进行卡方检验。各组表达水平间差异无显著性(P>0.05)。
1.6 Daxx阳性组的缓解率(56.3%)低于阴性组(91.7%),两者间差异具有显著性意义(P<0.05)。
2 E2F1的表达情况
2.1 E2F1在观察组患儿中的阳性表达率(57.5%)明显高于对照组(20%),两者间的差异具有显著性(χ2=7.576,P<0.05)。
2.2 E2F1在AML组患儿中的阳性表达率(64.7%)与ALL组(52.2%)相比,两者间的差异无显著性(χ2=0.628,P>0.05)。
2.3 E2F1在ALL-L1组患儿中的阳性表达率(33.3%)与ALL-L2组(55%)相比,两者间的差异无显著性(P=0.59, P>0.05)。
2.4 E2F1在ALL高危组的阳性表达率(71.4%)与标危组(56.3%)相比,两者间的差异无显著性(P=0.657,P>0.05)。E2F1在ALL高危组的阳性表达率与对照组(20%)相比,两者间的差异具有显著性(P=0.023,P<0.05)。E2F1在ALL标危组的阳性表达率与对照组相比,两者间的差异具有显著性(χ2=5.063,P<0.05)。
2.5 E2F1在17例AML组在各亚型组中的阳性例数依次为3例、3例、3例、2例、0例、0例。阳性率依次为75%、75%、75%、66.67%、0%、0%。因M6、M7各仅有1例且无阳性表达,故将M2、M3、M4、M5各组间进行卡方检验。各组表达水平间差异无显著性(P>0.05)。
2.6 E2F1阳性组的缓解率(69.6%)低于阴性组(88.2%),两者间差异无显著性(P>0.05)。
3.在观察组患儿中,Daxx与E2F1的表达水平进行相关分析:χ2=14.339,P<0.05,说明二者呈正相关关系。
结论:
1 Daxx和E2F1在儿童急性白血病初诊时为高水平表达,提示它们可以作为急性白血病的一种检测指标。
2 Daxx在AML中的表达水平高于ALL,说明它的表达与AL的分型具有一定相关性。Daxx阴性组在AL中的缓解率高于阳性组,说明Daxx可能成为提示儿童AL临床预后的指标之一。
3实验表明Daxx与E2F1在儿童急性白血病中表达正相关,提示二者在儿童急性白血病的发生发展过程中可能存在某种协同作用。
Objective: Daxx (death domain associate protein), a kind of multifunction nucleoprotein, plays an important part in cell apoptosis, transcriptional control, viral infection and so on. E2F1 (E2 promoter binding factor-1), transcription factor, an important member of E2F family,plays a key point in the proceeding of cell cycle regulation and the process of cell multiplication, and cell multiplication could be stimulated by the over expression of E2F1. In this study we used the method of immunohistochemical streptavidin-perosidase (IHC, SP) to detect the expression of Daxx and E2F1 in bone marrow cell (BMC) of childhood acute leukemia (AL), and research their effect in the process of leukemia. It may provide a new way for childhood acute leukemia’s mechanisms, a theoretical basis for the early diagnosis of AL and new targets for the prevention and treatment of early leukemia.
Methods:
1 Patients and groups: 40 children who were newly diagnosed with acute leukemia were collected in our hospital from June, 2008 to June, 2009, as experiment group. There were 23 patients with acute lymphoblastic leukemia (ALL), which includes 3 cases of L1 and 20 cases of L2 (with no L3 case); and 7 cases of high risk, 16 cases of standard risk. There were 17 patients with acute myeloblastic leukemia (AML) which includes 4 cases of M2 ,4 cases of M3 , 4 cases of M4 ,3 cases of M5 , 1 case of M6 and 1 case of M7 (no M1 case). The control group included 20 cases of non-malignant hematological disease children whose sex and age matched with experiment group.
2 Samples collection and operating sequence: 0.2ml bone marrow were collected from all of the 40 patients with acute leukemia and 20 cases of non-malignant hematological disease children, after film preparation, they were all fixed by acetone of 4℃for 30 minutes, then preserve them in -20℃ for reserve. Daxx and E2F1 were all measured by SP.
3 Statistic analysis: SPSS 13.0 was used to analysis the data. Analysis methods included chi square test (or Fisher exact propability) and correlation analysis.A P value of less than 0.05 was considered as significant.
Results:
1 The expression of Daxx in bone marrow cell
1.1 The positive rate of Daxx protein in 40 acute leukemia patients(40%) was significantly higher than the rate of 20 control cases(10%) (χ2=5.71, P<0.05).
1.2 The positive rate of Daxx protein in 17 AML patients(58.8%) was significantly higher than the rate of ALL cases(26.1%) (χ2=4.365, P<0.05).
1.3 The positive rate of Daxx protein in ALL-L1(33.3%) and in ALL-L2 patients(25%) were basically the same, there was no significant difference between them(P=1,P>0.05).
1.4 The positive rate of Daxx protein in ALL who were high risk(ALL-HR) patients(57.1%) was significantly higher than those standard risk (ALL-SR)cases(12.5%) (P=0.045,P<0.05). The positive rate of Daxx protein in ALL-HR group was significantly higer than the rate of control group(10%) (P=0.024,P<0.05); and the difference between the rate of ALL-SR and control group was no significance (P=1,P>0.05).
1.5 There were 17 patients with acute myeloblastic leukemia (AML). In all of the hypotypes group,Daxx expression cases were 3, 3, 2, 2, 0, 0 in turns. The rate was 75%, 75%, 50%, 66.67%, 0%, 0% in turns. For there was only 1 case in AML-M6 and 1 in AML- M7, make chi square test among the groups of M2, M3, M4, M5. the diference among them was no significance (P>0.05).
1.6 The CR rate of the positive group(56.3%) was lower than the negative group(91.7%). The diference was significant (P<0.05).
2 The expression of E2F1 in bone marrow cell
2.1 The positive rate of E2F1 protein in 40 acute leukemia patients(57.5%) was significantly higher than in 20 control cases(20%) (χ2=7.576, P<0.05).
2.2 The positive rate of E2F1 protein in AML(64.7%) and in ALL patients(52.2%) were basically the same, there was no significant difference between them(P=0.59, P>0.05).
2.3 The positive rate of E2F1 protein in ALL-L1(33.3%) and in ALL-L2 patients(55%) were basically the same, there was no significant difference between them(P=0.59, P>0.05).
2.4 There was no difference between the expression of E2F1 protein in ALL high risk(ALL-HR) patients(71.4%) and those stsndard risk (ALL-SR)cases(56.3%) (P=0.657,P>0.05). The positive rate of E2F1 protein in ALL-HR group and the rate of ALL-SR group were all significantly higer than the rate of control group(20%) (P<0.05).
2.5 There were 17 patients with acute myeloblastic leukemia (AML). In all of the hypotype group,Daxx expression cases were 3, 3, 3, 2, 0, 0 in turns. The rate was 75%, 75%, 75%, 66.67%, 0%, 0% in turns. For there was only 1 case in AML- M6 and 1 in AML- M7, make chi square test among the group of M2, M3, M4, M5. The diference was no significance (P>0.05).
2.6 the CR rate was not significant between the group of negative(69.6%) and positive(88.2%) (P>0.05).
3 In 40 patients with acute leukemia, the expression of Daxx was positive correlated with the expression rate of E2F1,by the method of correlation analysis (χ2=14.339, P <0.05).
Conclusions:
1 High expression level of Daxx and E2F1 in childhood acute leukemia of newly diagnosed, it indicates that they could be used as a detective index.
2 Daxx expression in AML was higher than in ALL, which indicates that Daxx is correlated with the classification of acute leukemia.The remission rate of negative group which expressed Daxx in AL was higher than the positive group. It indicates that Daxx may be an index of clinical prognostic in childhood AL.
3 The experiment shows that Daxx and E2F1 are direct correlation. They were possibily cooperated in the process of childhood acute leukemia genesis and growth.
方法:
1病例及分组:本研究将2008年6月-2009年6月于我院确诊的初诊未治急性白血病患儿40例作为观察组;包括急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)组23例、急性髓细胞性白血病(acute myelocytic leukemia, AML)组17例。ALL组包括L1 3例、L2 20例、无L3病例,其中高危7例,标危16例;AML组包括M2 4例、M3 4例、M4 4例、M53例、M6 1例、M7 1例、无M1病例。另将性别和年龄与观察组相匹配的20例非恶性血液病患儿作为对照组。
2标本采集及处理:分别抽取观察组和对照组每个患儿骨髓液0.2ml,涂片后4℃丙酮固定30分钟,-20℃保存备用,之后应用免疫组化SP法检测Daxx和E2F1的表达。
3统计学分析:应用SPSS13.0统计学软件对所得数据进行卡方检验(或Fisher确切概率法)及相关分析;以P<0.05为差异具有显著性意义
结果:
1 Daxx的表达情况
1.1 Daxx蛋白在观察组患儿中的阳性表达率(40%)明显高于对照组(10%),两者间的差异具有显著性(χ2=5.71,P<0.05)。
1.2 Daxx蛋白在AML组患儿中的阳性表达率(58.8%)高于ALL组(26.1%),两者间的差异具有显著性(χ2=4.365,P<0.05)。
1.3 Daxx在ALL- L1组患儿中的阳性表达率(33.3%)与ALL- L2组(25%)相比,两者间的差异无显著性(P=1, P>0.05)。
1.4 Daxx在ALL高危组的阳性表达率(57.1%)明显高于标危组(12.5%),两者间的差异具有显著性(P=0.045,P<0.05)。Daxx在ALL高危组的阳性表达率与对照组(10%)相比,两者间的差异具有显著性(P=0.024,P<0.05);Daxx在ALL标危组的阳性表达率与对照组相比,两者间的差异无显著性(P=1.0,P>0.05)。
1.5 Daxx在17例AML组各亚型组中的阳性例数依次为3例、3例、2例、2例、0例、0例。阳性率依次为75%、75%、50%、66.67%、0%、0%。因M6、M7各仅有1例且无阳性表达,故将M2、M3、M4、M5各组间进行卡方检验。各组表达水平间差异无显著性(P>0.05)。
1.6 Daxx阳性组的缓解率(56.3%)低于阴性组(91.7%),两者间差异具有显著性意义(P<0.05)。
2 E2F1的表达情况
2.1 E2F1在观察组患儿中的阳性表达率(57.5%)明显高于对照组(20%),两者间的差异具有显著性(χ2=7.576,P<0.05)。
2.2 E2F1在AML组患儿中的阳性表达率(64.7%)与ALL组(52.2%)相比,两者间的差异无显著性(χ2=0.628,P>0.05)。
2.3 E2F1在ALL-L1组患儿中的阳性表达率(33.3%)与ALL-L2组(55%)相比,两者间的差异无显著性(P=0.59, P>0.05)。
2.4 E2F1在ALL高危组的阳性表达率(71.4%)与标危组(56.3%)相比,两者间的差异无显著性(P=0.657,P>0.05)。E2F1在ALL高危组的阳性表达率与对照组(20%)相比,两者间的差异具有显著性(P=0.023,P<0.05)。E2F1在ALL标危组的阳性表达率与对照组相比,两者间的差异具有显著性(χ2=5.063,P<0.05)。
2.5 E2F1在17例AML组在各亚型组中的阳性例数依次为3例、3例、3例、2例、0例、0例。阳性率依次为75%、75%、75%、66.67%、0%、0%。因M6、M7各仅有1例且无阳性表达,故将M2、M3、M4、M5各组间进行卡方检验。各组表达水平间差异无显著性(P>0.05)。
2.6 E2F1阳性组的缓解率(69.6%)低于阴性组(88.2%),两者间差异无显著性(P>0.05)。
3.在观察组患儿中,Daxx与E2F1的表达水平进行相关分析:χ2=14.339,P<0.05,说明二者呈正相关关系。
结论:
1 Daxx和E2F1在儿童急性白血病初诊时为高水平表达,提示它们可以作为急性白血病的一种检测指标。
2 Daxx在AML中的表达水平高于ALL,说明它的表达与AL的分型具有一定相关性。Daxx阴性组在AL中的缓解率高于阳性组,说明Daxx可能成为提示儿童AL临床预后的指标之一。
3实验表明Daxx与E2F1在儿童急性白血病中表达正相关,提示二者在儿童急性白血病的发生发展过程中可能存在某种协同作用。
Objective: Daxx (death domain associate protein), a kind of multifunction nucleoprotein, plays an important part in cell apoptosis, transcriptional control, viral infection and so on. E2F1 (E2 promoter binding factor-1), transcription factor, an important member of E2F family,plays a key point in the proceeding of cell cycle regulation and the process of cell multiplication, and cell multiplication could be stimulated by the over expression of E2F1. In this study we used the method of immunohistochemical streptavidin-perosidase (IHC, SP) to detect the expression of Daxx and E2F1 in bone marrow cell (BMC) of childhood acute leukemia (AL), and research their effect in the process of leukemia. It may provide a new way for childhood acute leukemia’s mechanisms, a theoretical basis for the early diagnosis of AL and new targets for the prevention and treatment of early leukemia.
Methods:
1 Patients and groups: 40 children who were newly diagnosed with acute leukemia were collected in our hospital from June, 2008 to June, 2009, as experiment group. There were 23 patients with acute lymphoblastic leukemia (ALL), which includes 3 cases of L1 and 20 cases of L2 (with no L3 case); and 7 cases of high risk, 16 cases of standard risk. There were 17 patients with acute myeloblastic leukemia (AML) which includes 4 cases of M2 ,4 cases of M3 , 4 cases of M4 ,3 cases of M5 , 1 case of M6 and 1 case of M7 (no M1 case). The control group included 20 cases of non-malignant hematological disease children whose sex and age matched with experiment group.
2 Samples collection and operating sequence: 0.2ml bone marrow were collected from all of the 40 patients with acute leukemia and 20 cases of non-malignant hematological disease children, after film preparation, they were all fixed by acetone of 4℃for 30 minutes, then preserve them in -20℃ for reserve. Daxx and E2F1 were all measured by SP.
3 Statistic analysis: SPSS 13.0 was used to analysis the data. Analysis methods included chi square test (or Fisher exact propability) and correlation analysis.A P value of less than 0.05 was considered as significant.
Results:
1 The expression of Daxx in bone marrow cell
1.1 The positive rate of Daxx protein in 40 acute leukemia patients(40%) was significantly higher than the rate of 20 control cases(10%) (χ2=5.71, P<0.05).
1.2 The positive rate of Daxx protein in 17 AML patients(58.8%) was significantly higher than the rate of ALL cases(26.1%) (χ2=4.365, P<0.05).
1.3 The positive rate of Daxx protein in ALL-L1(33.3%) and in ALL-L2 patients(25%) were basically the same, there was no significant difference between them(P=1,P>0.05).
1.4 The positive rate of Daxx protein in ALL who were high risk(ALL-HR) patients(57.1%) was significantly higher than those standard risk (ALL-SR)cases(12.5%) (P=0.045,P<0.05). The positive rate of Daxx protein in ALL-HR group was significantly higer than the rate of control group(10%) (P=0.024,P<0.05); and the difference between the rate of ALL-SR and control group was no significance (P=1,P>0.05).
1.5 There were 17 patients with acute myeloblastic leukemia (AML). In all of the hypotypes group,Daxx expression cases were 3, 3, 2, 2, 0, 0 in turns. The rate was 75%, 75%, 50%, 66.67%, 0%, 0% in turns. For there was only 1 case in AML-M6 and 1 in AML- M7, make chi square test among the groups of M2, M3, M4, M5. the diference among them was no significance (P>0.05).
1.6 The CR rate of the positive group(56.3%) was lower than the negative group(91.7%). The diference was significant (P<0.05).
2 The expression of E2F1 in bone marrow cell
2.1 The positive rate of E2F1 protein in 40 acute leukemia patients(57.5%) was significantly higher than in 20 control cases(20%) (χ2=7.576, P<0.05).
2.2 The positive rate of E2F1 protein in AML(64.7%) and in ALL patients(52.2%) were basically the same, there was no significant difference between them(P=0.59, P>0.05).
2.3 The positive rate of E2F1 protein in ALL-L1(33.3%) and in ALL-L2 patients(55%) were basically the same, there was no significant difference between them(P=0.59, P>0.05).
2.4 There was no difference between the expression of E2F1 protein in ALL high risk(ALL-HR) patients(71.4%) and those stsndard risk (ALL-SR)cases(56.3%) (P=0.657,P>0.05). The positive rate of E2F1 protein in ALL-HR group and the rate of ALL-SR group were all significantly higer than the rate of control group(20%) (P<0.05).
2.5 There were 17 patients with acute myeloblastic leukemia (AML). In all of the hypotype group,Daxx expression cases were 3, 3, 3, 2, 0, 0 in turns. The rate was 75%, 75%, 75%, 66.67%, 0%, 0% in turns. For there was only 1 case in AML- M6 and 1 in AML- M7, make chi square test among the group of M2, M3, M4, M5. The diference was no significance (P>0.05).
2.6 the CR rate was not significant between the group of negative(69.6%) and positive(88.2%) (P>0.05).
3 In 40 patients with acute leukemia, the expression of Daxx was positive correlated with the expression rate of E2F1,by the method of correlation analysis (χ2=14.339, P <0.05).
Conclusions:
1 High expression level of Daxx and E2F1 in childhood acute leukemia of newly diagnosed, it indicates that they could be used as a detective index.
2 Daxx expression in AML was higher than in ALL, which indicates that Daxx is correlated with the classification of acute leukemia.The remission rate of negative group which expressed Daxx in AL was higher than the positive group. It indicates that Daxx may be an index of clinical prognostic in childhood AL.
3 The experiment shows that Daxx and E2F1 are direct correlation. They were possibily cooperated in the process of childhood acute leukemia genesis and growth.
引文
1胡亚美,江载芳.诸福堂实用儿科学.第7版.北京:人民出版社, 2002:2199
2 Just U, Friel J, Heberlein C, et al. Upregulation of lineage specific receptors and ligands in multipotential progenitor cells is part of an endogenous program of differentiation. Growth Factors, 1993, 9(4): 291-300
3 Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimu- lating factor signaling and neutrophil development in CCAAT enhancer binding proteinα-deficient mice. Proc Natl Acad Sci USA, 1997, 94(2):569-574
4 Slansky JE, Farnham PJ. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol, 1996, 208:1-30
5 Yang X, Khosravi-Far R, Chang H Y, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell, 1997, 89(7):1067-1076
6 Pluta AF, EarnshawWC, Goldberg IG. Interphase-specific association of intrinsic centromere protein CENP-C with HDaxx, a death domain-binding protein implicated in Fas-mediated cell death. Cell Sci, 1998, 111 (14) : 2029-2041
7 Kiriakidou M, Driscoll DA, Lopez-Guisa JM, et al. Cloning and expression of primate Daxx cDNAs and mapping of the human gene to chromosome 6p21.3 in the MHC region. DNA Cell Biol, 1997, 16(11):1289-1298
8 Lin DY, Lai MZ, Ann DK, et al. Promyelocytic leukemia protein(PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. J Biol Chem, 2003, 278(18): 15958-15965
9 Song J J, Lee Y J. Daxx deletion mutant induced apoptpsis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. J Cell Biochem, 2004,92(6):1257-1270
10苏波,万艳平,廖端芳.细胞凋亡通路及转录调控中的Daxx.中国病理生理杂志,2005,21(3):617-620
11 Michaelson JS, Bader D, Kuo F, et al. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev, 1999, 13(15):1918-1923
12唐旭红,何爱桃,万艳平. hDaxx及其删除突变体在真核细胞中的表达与鉴定.南华大学学报:医学版,2002, 30(4):325-327
13 Michaelson JS, Leder P. RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX . J Cell Sci, 2003, 116 (Pt2): 345-352
14刘静,张柳清,胡群等. Daxx蛋白在儿童急性白血病中的表达及其临床意义.中国当代儿科杂志,2007, 9(1): 33-36
15 Villunger A, Huang DC, Holler N, et al. Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX , and Fas-mediated cell death does not involve DAXX, RIP, or RADD. J Immunol, 2000, 165:1337-1343
16邓金牛,李春蕊,刘文励等.去乙酰化酶抑制剂诱导白血病细胞凋亡过程中Daxx的表达变化.中华血液学杂志,2004, 25(5):312-313
17邓金牛,李春蕊,刘文励等. Daxx在恶性血液病中的表达.华中科技大学学报(医学版),2007, 36(6):729-731
18赵治国,郭丽娟,高艳红等.胃癌组织中Daxx和Fas蛋白的表达.郑州大学学报,2008, 43, (4):661-663
19 Ishida S, Huang E, Zuzan H, et al. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol, 2001, 21:4684-4699
20田燕雏,葛炳生,张波等.pRB、E2F1在肺神经内分泌肿瘤中的表达及其临床意义.中华医学杂志,2001, 81(4):219-221
21 Yamasaki L. Balancing proliferation andapoptosis in vivo, the Goldilocks theory of E2F/Dpaction. Biochim Biophys Acta, 1999, 1423(2):M9-15
22 Yasui W, NaKa K, Suzuki T, et al. Expression of P27Kipl, cyclin E and E2F1 in primary and metastatic tumors of gastric carcinoma. Oncol Rep, 1999, 6(5): 983-987
23 Suzuki T, Yasui W, Yokozaki H, et al. Expression of the E2F family in human gastrointestinal carcinomas. Int J Cancer, 1999, 81(4): 535-538
24 Balasubram anian S, Ahamd N, Mukhtar H. Upregulation of E2F transcription factors in chemically induced mouse skin tumors. Int J Oncol, 1999, 15(2):387-390
25 Lai R, Medeiros LJ, Wilson CS, et al. Expression of the cell-elated proteins E2F1, p53, mdm2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. Mod pathol, 1988, 11(7):642-647
26 Rabbani F, Richon VM, Orlow I, et al. Prognostic significance of transcription factor E2F1 in bladder cancer genotypic and phenotypic characterization . J Natl Cancer Inst, 1999, 91(10):874-881
27宋娟,杨玉珍,陈艺丹. E2F1在胃癌中的表达及其与Survivin、P53的相关性.胃肠病学和肝病学杂志,2006,15(6):572
28 Bracken AP, Ciro M, Cocito A, et al. E2F target genes: unraveling the biology. Trends Biochem Sci, 2004, 29(8): 409-417
1 Kiriakidou M, Driscoll DA, Lopez-Guisa JM, et al. Cloning and expression of primate Daxx cDNAs and mapping of the human gene tochromosome 6p21.3 in the MHC region. DNA Cell Biol, 1997, 16(11):1289-1298
2李春蕊,黄伟,刘文励等. Daxx在急性白血病的表达及意义.中国组织化学与细胞化学杂志,2005,14(6): 618-622
3 Alkan S, Huang Q, Ergin M, et al. Survival role of protein kinase C(PKC) in chronic lymphocttic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. Am J Hematol, 2005,79(2):97-106
4邓金牛,李春蕊,刘文励等. Daxx在恶性血液病中的表达.华中科技大学学报(医学版),2007, 36(6):729-731
5 Santiago A, Godsey AC, Hossain J, et al. Identification of two independent SUMO-interacting motifs in Daxx: evolutionary conservation from Drosophila to humans and their biochemical functions. Cell Cycle, 2009, 8(1): 76-87
6 Yeung PL, Chen LY, Tsai SC, et al. Daxx contains two nuclear localization signals and interacts with importin alpha3. J Cell Biochem, 2008,103(2): 456-470
7 Song JJ, Lee YJ. Tryptophan 621 and serine 667 residues of Daxx regulate its nuclear export during glucose deprivation. J Biol, Chem, 2004, 279 (29): 30573-30578
8 Jung YS, Kim HY, Lee YJ, et al. Subcellular localization of Daxx determines its opposing functions in ischemic cell death. FEBS Lett, 2007, 581(5): 843-852
9 Yang X, Khosravi-Far R, Chang HY, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell, 1997, 89 (7):1067-1076
10 Khelifi AF, D’Alcontres MS, Salomoni P. Daxx is required for stress-induced cell death and JNK activation. Cell Death Differ, 2005, 12(7): 724-733
11 Song JJ, Lee YJ. Daxx deletion mutant induced apoptpsis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. J Cell Biochem, 2004, 92(6):1257-1270
12 Croxton R, Puto LA, Belle ID , et al. Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor- B. Cancer Res 2006, 66: 9026-9035
13 Boehrer S, Nowak D, Hochmuth S, et al. Daxx overexpression in T-lymphoblastic Jurkat cells enhances caspase-dependent death receptor and drug-induced apoptosis in distinctways. Cell Signal, 2005, 17(5): 581-595
14 Michaelson JS, Bader D, Kno F, et al. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev, 1999, 13(15):1918-1923
15 Chen LY, Chen JD. Daxx silencing sensitizes cells to multiple apoptotic pathways. Mol Cell Biol, 2003, 23(20): 7108-7121
16唐旭红,何爱桃,万艳平. hDaxx及其删除突变体在真核细胞中的表达与鉴定.南华大学学报:医学版,2002, 30(4):325-327
17 Maul GG, Negorev D, Bell P, et al. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J Struct Bio, 2000, 129(2-3): 278-287
18 Charette SJ, Lavoie JN, Lambert H, et al. Inhibition of Daxx-Mediated apoptosis by heart shock protein 27. Mol Cell Biol, 2000, 20(20):7602-7612
19李金丽,万艳平. Daxx研究进展.医学分子生物学杂志, 2006, 3(2): 139-142
20 Hollenbach AD, McPherson CJ, Mientjes EJ, et al. Daxx and histone deacetylaseⅡassociate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J Cell Sci, 2002, 115(Pt 16);3319-3330
21 Emelyanov AV, Kovac CR, Sepulveda MA, et al. The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells. J Biol Chem, 2002, 277(13): 11156-11164
22 Roubille F, Combes S, Leal-Sanchez J, et al. Myocardial expression of a dominant-negative form of daxx decreases infarct size and attenuatesapoptosis in vivo mouse model of ischemical/reperfusion injury. Circulation, 2007, 116: 2709-2717
23 Jung YS, Kim HY, Kim J, et al. Physical interactions and functional coupling between daxx and sodium hydrogen exchanger 1 in ischemic cell death. J Biol Chem, 2008, 283(2): 1018-1025
24沈勤,王芳. P14ARF、E2F1对结直肠癌发生发展的影响.现代肿瘤医学, 2009, 17(7):1391-1393
25陈良友,陆国乎.转录因子E2F与血管再狭窄的研究进展.中西医结合心脑血管疾病杂志,2005, 3(2): 153-155
26 Ho A, Dowdy SF, Regulation of G1cell-cycle progression by oncogenes and tumor suppressor genes. Curr Opin Genel Dev, 2002, 12(1): 47-52
27 Slansky JE, Farnham PJ. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol, 1996, 208:1-30
28 Giovanni A , Brugger FW, Keramaris E , et al. Involvement of cell cycle elements , cyclin-dependent kinases , pRb , and E2F·DP , in B-amyloid- induced neuronal death. J Biol Chem, 1999, 27(274):19011 - 19016
29 Canepa ET, Scassa ME, Ceruti JM, et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IMBMB Life, 2007, 59(7): 419-426
30王宏坤,梁建芳,郑绘霞等.胃肠道间质肿瘤中E2F1和p16INK4α蛋白的表达与预后的关系.山西医科大学学报,2007,38(10):882-885
31 Degregori J, Leone G Miron A, et al. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Nartl Acad Sci USA, 1997, 94(14): 7245-7250
32 Almasan A, Yin Y, Kelly RE, et al. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Nartl Acad Sci USA, 1995, 92(12): 5436-5440
33 Shan B, Durfee T, Lee WH. Disruption of RB/E2F interaction by single point mutations in E2F1 enhances S-phase entry and apoptosis. Proc Nartl Acad Sci USA, 1996, 93(2): 679-684
34郭丽娟,高艳红,赵治国. Daxx蛋白在胃癌组织中的表达及意义.河南医学研究,2007,16(4): 314-316
35喻红霞,胡建达,陈鑫基等. Daxx基因在急性淋巴细胞白血病中表达的初步研究.白血病·淋巴瘤, 2005,14(2):99-100
36刘静,张柳清,胡群等. Daxx蛋白在儿童急性白血病中的表达及其临床意义.中国当代儿科杂志,2007, 9(1): 33-36
37 Li Q, Boyer C, Lee J, et al. A novel approach to thymidylate synthase as a target for cancer chemotherapy. Mol Phar, 2001, 59(3): 446-452
38鲍伟民,张荣,周范民等.胶质瘤中E2F1、MDM2的表达及其与肿瘤恶性程度的关系.中华神经医学杂志,2006, 5(4): 390-393
39 Yasui W, NaKa K, Suzuki T, et al. Expression of P27 Kipl, cyclin E and E2F1 in primary and metastatic tumors of gastric carcinoma. Oncol Rep, 1999, 6(5): 983-987
40 Lai R, Medeiros LJ, Wilson CS, et al. Expression of the cell-elated proteins E2F1, p53, mdm2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. Mod pathol, 1988, 11(7):642-647
2 Just U, Friel J, Heberlein C, et al. Upregulation of lineage specific receptors and ligands in multipotential progenitor cells is part of an endogenous program of differentiation. Growth Factors, 1993, 9(4): 291-300
3 Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimu- lating factor signaling and neutrophil development in CCAAT enhancer binding proteinα-deficient mice. Proc Natl Acad Sci USA, 1997, 94(2):569-574
4 Slansky JE, Farnham PJ. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol, 1996, 208:1-30
5 Yang X, Khosravi-Far R, Chang H Y, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell, 1997, 89(7):1067-1076
6 Pluta AF, EarnshawWC, Goldberg IG. Interphase-specific association of intrinsic centromere protein CENP-C with HDaxx, a death domain-binding protein implicated in Fas-mediated cell death. Cell Sci, 1998, 111 (14) : 2029-2041
7 Kiriakidou M, Driscoll DA, Lopez-Guisa JM, et al. Cloning and expression of primate Daxx cDNAs and mapping of the human gene to chromosome 6p21.3 in the MHC region. DNA Cell Biol, 1997, 16(11):1289-1298
8 Lin DY, Lai MZ, Ann DK, et al. Promyelocytic leukemia protein(PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. J Biol Chem, 2003, 278(18): 15958-15965
9 Song J J, Lee Y J. Daxx deletion mutant induced apoptpsis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. J Cell Biochem, 2004,92(6):1257-1270
10苏波,万艳平,廖端芳.细胞凋亡通路及转录调控中的Daxx.中国病理生理杂志,2005,21(3):617-620
11 Michaelson JS, Bader D, Kuo F, et al. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev, 1999, 13(15):1918-1923
12唐旭红,何爱桃,万艳平. hDaxx及其删除突变体在真核细胞中的表达与鉴定.南华大学学报:医学版,2002, 30(4):325-327
13 Michaelson JS, Leder P. RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX . J Cell Sci, 2003, 116 (Pt2): 345-352
14刘静,张柳清,胡群等. Daxx蛋白在儿童急性白血病中的表达及其临床意义.中国当代儿科杂志,2007, 9(1): 33-36
15 Villunger A, Huang DC, Holler N, et al. Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX , and Fas-mediated cell death does not involve DAXX, RIP, or RADD. J Immunol, 2000, 165:1337-1343
16邓金牛,李春蕊,刘文励等.去乙酰化酶抑制剂诱导白血病细胞凋亡过程中Daxx的表达变化.中华血液学杂志,2004, 25(5):312-313
17邓金牛,李春蕊,刘文励等. Daxx在恶性血液病中的表达.华中科技大学学报(医学版),2007, 36(6):729-731
18赵治国,郭丽娟,高艳红等.胃癌组织中Daxx和Fas蛋白的表达.郑州大学学报,2008, 43, (4):661-663
19 Ishida S, Huang E, Zuzan H, et al. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol, 2001, 21:4684-4699
20田燕雏,葛炳生,张波等.pRB、E2F1在肺神经内分泌肿瘤中的表达及其临床意义.中华医学杂志,2001, 81(4):219-221
21 Yamasaki L. Balancing proliferation andapoptosis in vivo, the Goldilocks theory of E2F/Dpaction. Biochim Biophys Acta, 1999, 1423(2):M9-15
22 Yasui W, NaKa K, Suzuki T, et al. Expression of P27Kipl, cyclin E and E2F1 in primary and metastatic tumors of gastric carcinoma. Oncol Rep, 1999, 6(5): 983-987
23 Suzuki T, Yasui W, Yokozaki H, et al. Expression of the E2F family in human gastrointestinal carcinomas. Int J Cancer, 1999, 81(4): 535-538
24 Balasubram anian S, Ahamd N, Mukhtar H. Upregulation of E2F transcription factors in chemically induced mouse skin tumors. Int J Oncol, 1999, 15(2):387-390
25 Lai R, Medeiros LJ, Wilson CS, et al. Expression of the cell-elated proteins E2F1, p53, mdm2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. Mod pathol, 1988, 11(7):642-647
26 Rabbani F, Richon VM, Orlow I, et al. Prognostic significance of transcription factor E2F1 in bladder cancer genotypic and phenotypic characterization . J Natl Cancer Inst, 1999, 91(10):874-881
27宋娟,杨玉珍,陈艺丹. E2F1在胃癌中的表达及其与Survivin、P53的相关性.胃肠病学和肝病学杂志,2006,15(6):572
28 Bracken AP, Ciro M, Cocito A, et al. E2F target genes: unraveling the biology. Trends Biochem Sci, 2004, 29(8): 409-417
1 Kiriakidou M, Driscoll DA, Lopez-Guisa JM, et al. Cloning and expression of primate Daxx cDNAs and mapping of the human gene tochromosome 6p21.3 in the MHC region. DNA Cell Biol, 1997, 16(11):1289-1298
2李春蕊,黄伟,刘文励等. Daxx在急性白血病的表达及意义.中国组织化学与细胞化学杂志,2005,14(6): 618-622
3 Alkan S, Huang Q, Ergin M, et al. Survival role of protein kinase C(PKC) in chronic lymphocttic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. Am J Hematol, 2005,79(2):97-106
4邓金牛,李春蕊,刘文励等. Daxx在恶性血液病中的表达.华中科技大学学报(医学版),2007, 36(6):729-731
5 Santiago A, Godsey AC, Hossain J, et al. Identification of two independent SUMO-interacting motifs in Daxx: evolutionary conservation from Drosophila to humans and their biochemical functions. Cell Cycle, 2009, 8(1): 76-87
6 Yeung PL, Chen LY, Tsai SC, et al. Daxx contains two nuclear localization signals and interacts with importin alpha3. J Cell Biochem, 2008,103(2): 456-470
7 Song JJ, Lee YJ. Tryptophan 621 and serine 667 residues of Daxx regulate its nuclear export during glucose deprivation. J Biol, Chem, 2004, 279 (29): 30573-30578
8 Jung YS, Kim HY, Lee YJ, et al. Subcellular localization of Daxx determines its opposing functions in ischemic cell death. FEBS Lett, 2007, 581(5): 843-852
9 Yang X, Khosravi-Far R, Chang HY, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell, 1997, 89 (7):1067-1076
10 Khelifi AF, D’Alcontres MS, Salomoni P. Daxx is required for stress-induced cell death and JNK activation. Cell Death Differ, 2005, 12(7): 724-733
11 Song JJ, Lee YJ. Daxx deletion mutant induced apoptpsis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. J Cell Biochem, 2004, 92(6):1257-1270
12 Croxton R, Puto LA, Belle ID , et al. Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor- B. Cancer Res 2006, 66: 9026-9035
13 Boehrer S, Nowak D, Hochmuth S, et al. Daxx overexpression in T-lymphoblastic Jurkat cells enhances caspase-dependent death receptor and drug-induced apoptosis in distinctways. Cell Signal, 2005, 17(5): 581-595
14 Michaelson JS, Bader D, Kno F, et al. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev, 1999, 13(15):1918-1923
15 Chen LY, Chen JD. Daxx silencing sensitizes cells to multiple apoptotic pathways. Mol Cell Biol, 2003, 23(20): 7108-7121
16唐旭红,何爱桃,万艳平. hDaxx及其删除突变体在真核细胞中的表达与鉴定.南华大学学报:医学版,2002, 30(4):325-327
17 Maul GG, Negorev D, Bell P, et al. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J Struct Bio, 2000, 129(2-3): 278-287
18 Charette SJ, Lavoie JN, Lambert H, et al. Inhibition of Daxx-Mediated apoptosis by heart shock protein 27. Mol Cell Biol, 2000, 20(20):7602-7612
19李金丽,万艳平. Daxx研究进展.医学分子生物学杂志, 2006, 3(2): 139-142
20 Hollenbach AD, McPherson CJ, Mientjes EJ, et al. Daxx and histone deacetylaseⅡassociate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J Cell Sci, 2002, 115(Pt 16);3319-3330
21 Emelyanov AV, Kovac CR, Sepulveda MA, et al. The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells. J Biol Chem, 2002, 277(13): 11156-11164
22 Roubille F, Combes S, Leal-Sanchez J, et al. Myocardial expression of a dominant-negative form of daxx decreases infarct size and attenuatesapoptosis in vivo mouse model of ischemical/reperfusion injury. Circulation, 2007, 116: 2709-2717
23 Jung YS, Kim HY, Kim J, et al. Physical interactions and functional coupling between daxx and sodium hydrogen exchanger 1 in ischemic cell death. J Biol Chem, 2008, 283(2): 1018-1025
24沈勤,王芳. P14ARF、E2F1对结直肠癌发生发展的影响.现代肿瘤医学, 2009, 17(7):1391-1393
25陈良友,陆国乎.转录因子E2F与血管再狭窄的研究进展.中西医结合心脑血管疾病杂志,2005, 3(2): 153-155
26 Ho A, Dowdy SF, Regulation of G1cell-cycle progression by oncogenes and tumor suppressor genes. Curr Opin Genel Dev, 2002, 12(1): 47-52
27 Slansky JE, Farnham PJ. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol, 1996, 208:1-30
28 Giovanni A , Brugger FW, Keramaris E , et al. Involvement of cell cycle elements , cyclin-dependent kinases , pRb , and E2F·DP , in B-amyloid- induced neuronal death. J Biol Chem, 1999, 27(274):19011 - 19016
29 Canepa ET, Scassa ME, Ceruti JM, et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IMBMB Life, 2007, 59(7): 419-426
30王宏坤,梁建芳,郑绘霞等.胃肠道间质肿瘤中E2F1和p16INK4α蛋白的表达与预后的关系.山西医科大学学报,2007,38(10):882-885
31 Degregori J, Leone G Miron A, et al. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Nartl Acad Sci USA, 1997, 94(14): 7245-7250
32 Almasan A, Yin Y, Kelly RE, et al. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Nartl Acad Sci USA, 1995, 92(12): 5436-5440
33 Shan B, Durfee T, Lee WH. Disruption of RB/E2F interaction by single point mutations in E2F1 enhances S-phase entry and apoptosis. Proc Nartl Acad Sci USA, 1996, 93(2): 679-684
34郭丽娟,高艳红,赵治国. Daxx蛋白在胃癌组织中的表达及意义.河南医学研究,2007,16(4): 314-316
35喻红霞,胡建达,陈鑫基等. Daxx基因在急性淋巴细胞白血病中表达的初步研究.白血病·淋巴瘤, 2005,14(2):99-100
36刘静,张柳清,胡群等. Daxx蛋白在儿童急性白血病中的表达及其临床意义.中国当代儿科杂志,2007, 9(1): 33-36
37 Li Q, Boyer C, Lee J, et al. A novel approach to thymidylate synthase as a target for cancer chemotherapy. Mol Phar, 2001, 59(3): 446-452
38鲍伟民,张荣,周范民等.胶质瘤中E2F1、MDM2的表达及其与肿瘤恶性程度的关系.中华神经医学杂志,2006, 5(4): 390-393
39 Yasui W, NaKa K, Suzuki T, et al. Expression of P27 Kipl, cyclin E and E2F1 in primary and metastatic tumors of gastric carcinoma. Oncol Rep, 1999, 6(5): 983-987
40 Lai R, Medeiros LJ, Wilson CS, et al. Expression of the cell-elated proteins E2F1, p53, mdm2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. Mod pathol, 1988, 11(7):642-647