维甲酸衍生物诱导白血病细胞分化的活性筛选、4-氨基2-三氟甲基苯基维甲酸酯诱导细胞分化及对细胞周期的影响
|
摘要
目的:本研究观察维甲酸衍生物对白血病细胞株K562和NB4细胞的增殖的影响和诱导分化活性,并筛选出有具有药理学活性的衍生物进行药效学和诱导分化机制的研究。
方法:
1.新型维甲酸类衍生物作用于K562和NB4细胞后,通过MTT法检测细胞的增殖;瑞氏染色法在倒置相差显微镜下观察加药处理前后细胞形态学变化。NBT还原实验法分析细胞的分化指标。FCM检测分析细胞周期和细胞表面分化抗原CD_(11b)、CD_(13)变化。
2.筛选出具有活性的化合物后,采用细胞计数方法观察白血病细胞在不同浓度的药物作用下生长曲线的改变, NBT还原实验法分析细胞在不同浓度作用下的分化指标,FCM检测分析细胞周期及K562细胞表面分化抗原CD_(45)、CD_(71)、CD_(117)和NB4细胞表面分化抗原CD_(11b)、CD_(13)、CD_(14)的变化。RT-PCR检测细胞周期相关因子Cyclin D1、Cyclin E、PCNA、CDK2、CDK4、CDK6、P21~(cip1)、P27~(kip1)、P57~(kip2) mRNA表达改变。Western Blot法检测cyclin D1、CDK4蛋白、PML/RARα融合蛋白和RARα蛋白表达的改变。
结果:
1.新型维甲酸衍生物作用3d后,4a-02,5a-02抑制K562和NB4细胞增殖作用呈剂量依赖性增加,10~(-5) mol/L抑制作用最强。维甲酸衍生物(10~(-5) mol/L)的诱导分化活性则表现在油镜下观察白血病细胞向粒系分化成熟的改变,2a-03,4a-02,5a-02,6a-02作用后NBT阳性细胞率增加,K562细胞表面分化抗原CD11b在2a-03,3a-02,4a-01,5a-02作用后表达量增加,NB4细胞在2a-01,2a-02,2a-03,4a-01,5a-01,5a-02作用后,CD11b增加同时CD13表达则减少。通过对细胞周期的分析,发现2a-03,4a-01,4a-02,5a-02对K562和NB4细胞周期均有影响,表现为G0/G1期细胞表达量增加,S期细胞表达量减少,呈G1期阻滞。
2.经过活性筛选发现,维甲酸衍生物4-氨基-2-三氟甲基苯基维甲酸酯(4-amino-2-trifluoromethyl-phenyl retinate, ATPR)是抑制增殖和诱导分化活性较强的衍生物,进行药效学研究发现,ATPR呈浓度依赖和时间性依赖抑制K562和NB4细胞增殖的作用。ATPR诱导分化活性表现为NBT阳性细胞率增加,NB4细胞表面分化抗原CD11b表达增加,CD13表达减少,CD14表达增加,作用与阳性对照ATRA相类似。并随作用时间延长而变化加大。ATPR作用3d后G0/G1期细胞表达量增加,S期细胞表达量减少,呈G1期阻滞。周期相关因子Cyclin D1、Cyclin E、CDK2、CDK4、CDK6、mRNA在ATPR作用3d后表达有减少改变,PCNA mRNA在ATPR作用7d后有减少改变。P57~(kip2)mRNA有明显增加的变化,但P21~(cip1)、P27~(kip1)mRNA不但没有增加,反而有略减少的趋势。cyclin D1和CDK4蛋白表达减少,PML/RARα融合蛋白和RARα蛋白表达也呈减少的改变。
结论:
1.维甲酸衍生物(2a-03、4a-02、5a-02)是抑制增殖和诱导分化活性较强的衍生物,提示以氨基三氟甲基苯基维甲酸酯为出发点开发具有更好的诱导肿瘤细胞分化和抑制增殖活性的维甲酸类药物具有重大意义。
2. ATPR(4a-02)有较强的抑制K562和NB4细胞增殖并诱导其分化的活性,并通过上调P57kip2mRNA,抑制Cyclin-CDK激酶复合物,发挥细胞周期阻滞的作用。
Objective:To investigate the proliferation inhibition and differentiation induction activities of 10 retionoic acid derivatives in K562 and NB4 cells ,screening of the derivatives with pharmacological activity ,and investigate their pharmacodynamics and mechanism of inducing differentiation .
Methods: 1、Cell proliferation was assessed by MTT assay before and after the treatment with retionoic acid derivatives in vitro.Morphologic changes were observed after Wright’s staining using inverted phase contrast microscope.Cell differentiation indexs were analyzed by NBT reduction test.Cell cycle and the expression of the maturation specific cell surface markers CD_(11b), CD_(13) were determined by FCM analysis.
2、After screening of the derivatives with pharmacological activity,the changes of growth curve induced by different concentrations of derivatives were analysed by cell counting. Cell differentiation indexs were analyzed by NBT reduction test.Cell cycle,the expression of the maturation specific cell surface markers CD_(45)、CD_(71)、CD_(117) of K562 cells and CD11b、CD_(13)、CD_(14) of NB4 cells were detected by FCM.The expression of cell cycle-related factors such as Cyclin D1、Cyclin E、PCNA、CDK2、CDK4、CDK6、P21~(cip1)、P27~(kip1)、P57~(kip2) mRNA was measured by RT-PCR.Western blotting was performed to detect the expression of protein cyclin D1, CDK4 protein, PML / RARαand RARα.
Results:
1.The growth of K562 and NB4 cells was inhibited in a dose-dependent manner after the treatment with retinoic acid derivatives for 3 days.The changes of differentiation and maturation of leukemic cells induced by 10 retinoic acid derivatives at the concentration of 10-5 mol/L were observed through immersion objective.NBT reduction test indicated that the retinoic acid derivatives could induce differentiation of leukemic cells and increase the positive cell ratio.The expression level of the maturation specific cell surface marker CD11b was increased while the expression level of CD13 was decreased.The proportion of cells in G0/G1 phase was increased.Cell cycle progression was blocked in the G1 phase.
2. Through the above analysis and comparison of experimental results, found that 4 -amino-2-trifluoromethyl-phenyl ester of retinoic acid (4-amino-2-trifluoromethyl-phenyl retinate, ATPR) has powerful activity in inbibiting proliferation and inducing differentiation . After the treatment with ATPR,the growth of leukemic cells was inhibited in a dose-dependent and time-dependent manner.The NBT positive cell ratio,the expression level of the maturation specific cell surface marker CD11b、CD14 of NB4 cells were increased while the expression level of CD13 was decreased,which was similar to ATRA.The longer, the greater the change.The proportion of cells in G0/G1 phase increased while S phase cells decreased. Cell cycle progression was blocked in the G1 phase. The expression level of Cyclin D1、Cyclin E、CDK2、CDK4、CDK6、mRNA decreased after 3 days, while PCNA mRNA decreased after 7 days treatment with ATPR and the expression level of P57 kip2 mRNA was significantly increased.
Conclusion:
1. Above of the all,the retinoic acid derivatives retinoid 2a-03, 4a-02 and 5a-02 have powerful activity in inhibiting proliferation and inducing cell differentiation., suggesting that it is significant to develop a better retinoic acid-type drug with amino trifluoromethyl phenyl retinate as the starting point.
2. ATPR (4a-02) has powerful activity in inbibiting proliferation and inducing differentiation through increasing the expression level of P57 kip2 mRNA to inhibit Cyclin-CDK kinase which plays a role in cell cycle arrest.
方法:
1.新型维甲酸类衍生物作用于K562和NB4细胞后,通过MTT法检测细胞的增殖;瑞氏染色法在倒置相差显微镜下观察加药处理前后细胞形态学变化。NBT还原实验法分析细胞的分化指标。FCM检测分析细胞周期和细胞表面分化抗原CD_(11b)、CD_(13)变化。
2.筛选出具有活性的化合物后,采用细胞计数方法观察白血病细胞在不同浓度的药物作用下生长曲线的改变, NBT还原实验法分析细胞在不同浓度作用下的分化指标,FCM检测分析细胞周期及K562细胞表面分化抗原CD_(45)、CD_(71)、CD_(117)和NB4细胞表面分化抗原CD_(11b)、CD_(13)、CD_(14)的变化。RT-PCR检测细胞周期相关因子Cyclin D1、Cyclin E、PCNA、CDK2、CDK4、CDK6、P21~(cip1)、P27~(kip1)、P57~(kip2) mRNA表达改变。Western Blot法检测cyclin D1、CDK4蛋白、PML/RARα融合蛋白和RARα蛋白表达的改变。
结果:
1.新型维甲酸衍生物作用3d后,4a-02,5a-02抑制K562和NB4细胞增殖作用呈剂量依赖性增加,10~(-5) mol/L抑制作用最强。维甲酸衍生物(10~(-5) mol/L)的诱导分化活性则表现在油镜下观察白血病细胞向粒系分化成熟的改变,2a-03,4a-02,5a-02,6a-02作用后NBT阳性细胞率增加,K562细胞表面分化抗原CD11b在2a-03,3a-02,4a-01,5a-02作用后表达量增加,NB4细胞在2a-01,2a-02,2a-03,4a-01,5a-01,5a-02作用后,CD11b增加同时CD13表达则减少。通过对细胞周期的分析,发现2a-03,4a-01,4a-02,5a-02对K562和NB4细胞周期均有影响,表现为G0/G1期细胞表达量增加,S期细胞表达量减少,呈G1期阻滞。
2.经过活性筛选发现,维甲酸衍生物4-氨基-2-三氟甲基苯基维甲酸酯(4-amino-2-trifluoromethyl-phenyl retinate, ATPR)是抑制增殖和诱导分化活性较强的衍生物,进行药效学研究发现,ATPR呈浓度依赖和时间性依赖抑制K562和NB4细胞增殖的作用。ATPR诱导分化活性表现为NBT阳性细胞率增加,NB4细胞表面分化抗原CD11b表达增加,CD13表达减少,CD14表达增加,作用与阳性对照ATRA相类似。并随作用时间延长而变化加大。ATPR作用3d后G0/G1期细胞表达量增加,S期细胞表达量减少,呈G1期阻滞。周期相关因子Cyclin D1、Cyclin E、CDK2、CDK4、CDK6、mRNA在ATPR作用3d后表达有减少改变,PCNA mRNA在ATPR作用7d后有减少改变。P57~(kip2)mRNA有明显增加的变化,但P21~(cip1)、P27~(kip1)mRNA不但没有增加,反而有略减少的趋势。cyclin D1和CDK4蛋白表达减少,PML/RARα融合蛋白和RARα蛋白表达也呈减少的改变。
结论:
1.维甲酸衍生物(2a-03、4a-02、5a-02)是抑制增殖和诱导分化活性较强的衍生物,提示以氨基三氟甲基苯基维甲酸酯为出发点开发具有更好的诱导肿瘤细胞分化和抑制增殖活性的维甲酸类药物具有重大意义。
2. ATPR(4a-02)有较强的抑制K562和NB4细胞增殖并诱导其分化的活性,并通过上调P57kip2mRNA,抑制Cyclin-CDK激酶复合物,发挥细胞周期阻滞的作用。
Objective:To investigate the proliferation inhibition and differentiation induction activities of 10 retionoic acid derivatives in K562 and NB4 cells ,screening of the derivatives with pharmacological activity ,and investigate their pharmacodynamics and mechanism of inducing differentiation .
Methods: 1、Cell proliferation was assessed by MTT assay before and after the treatment with retionoic acid derivatives in vitro.Morphologic changes were observed after Wright’s staining using inverted phase contrast microscope.Cell differentiation indexs were analyzed by NBT reduction test.Cell cycle and the expression of the maturation specific cell surface markers CD_(11b), CD_(13) were determined by FCM analysis.
2、After screening of the derivatives with pharmacological activity,the changes of growth curve induced by different concentrations of derivatives were analysed by cell counting. Cell differentiation indexs were analyzed by NBT reduction test.Cell cycle,the expression of the maturation specific cell surface markers CD_(45)、CD_(71)、CD_(117) of K562 cells and CD11b、CD_(13)、CD_(14) of NB4 cells were detected by FCM.The expression of cell cycle-related factors such as Cyclin D1、Cyclin E、PCNA、CDK2、CDK4、CDK6、P21~(cip1)、P27~(kip1)、P57~(kip2) mRNA was measured by RT-PCR.Western blotting was performed to detect the expression of protein cyclin D1, CDK4 protein, PML / RARαand RARα.
Results:
1.The growth of K562 and NB4 cells was inhibited in a dose-dependent manner after the treatment with retinoic acid derivatives for 3 days.The changes of differentiation and maturation of leukemic cells induced by 10 retinoic acid derivatives at the concentration of 10-5 mol/L were observed through immersion objective.NBT reduction test indicated that the retinoic acid derivatives could induce differentiation of leukemic cells and increase the positive cell ratio.The expression level of the maturation specific cell surface marker CD11b was increased while the expression level of CD13 was decreased.The proportion of cells in G0/G1 phase was increased.Cell cycle progression was blocked in the G1 phase.
2. Through the above analysis and comparison of experimental results, found that 4 -amino-2-trifluoromethyl-phenyl ester of retinoic acid (4-amino-2-trifluoromethyl-phenyl retinate, ATPR) has powerful activity in inbibiting proliferation and inducing differentiation . After the treatment with ATPR,the growth of leukemic cells was inhibited in a dose-dependent and time-dependent manner.The NBT positive cell ratio,the expression level of the maturation specific cell surface marker CD11b、CD14 of NB4 cells were increased while the expression level of CD13 was decreased,which was similar to ATRA.The longer, the greater the change.The proportion of cells in G0/G1 phase increased while S phase cells decreased. Cell cycle progression was blocked in the G1 phase. The expression level of Cyclin D1、Cyclin E、CDK2、CDK4、CDK6、mRNA decreased after 3 days, while PCNA mRNA decreased after 7 days treatment with ATPR and the expression level of P57 kip2 mRNA was significantly increased.
Conclusion:
1. Above of the all,the retinoic acid derivatives retinoid 2a-03, 4a-02 and 5a-02 have powerful activity in inhibiting proliferation and inducing cell differentiation., suggesting that it is significant to develop a better retinoic acid-type drug with amino trifluoromethyl phenyl retinate as the starting point.
2. ATPR (4a-02) has powerful activity in inbibiting proliferation and inducing differentiation through increasing the expression level of P57 kip2 mRNA to inhibit Cyclin-CDK kinase which plays a role in cell cycle arrest.
引文
[1]王慕狄.儿科学[M]. 5版,北京:人民卫生出版社, 2001: 378-9.
[2] Evans TR, Kaye SB. Retinoids: Present Role and Future Potential[J]. Cancer, 1999, 80(1-2): 1-8.
[3] Shen J, Shi JB, Chen FH, et al. Synthesis and anti-tumor activity of all-trans retinoic acid derivatives[J]. Chin. Chem. Letters. 2009 20(7):805-7.
[4]沈娟,石静波,陈飞虎,等.维甲酸衍生物的合成及其抗肿瘤活性筛选[J].中国新药杂志, 2009, 18(11): 86-9.
[5] Montoro E,Lemus D, Echemendia M, et al. Comparative evaluation of the nitrate reduction assay, the MTT test, and the resazurin microtitre assay for drug susceptibility testing of clinical isolates of Mycobacterium tuberculosis[J]. J Antimicrob Chemother, 2005, 55(4): 500 - 5.
[6]张彦,蒋纪恺,刘小珊,等.苦参碱诱导K562白血病细胞分化和凋亡的实验研究[J].癌症, 2000, 19(8): 756—758.
[7] Kang S N, Kim S H, Chung S W, et a1.Enhancement of l alpha,25-dihydroxyvitamin D (3)-induced differentiation of human leukacmia HL一60 cells into monocytes by parthenolidevia inhibition of NF-kappa B activity[J].Br J Pharmacol, 2002,135(5):1235-44.
[8]Fang J, Chen S J, Tong J H,et a1.Treatment of acute promyelocytic leukemia with ATRA and A8203: a model of molecular target-based cancer thempy[J].Cancer Biol Ther, 2002, l(6): 614-20.
[9]李哲,闫曼,马静.小剂量化疗联合三氧化二砷治疗急性早幼粒细胞白血病[J].临床内科杂志, 2008, 25(1): 66.
[10]王冠军.三氧化二砷联合小剂量全反式维A酸诱导急性早幼粒细胞白血病缓解的疗效分析[J].中华医学杂志,2005, 85(16): 1093-6.
[11] Raffoux E, Chaibi P, Dombret H, et al. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica, 2005, 90: 986-8.
[12]赵淑清,李军民,周励.丙戊酸钠诱导髓系白血病分化、凋亡作用及其机制研究[J].上海医学,2007,30(11): 847- 51.
[13]景莉,王秦,李晓明.丹参酮ⅡA对急性早幼粒细胞白学病作用的研究进展[J].中国药房, 2006, 17(12): 942-3.
[14] World Cancer Research Fund/American Institute for Cancer Research. Vitamin. In: Food Nutrition and the Prevention of Cancer, a Global Perspective: American Institute for Cancer Research Press, 1997.404-416
[15] Wang ZY, Chen Z, Huang W, et al. Problems existing in differentiation therapy of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA)[J]. Blood Cells, 1993, 19(3): 633-41.
[16] Leung AY, Verfaillie CM. All-trans retinoic acid (ATRA) enhances maintenance of primitive human hematopoietic progenitors and skews them towards myeloid differentiation in a stroma-noncontact culture system[J]. Exp Hematol, 2005, 33(4): 422-7.
[17] Zhang H, Wang Z, Zhou J. Cytoplasm prepared from all-trans retinoic acid (ATRA)-treated human hematopoietic progenitor cells induces differentiation of both ATRA sensitive and ATRA resistant leukemia cells[J]. Biol Pharm Bull, 2004, 27(4): 570-3.
[18] Zhu J, Shi XG, Chu HY, et al. Effect of retinoic acid isomers on proliferation, differentiation and PML relocalization in the APL cell line NB4[J]. Leukemia, 1995, 9(2): 302-9.
[19]王振义,陈竺主编.肿瘤的诱导分化和凋亡疗法[M].第1版.上海科学技术出版社, 1999: 142.
[20]王金发.细胞生物学[M].第一版.北京:科学出版社, 2003, 508-12
[21] Harper JW,Adami GR,Wei N, et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases[J]. Cell, 1993, 75(4): 805-16.
[1] Chen Z, Tong JH, Dong S, et al. Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia. [J]. Genes Chromosomes Cancer. 1996; 15: 147-56.
[2] Breitman TR, Selonick SE, Collins SJ, et al. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid[J]. Proc Natl Acad Sci USA, 1980, 77(5): 2936-40.
[3] Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. [J]. Semin Hematol, 2001; 38(1): 13-25.
[4] Collins SJ. Acute promyelocytic leukemia: relieving repression induces remission[J]. Blood, 1998; 91(8):2631-3.
[5] Shen J, Shi JB, Chen F H, et al. Synthesis and anti-tumor activity of all-trans retinoic acid derivatives[J]. Chin. Chem. Letters. 2009; 20(7): 805-7.
[6]沈娟,石静波,陈飞虎等.维甲酸衍生物的合成及其抗肿瘤活性筛选[J]中国新药杂志2009,18(11):86-9.
[7]阮晶晶,陈飞虎,徐佼,等.新型维甲酸衍生物诱导NB4细胞分化的初步研究[J].中国临床药理学与治疗学, 2008, 13(11): 1237-42.
[8]康健,夏春咸,姚壮凯,等.全反式维甲酸对胃癌患者免疫功能、肿瘤细胞增殖及其预后的干预作用研究[J].实用临床医药杂志, 2006,10(5): 84-6.
[9] Arce F, G?tjens-Boniche O, Vargas E, et al. Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2[J]. Cancer Lett, 2005; 229(2): 271-81.
[10] El-Metwally TH, Hussein MR, Pour PM, et al. High concentrations of retinoids induce differentiation and late apoptosis in pancreatic cancer cells in vitro [J]. Cancer Biol Ther, 2005; 4(5): 602-11.
[11] Wen J, Wang L, Zhang M, et al. Repression of telomerase activity during in vitro differentiation of osteosarcoma cells [J].cancer Invest, 2002; 20(1):38 - 45.
[12]张岩,姜侃,夏仁云,等.全反式维甲酸体外诱导分化对人骨肉瘤MG-63细胞侵袭转移的影响[J].华中科技大学学报(医学版), 2006; 35(5): 613-6.
[13]吴向华,叶开和,胡爱群.全反式维甲酸和阿糖胞苷对HL-60细胞端粒酶活性的影响[J].中国临床药理学与治疗学杂志, 2000, 5(1): 47-50.
[14]刘凌波.髓系造血细胞分化抗原和分化调控的进展[J].国外医学生理、病理科学与临床分册,1996,16(1):11一13
[15] Niitsu N, Umeda M,Honma Y.Myeloid and monocytold leukemia cells have different sensitivity to differentiation-inducing activity of deoxyadenosine analogs[J].Leuk Res, 2000, 24(1): 1-9.
[16] Yamamoto-Yamaguehi Y,Okabe-Kado J,Kasukabe T,et a1.Induction of differentiation of human myeloid leukemia cells by immunosuppressant macrolides (rapamycin and FK506) and calcium/ealmodulin-dependent kinase inhibitom[J]. Exp Hematol, 2001, 29(5): 582-8.
[17] Pahl HL, Rosmarin AG, Tenen DG. et al. Characterization of the myeloid-specific CD11b promoter[J]. Blood, 1992; 79(4): 865-70.
[18] Barber N, Belov L, Christopherson RI. All-trans retinoic acid induces different immunophenotypic changes on human HL60 and NB4 myeloid leukaemias[J]. Leuk Res. 2008; 32(2):315-22
[19]袁晓军,廖清奎,罗春华,等.全反式维甲酸对K562细胞的诱导分化作用[J].中国当代儿科杂志, 2003; 5(1): 8-11.
[20]钟璐,陈芳源,韩洁英,等. Study on effects of quercetin on PML gene and protein in leukemia cell lines[J],上海第二医科大学学报(英文版), 2003; 15 (1):12-5
[21] Stamatoyannopoulos G, PhilipW, Roger M, et al. The molecular basis of blood disease (3 rd edition) [M ].北京:人民卫生出版社, 2001: 38.
[22] Yoshida H, Kitamura K, Tanaka K et al. Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. [J]. Cancer Res, 1996; 56(13): 2945
[23] Raelson JV, Nervi C, Rosenauer A, et al. The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells[J]. Blood, 1996, 88(8): 2826-32.
[24]Studzinski GP, Harrison LE. Differentiation-related changes in the cell cycle traverse[J].Int Rev Cytol, 1999;189: 1-58
[25] Gorin NC, Estey E, Jones RJ,.New developments in the therapy of acute myelocytic leukemia[J]. Hematology Am Soc Hematol Educ Program, 2000:69-89.
[26] Liu Y, Xi L, Liao G, et a1 . Inhibition of PC cell-derived growth factor(PCDGF)/granulin-epithelin precursor(GEP) decreased cell proliferation and invasion through down-regulation of cyclin D and CDK4 and inactivation of MMP-2[J].BMC cancer, 2007, 29(7): 22-26.
[27] Muller C, Yang R, Park DJ, et al. The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia. Blood, 2000, 96 (12): 3894- 9.
[28]王颖,徐世荣.细胞周期蛋白E与白血病[J].中华血液学杂志, 2001, 22(4): 219-21.
[29] Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition[J]. Cancer Cell, 2003, 3(3): 233-45.
[30]许秋岩,张海燕,李卫红等.人神经前体细胞分化过程中p27kip的作用及其调节机制研究[J].中国药理学通报, 2008, 22(8): 1011-4.
[31] Agami R, Bernards R. Distinct initiation and maintenance mechanisms cooperate toinduce G1cell cycle arrest in response to DNA damage[J]. Cell, 2000, 102(1):55-66
[32] Kastan MB, Bartek J. Cell-cycle checkpoint and cancer[J]. Nature, 2004, 432(7015):316-22.
[33] Roberts JM, Sherr CJ. Bared essentials of CDK2 and cyclin E[J]. Nat Genet, 2003, 35(1): 9-10.
[34] Le Saqe C, Naqet R, Eqan D A, et al. Regulation of the p27 (Kipl) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation[J]. EMBO J, 2007, 12: 1-5.
[35] Heeren P, Phukker J, Van Dullemen H, et al. Prognostic role of cyclooxygenase-2 expression esophageal carcinoma[J]. Cancer letters, 2005, 225(2): 283-9.
[36] Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors[J]. Gene Deve, 2000.14(24): 3115-25.
[1]王金发.细胞生物学[M].第一版.北京:科学出版社, 2003, 508-12
[2]王霞,李萍.细胞周期调控与肿瘤研究进展[J].中国医学检验杂志, 2006, 7(1): 59-61.
[3] Nakayama KI, Htakeyama S, Nakayama K. Regulation by proteolysis of cyclin E and p27kip1[J] Biochem Biophys Res Commun, 2001,282(4): 853-60.
[4] Baker GL, Landis MW, Hinds PW, et a1. Multiple functions of Dtype cyclins canantagonize pRb-mediated suppression of proliferation[J]. Cell Cycle, 2005, 4(2): 330-8.
[5]王银龙,周洲,王元银,等.口腔鳞癌中Cyclin D1和Bcl-2蛋白表达相关性的研究[J].安徽医药, 2006, 10(6): 436-7.
[6] Obaya AJ, Sedivy JM. Regulation of cyclin-CDK activity in mammalian cells[J] Cell Mol Life Sci, 2002, 59(1): 126-42.
[7] Pines J. Mitosis: A matter of getting rid of the right protein at the right time[J]. T Cell Biol, 2006, 16(1): 55-63.18.
[8] Kaldis P. The cdk-activating kinase(CAK): from yeast to mammals[J]. Cell Mol Life Sci, 1999, 55(2): 284-96.
[9] Nilsson I,Hoffmann I.Cell cycle regulation by the CDC25 phosphatase[J] Prog Cell Cycle Res,2000,4:107-14.
[10] Hagopian JC,Kirley MP,Stevnson LM,et a1.Kinetic basis for activation of CDK2/cyclin A by phosphorylation[J].J Bion Chen,2001,276(1):275-80.
[11] Morgan DO. Principles of CDK regulation[J] Nature, 1995, 374(6518): 131-4.
[12] Polyak K, Lee MH, Erdjument-Bromage H, et a1 . Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals[J] Cell, 1994, 78(1):59-66
[13] Russo AA, Jeffrey PD, Patten AK, et a1.Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex[J] Nature, 1996, 382(6598): 295-6
[14]徐静.细胞周期调节蛋白Skp,p27在妇科恶性肿瘤中的研究进展[J]安徽医药, 2007, 11(6): 484-6.
[15]卢瑞南,盛瑞兰,李建勇. P27(Kip1)的研究进展[J]。国外医学(分子生物学分册),2003,25(3):171-174.
[16] Ponce-Castaňeda WV, Lee MH, Latres E et a1. p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors[J] Cancer Res, 1995, 55(6): 1211-4.
[17] Katayose Y, Kim M, Rakkar AN et a1. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27[J]. Cancer Res, 1997,57(24): 5441-5.
[18] Tsukiyama T, Ishida N, Shirane M, et a1. Down-regulation of p27Kipl expression is required for development and function of T cells[J] J Immunol, 2001, 166(1): 304-12
[19] Chen TC, Nq KF, Lien JM et a1. Mutational analysis of the p27(kip1) gene in hepatocellular carcinoma[J] Cancer Lett, 2000, 153(1-2): 169-73.
[20] Mamillapalli R, Gavrilova N, Mihaylova VT et al. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2)[J]. Curr Biol, 2001,11(4): 263-7.
[21] Hartmann W, Waha A, Koch A, et a1. p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2 and H19[J] Am J Pathol, 2000, 157(9): 1393-403.
[22]杨涛,屈建强. p57kip2与脑胶质瘤研究进展[J]中华神经外科疾病研究杂志, 2007, 6(3): 286-8.
[23] Reid LH, Crider-Miller SJ, West A, et al. Genomic organization of the human P57KIP2 gene and its analysis in the G401 Wilm’s tumor assay[J]. Cancer Res, 1996, 56(6): 1214-8.
[24] Matsuoka S, Edwards MC, Bai C, et a1. P57KIP2, a structurally distinct member of the P21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene[J] Genes Dev, 1995, 9(6): 650-62.
[25] Kamb A, Gruis NA, Weaver-Feldhaus J et al. A cell cycle regulator potentially involved in genesis of many tumor types[J] Science, 1994, 264(5157): 436-40.
[26] Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et a1. The Polycombgroup proteins bind throughout the INK4A -ARF locus and are disassociated in senescent cells[J]. Genes Dev, 2007, 21(5): 525-30.
[27]郑瑞玑,沈建箴. INK系列抑癌基因(p16、p15、p18、p19)在白血病研究进展[J]医学综述, 2005, 11(2): 127-9.
[28] Giacinti C, Giordano A. RB and cell cycle progression[J]. Oncogene, 2006, 25(38):5220- 7.
[29] Graňa X,Reddy EP.Cell cycle control in mammalian cell: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors(CKIs)[J] Oncogene, 1995 , l1(2): 201-9.
[30]高燕,林莉萍,丁健.细胞周期调控的研究进展[J].生命科学, 2005, 17(4): 318-22.
[31]陈军. P53蛋白研究新进展[J].国外医学(卫生学分册), 2002, 29(2): 104-9.
[32]Waga S, Hannon GJ, Beach D et a1. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA[J] Nature, 1994, 369(6481): 574-8.
[33] Nakao M, Yokota S, Kaneko H, et al. Alterations of CDKN2 gene structure in childhood acute lymphoblastic leukemia: mutations of CDKN2 are observed preferentially in T lineage. [J]. Leukemia, 1996,10(2): 249-54.
[34] Decker T, Schneller F, Hipp S, et al . Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27[J]. leukemia, 2002,16(3): 327-34
[35] Wolowiec D, Ciszak L, Kosmaczewska A, et al. Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia[J]. Haematologica, 2001, 86 (12): 1296-304.
[36] Iida H, Towatari M, Tanimoto M, et al. Overexpression of cyclin E in acute myelogenous leukemia [J]. B1ood, 1997, 90(9): 3707-13.
[37]李红华,汪月增,楼方定.急性白血病患者周期蛋白D1mRNA表达及其临床意义[J].中华血液学杂志, 1999, 20(7): 357-358
[38]吴穗晶,杜欣,陈运贤,等.细胞周期蛋白与急性白血病预后[J].癌症, 2003, 22(8): 852-4.
[39]J: 34 Grzanka,Styczynski.Expressiono fc yclinA inh umanl eukemiac elllines HL-60 and K-562 at the level of light and electron microscope byusingim munocytochemicalm ethods.Neoplasma.2001:48(2):112-115
[40] M?ller C, Yang R, Park DJ, et al . The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocyticleukemia [J]. Blood, 2000, 96(12): 3894-9.
[41]卢瑞南,盛瑞兰等,李建勇,等.急慢性白血病p27( Kipl)表达及其临床意义[J].中国实验血液学杂志, 2004, 12(3): 291-7.
[42]施均,邵宗鸿,刘鸿,等.骨髓增生异常综合征细胞周期调控基因表达谱的研究[J].中华血液学杂志, 2005, 26(1): 10-14
[43] Matushansky I, Radparvar F, Skoultchi AI. Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1 [J]. Proc Natl Acad Sci U S A, 2000, 97(26): 14317-22.
[44] Sauerbrey A, H?fer R, Zintl F, et al. Analysis of cyclin D1 in de novo and relapsed childhood acute lymphoblastic leukemia [J].Anticancer Res, 1999, 19 (1B ): 645-9.
[45] Volm M, Koom?gi R, Stammler G, et al. Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, p16INK4A) in childhood acute lymphoblastic leukemia [J]. Int J Cancer, 1997, 74(5): 508-12.
[46]张乐萍,李静.周期蛋白D3在小儿急性白血病细胞中的表达及其作用研究[J].中华血液学杂志, 1999, 20(7): 347-9.
[47] Komuro H, Valentine MB, Rubnitz JE, et al. p27KIP1 deletions in childhood acute lymphoblastic leukemia. [J]. Neoplasia, 1999, 1(3): 253-61.
[2] Evans TR, Kaye SB. Retinoids: Present Role and Future Potential[J]. Cancer, 1999, 80(1-2): 1-8.
[3] Shen J, Shi JB, Chen FH, et al. Synthesis and anti-tumor activity of all-trans retinoic acid derivatives[J]. Chin. Chem. Letters. 2009 20(7):805-7.
[4]沈娟,石静波,陈飞虎,等.维甲酸衍生物的合成及其抗肿瘤活性筛选[J].中国新药杂志, 2009, 18(11): 86-9.
[5] Montoro E,Lemus D, Echemendia M, et al. Comparative evaluation of the nitrate reduction assay, the MTT test, and the resazurin microtitre assay for drug susceptibility testing of clinical isolates of Mycobacterium tuberculosis[J]. J Antimicrob Chemother, 2005, 55(4): 500 - 5.
[6]张彦,蒋纪恺,刘小珊,等.苦参碱诱导K562白血病细胞分化和凋亡的实验研究[J].癌症, 2000, 19(8): 756—758.
[7] Kang S N, Kim S H, Chung S W, et a1.Enhancement of l alpha,25-dihydroxyvitamin D (3)-induced differentiation of human leukacmia HL一60 cells into monocytes by parthenolidevia inhibition of NF-kappa B activity[J].Br J Pharmacol, 2002,135(5):1235-44.
[8]Fang J, Chen S J, Tong J H,et a1.Treatment of acute promyelocytic leukemia with ATRA and A8203: a model of molecular target-based cancer thempy[J].Cancer Biol Ther, 2002, l(6): 614-20.
[9]李哲,闫曼,马静.小剂量化疗联合三氧化二砷治疗急性早幼粒细胞白血病[J].临床内科杂志, 2008, 25(1): 66.
[10]王冠军.三氧化二砷联合小剂量全反式维A酸诱导急性早幼粒细胞白血病缓解的疗效分析[J].中华医学杂志,2005, 85(16): 1093-6.
[11] Raffoux E, Chaibi P, Dombret H, et al. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica, 2005, 90: 986-8.
[12]赵淑清,李军民,周励.丙戊酸钠诱导髓系白血病分化、凋亡作用及其机制研究[J].上海医学,2007,30(11): 847- 51.
[13]景莉,王秦,李晓明.丹参酮ⅡA对急性早幼粒细胞白学病作用的研究进展[J].中国药房, 2006, 17(12): 942-3.
[14] World Cancer Research Fund/American Institute for Cancer Research. Vitamin. In: Food Nutrition and the Prevention of Cancer, a Global Perspective: American Institute for Cancer Research Press, 1997.404-416
[15] Wang ZY, Chen Z, Huang W, et al. Problems existing in differentiation therapy of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA)[J]. Blood Cells, 1993, 19(3): 633-41.
[16] Leung AY, Verfaillie CM. All-trans retinoic acid (ATRA) enhances maintenance of primitive human hematopoietic progenitors and skews them towards myeloid differentiation in a stroma-noncontact culture system[J]. Exp Hematol, 2005, 33(4): 422-7.
[17] Zhang H, Wang Z, Zhou J. Cytoplasm prepared from all-trans retinoic acid (ATRA)-treated human hematopoietic progenitor cells induces differentiation of both ATRA sensitive and ATRA resistant leukemia cells[J]. Biol Pharm Bull, 2004, 27(4): 570-3.
[18] Zhu J, Shi XG, Chu HY, et al. Effect of retinoic acid isomers on proliferation, differentiation and PML relocalization in the APL cell line NB4[J]. Leukemia, 1995, 9(2): 302-9.
[19]王振义,陈竺主编.肿瘤的诱导分化和凋亡疗法[M].第1版.上海科学技术出版社, 1999: 142.
[20]王金发.细胞生物学[M].第一版.北京:科学出版社, 2003, 508-12
[21] Harper JW,Adami GR,Wei N, et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases[J]. Cell, 1993, 75(4): 805-16.
[1] Chen Z, Tong JH, Dong S, et al. Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia. [J]. Genes Chromosomes Cancer. 1996; 15: 147-56.
[2] Breitman TR, Selonick SE, Collins SJ, et al. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid[J]. Proc Natl Acad Sci USA, 1980, 77(5): 2936-40.
[3] Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. [J]. Semin Hematol, 2001; 38(1): 13-25.
[4] Collins SJ. Acute promyelocytic leukemia: relieving repression induces remission[J]. Blood, 1998; 91(8):2631-3.
[5] Shen J, Shi JB, Chen F H, et al. Synthesis and anti-tumor activity of all-trans retinoic acid derivatives[J]. Chin. Chem. Letters. 2009; 20(7): 805-7.
[6]沈娟,石静波,陈飞虎等.维甲酸衍生物的合成及其抗肿瘤活性筛选[J]中国新药杂志2009,18(11):86-9.
[7]阮晶晶,陈飞虎,徐佼,等.新型维甲酸衍生物诱导NB4细胞分化的初步研究[J].中国临床药理学与治疗学, 2008, 13(11): 1237-42.
[8]康健,夏春咸,姚壮凯,等.全反式维甲酸对胃癌患者免疫功能、肿瘤细胞增殖及其预后的干预作用研究[J].实用临床医药杂志, 2006,10(5): 84-6.
[9] Arce F, G?tjens-Boniche O, Vargas E, et al. Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2[J]. Cancer Lett, 2005; 229(2): 271-81.
[10] El-Metwally TH, Hussein MR, Pour PM, et al. High concentrations of retinoids induce differentiation and late apoptosis in pancreatic cancer cells in vitro [J]. Cancer Biol Ther, 2005; 4(5): 602-11.
[11] Wen J, Wang L, Zhang M, et al. Repression of telomerase activity during in vitro differentiation of osteosarcoma cells [J].cancer Invest, 2002; 20(1):38 - 45.
[12]张岩,姜侃,夏仁云,等.全反式维甲酸体外诱导分化对人骨肉瘤MG-63细胞侵袭转移的影响[J].华中科技大学学报(医学版), 2006; 35(5): 613-6.
[13]吴向华,叶开和,胡爱群.全反式维甲酸和阿糖胞苷对HL-60细胞端粒酶活性的影响[J].中国临床药理学与治疗学杂志, 2000, 5(1): 47-50.
[14]刘凌波.髓系造血细胞分化抗原和分化调控的进展[J].国外医学生理、病理科学与临床分册,1996,16(1):11一13
[15] Niitsu N, Umeda M,Honma Y.Myeloid and monocytold leukemia cells have different sensitivity to differentiation-inducing activity of deoxyadenosine analogs[J].Leuk Res, 2000, 24(1): 1-9.
[16] Yamamoto-Yamaguehi Y,Okabe-Kado J,Kasukabe T,et a1.Induction of differentiation of human myeloid leukemia cells by immunosuppressant macrolides (rapamycin and FK506) and calcium/ealmodulin-dependent kinase inhibitom[J]. Exp Hematol, 2001, 29(5): 582-8.
[17] Pahl HL, Rosmarin AG, Tenen DG. et al. Characterization of the myeloid-specific CD11b promoter[J]. Blood, 1992; 79(4): 865-70.
[18] Barber N, Belov L, Christopherson RI. All-trans retinoic acid induces different immunophenotypic changes on human HL60 and NB4 myeloid leukaemias[J]. Leuk Res. 2008; 32(2):315-22
[19]袁晓军,廖清奎,罗春华,等.全反式维甲酸对K562细胞的诱导分化作用[J].中国当代儿科杂志, 2003; 5(1): 8-11.
[20]钟璐,陈芳源,韩洁英,等. Study on effects of quercetin on PML gene and protein in leukemia cell lines[J],上海第二医科大学学报(英文版), 2003; 15 (1):12-5
[21] Stamatoyannopoulos G, PhilipW, Roger M, et al. The molecular basis of blood disease (3 rd edition) [M ].北京:人民卫生出版社, 2001: 38.
[22] Yoshida H, Kitamura K, Tanaka K et al. Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. [J]. Cancer Res, 1996; 56(13): 2945
[23] Raelson JV, Nervi C, Rosenauer A, et al. The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells[J]. Blood, 1996, 88(8): 2826-32.
[24]Studzinski GP, Harrison LE. Differentiation-related changes in the cell cycle traverse[J].Int Rev Cytol, 1999;189: 1-58
[25] Gorin NC, Estey E, Jones RJ,.New developments in the therapy of acute myelocytic leukemia[J]. Hematology Am Soc Hematol Educ Program, 2000:69-89.
[26] Liu Y, Xi L, Liao G, et a1 . Inhibition of PC cell-derived growth factor(PCDGF)/granulin-epithelin precursor(GEP) decreased cell proliferation and invasion through down-regulation of cyclin D and CDK4 and inactivation of MMP-2[J].BMC cancer, 2007, 29(7): 22-26.
[27] Muller C, Yang R, Park DJ, et al. The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia. Blood, 2000, 96 (12): 3894- 9.
[28]王颖,徐世荣.细胞周期蛋白E与白血病[J].中华血液学杂志, 2001, 22(4): 219-21.
[29] Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition[J]. Cancer Cell, 2003, 3(3): 233-45.
[30]许秋岩,张海燕,李卫红等.人神经前体细胞分化过程中p27kip的作用及其调节机制研究[J].中国药理学通报, 2008, 22(8): 1011-4.
[31] Agami R, Bernards R. Distinct initiation and maintenance mechanisms cooperate toinduce G1cell cycle arrest in response to DNA damage[J]. Cell, 2000, 102(1):55-66
[32] Kastan MB, Bartek J. Cell-cycle checkpoint and cancer[J]. Nature, 2004, 432(7015):316-22.
[33] Roberts JM, Sherr CJ. Bared essentials of CDK2 and cyclin E[J]. Nat Genet, 2003, 35(1): 9-10.
[34] Le Saqe C, Naqet R, Eqan D A, et al. Regulation of the p27 (Kipl) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation[J]. EMBO J, 2007, 12: 1-5.
[35] Heeren P, Phukker J, Van Dullemen H, et al. Prognostic role of cyclooxygenase-2 expression esophageal carcinoma[J]. Cancer letters, 2005, 225(2): 283-9.
[36] Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors[J]. Gene Deve, 2000.14(24): 3115-25.
[1]王金发.细胞生物学[M].第一版.北京:科学出版社, 2003, 508-12
[2]王霞,李萍.细胞周期调控与肿瘤研究进展[J].中国医学检验杂志, 2006, 7(1): 59-61.
[3] Nakayama KI, Htakeyama S, Nakayama K. Regulation by proteolysis of cyclin E and p27kip1[J] Biochem Biophys Res Commun, 2001,282(4): 853-60.
[4] Baker GL, Landis MW, Hinds PW, et a1. Multiple functions of Dtype cyclins canantagonize pRb-mediated suppression of proliferation[J]. Cell Cycle, 2005, 4(2): 330-8.
[5]王银龙,周洲,王元银,等.口腔鳞癌中Cyclin D1和Bcl-2蛋白表达相关性的研究[J].安徽医药, 2006, 10(6): 436-7.
[6] Obaya AJ, Sedivy JM. Regulation of cyclin-CDK activity in mammalian cells[J] Cell Mol Life Sci, 2002, 59(1): 126-42.
[7] Pines J. Mitosis: A matter of getting rid of the right protein at the right time[J]. T Cell Biol, 2006, 16(1): 55-63.18.
[8] Kaldis P. The cdk-activating kinase(CAK): from yeast to mammals[J]. Cell Mol Life Sci, 1999, 55(2): 284-96.
[9] Nilsson I,Hoffmann I.Cell cycle regulation by the CDC25 phosphatase[J] Prog Cell Cycle Res,2000,4:107-14.
[10] Hagopian JC,Kirley MP,Stevnson LM,et a1.Kinetic basis for activation of CDK2/cyclin A by phosphorylation[J].J Bion Chen,2001,276(1):275-80.
[11] Morgan DO. Principles of CDK regulation[J] Nature, 1995, 374(6518): 131-4.
[12] Polyak K, Lee MH, Erdjument-Bromage H, et a1 . Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals[J] Cell, 1994, 78(1):59-66
[13] Russo AA, Jeffrey PD, Patten AK, et a1.Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex[J] Nature, 1996, 382(6598): 295-6
[14]徐静.细胞周期调节蛋白Skp,p27在妇科恶性肿瘤中的研究进展[J]安徽医药, 2007, 11(6): 484-6.
[15]卢瑞南,盛瑞兰,李建勇. P27(Kip1)的研究进展[J]。国外医学(分子生物学分册),2003,25(3):171-174.
[16] Ponce-Castaňeda WV, Lee MH, Latres E et a1. p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors[J] Cancer Res, 1995, 55(6): 1211-4.
[17] Katayose Y, Kim M, Rakkar AN et a1. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27[J]. Cancer Res, 1997,57(24): 5441-5.
[18] Tsukiyama T, Ishida N, Shirane M, et a1. Down-regulation of p27Kipl expression is required for development and function of T cells[J] J Immunol, 2001, 166(1): 304-12
[19] Chen TC, Nq KF, Lien JM et a1. Mutational analysis of the p27(kip1) gene in hepatocellular carcinoma[J] Cancer Lett, 2000, 153(1-2): 169-73.
[20] Mamillapalli R, Gavrilova N, Mihaylova VT et al. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2)[J]. Curr Biol, 2001,11(4): 263-7.
[21] Hartmann W, Waha A, Koch A, et a1. p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2 and H19[J] Am J Pathol, 2000, 157(9): 1393-403.
[22]杨涛,屈建强. p57kip2与脑胶质瘤研究进展[J]中华神经外科疾病研究杂志, 2007, 6(3): 286-8.
[23] Reid LH, Crider-Miller SJ, West A, et al. Genomic organization of the human P57KIP2 gene and its analysis in the G401 Wilm’s tumor assay[J]. Cancer Res, 1996, 56(6): 1214-8.
[24] Matsuoka S, Edwards MC, Bai C, et a1. P57KIP2, a structurally distinct member of the P21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene[J] Genes Dev, 1995, 9(6): 650-62.
[25] Kamb A, Gruis NA, Weaver-Feldhaus J et al. A cell cycle regulator potentially involved in genesis of many tumor types[J] Science, 1994, 264(5157): 436-40.
[26] Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et a1. The Polycombgroup proteins bind throughout the INK4A -ARF locus and are disassociated in senescent cells[J]. Genes Dev, 2007, 21(5): 525-30.
[27]郑瑞玑,沈建箴. INK系列抑癌基因(p16、p15、p18、p19)在白血病研究进展[J]医学综述, 2005, 11(2): 127-9.
[28] Giacinti C, Giordano A. RB and cell cycle progression[J]. Oncogene, 2006, 25(38):5220- 7.
[29] Graňa X,Reddy EP.Cell cycle control in mammalian cell: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors(CKIs)[J] Oncogene, 1995 , l1(2): 201-9.
[30]高燕,林莉萍,丁健.细胞周期调控的研究进展[J].生命科学, 2005, 17(4): 318-22.
[31]陈军. P53蛋白研究新进展[J].国外医学(卫生学分册), 2002, 29(2): 104-9.
[32]Waga S, Hannon GJ, Beach D et a1. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA[J] Nature, 1994, 369(6481): 574-8.
[33] Nakao M, Yokota S, Kaneko H, et al. Alterations of CDKN2 gene structure in childhood acute lymphoblastic leukemia: mutations of CDKN2 are observed preferentially in T lineage. [J]. Leukemia, 1996,10(2): 249-54.
[34] Decker T, Schneller F, Hipp S, et al . Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27[J]. leukemia, 2002,16(3): 327-34
[35] Wolowiec D, Ciszak L, Kosmaczewska A, et al. Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia[J]. Haematologica, 2001, 86 (12): 1296-304.
[36] Iida H, Towatari M, Tanimoto M, et al. Overexpression of cyclin E in acute myelogenous leukemia [J]. B1ood, 1997, 90(9): 3707-13.
[37]李红华,汪月增,楼方定.急性白血病患者周期蛋白D1mRNA表达及其临床意义[J].中华血液学杂志, 1999, 20(7): 357-358
[38]吴穗晶,杜欣,陈运贤,等.细胞周期蛋白与急性白血病预后[J].癌症, 2003, 22(8): 852-4.
[39]J: 34 Grzanka,Styczynski.Expressiono fc yclinA inh umanl eukemiac elllines HL-60 and K-562 at the level of light and electron microscope byusingim munocytochemicalm ethods.Neoplasma.2001:48(2):112-115
[40] M?ller C, Yang R, Park DJ, et al . The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocyticleukemia [J]. Blood, 2000, 96(12): 3894-9.
[41]卢瑞南,盛瑞兰等,李建勇,等.急慢性白血病p27( Kipl)表达及其临床意义[J].中国实验血液学杂志, 2004, 12(3): 291-7.
[42]施均,邵宗鸿,刘鸿,等.骨髓增生异常综合征细胞周期调控基因表达谱的研究[J].中华血液学杂志, 2005, 26(1): 10-14
[43] Matushansky I, Radparvar F, Skoultchi AI. Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1 [J]. Proc Natl Acad Sci U S A, 2000, 97(26): 14317-22.
[44] Sauerbrey A, H?fer R, Zintl F, et al. Analysis of cyclin D1 in de novo and relapsed childhood acute lymphoblastic leukemia [J].Anticancer Res, 1999, 19 (1B ): 645-9.
[45] Volm M, Koom?gi R, Stammler G, et al. Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, p16INK4A) in childhood acute lymphoblastic leukemia [J]. Int J Cancer, 1997, 74(5): 508-12.
[46]张乐萍,李静.周期蛋白D3在小儿急性白血病细胞中的表达及其作用研究[J].中华血液学杂志, 1999, 20(7): 347-9.
[47] Komuro H, Valentine MB, Rubnitz JE, et al. p27KIP1 deletions in childhood acute lymphoblastic leukemia. [J]. Neoplasia, 1999, 1(3): 253-61.