NF-E2在红系造血调控作用中的研究
摘要
NF-E2(Nuclear factor erythroid 2)，属于基本亮氨酸链状蛋白。是红系特异性转录因子。它由两个亚基组成，其中小亚基p18广泛大量表达于各种组织中，而大亚基p45则属于组织限定性蛋白，只在造血前体细胞，红系细胞、巨核细胞、粒细胞及嗜酸细胞中有所表达。NF-E2能够与血红蛋白珠蛋白基因局部控制区域(LCR)中的增强子序列相结合从而促进其转录，在红系分化中起到至关重要的作用。在p45NF-E2表达缺陷的红白血病细胞株中，血红蛋白的表达极大的减低甚至消失，而外源p45NF-E2的导入则能够使血红蛋白的表达恢复，说明NF-E2对血红蛋白的表达起决定性作用。但是在基因敲除小鼠中，却没有见到明显的贫血改变，说明体内有某种因子可能起到代偿作用。基因敲除的小鼠多因为外周血小板缺失而出血死亡。说明NF-E2对巨核细胞分化形成血小板至关重要。
编码小鼠p45NF-E2的基因位于友好病毒的一个常见的插入位点Fli-2区域。在友好病毒诱导产生的一些红白血病细胞系中，友好病毒的插入导致一条等位基因失活，同时在肿瘤的形成过程中，另一条等位基因丢失。提示NF-E2可能在红白血病的发生中起到抗癌基因的作用。当应用友好病毒注射p45NF-E2基因敲除杂合子小鼠诱导红白血病时，与野生型小鼠相比发病率升高，只有来源于杂合子的原发肿瘤能够建立细胞系，并且大部分细胞系的建立都伴有另一条等位基因的丢失而导致p45NF-E2的完全失活。进一步确定了NF-E2具有抗癌基因的功能。
吉林人学博1学位论文
呼
心
为了探讨NF一EZ抗肿瘤作用的机制，我们应用p45NF一EZ缺陷的红白血
病细胞cB3和HB22.2作为细胞模型对其功能进行了研究。当外源P45NF一EZ
基因在CB3和HB 22.2中得到表达后，在两种细胞中都获得了血红蛋白的表
达。对肿瘤生长曲线的研究发现，在HB222细胞中，外源基因的表达极大
地抑制了肿瘤细胞的生长。对细胞周期相关蛋白的研究表明，NF一EZ能够通
过升高细胞周期素依赖的蛋白激酶(cDK)的抑制因子p27来发挥抗肿瘤作
用。但CB3细胞中却没有见到抑制肿瘤细胞生长的作用，同样地也没有p27
的改变，考虑可能是由于在CB3细胞中多种细胞缺陷，细胞环境相对不完整
所致。为了证实NF一EZ的抑制肿瘤功能，我们对HB60一5进行诱导分化，随
着诱导时间的延长，P45NF一EZ和血红蛋白的表达逐渐升高，同时也可以见到
p27的逐渐增加。p27作为细胞周期抑制因子，能够对各种CDK进行抑制，
但其主要的靶位则是抑制CDKZ的功能。反之，激活的CDKZ能够使p27第
187位苏氨酸磷酸化，从而被泛素依赖的蛋白酶体降解。在细胞周期的进行
中，cyclin Dl起到“开关”的作用，同时Cyclin Dl对p27的降解过程起到
重要的作用。当细胞受到外来因素的刺激时，首先出现cyclin Dl的升高，
而cyclin Dl与CDK4通过p27的组装作用而形成复合物，同时滞留了p27，
阻止其与Cyclin E/CDKZ复合物的结合而发挥抑制CDKZ的功能。我们检测
T转染外源P45NF一EZ的HB22.2细胞的Cyelin nl及CDK的改变，发现NF一EZ
可以降低Cyclin Dl与CDKZ的蛋白水平，同时应用免疫沉淀的方法研究蛋
白之间的相互作用表明P27与CDKZ的结合增多而发挥抑制作用。同样的在
HB60一5诱导分化的细胞当中，也可以见到Cycin DI和CDKZ同样的改变。
以上这些细胞周期相关蛋白的改变均发生在转录后水平。为了确定NF-EZ对
细胞周期蛋白的调节是否依赖于红系细胞分化，我们将p45NF一E2基因转染
到猴肾脏细胞cosl中，同样地得到了p27和cyclin Dl的改变，但是却没
有CDKZ水平和活性的变化，说明NF一EZ对p27和Cyclin Dl的调节不需要
勺/
口了
吉林人学搏尸尹位论文
造血细胞环境，但是完全发挥抑制细胞周期的作用则需要红系细胞分化参与
其中。
为了进一步寻求NF一EZ在红系造血调控中所发挥的作用，我们引用基因
芯片技术对NF一EZ所调节的基因进行了检测。我们首先检测了14.5天小鼠胚
胎肝脏中基因的变化，发现在p45NF一EZ基因敲除的小鼠胚胎肝脏中，与野
生型对照组相比，没有血红蛋白表达的差异，Northem Blot检测也证明了这
一点。从基因芯片的结果我们知道，在体内NF一EZ能够通过调节铁蛋白轻链
1及timeless同源基因而发挥影响铁代谢和生物节律的功能。在转基因细胞的
基因芯片检测中，我们发现NF一EZ能够上调G户a’A一1和EDRF基因，同时下
调Fli一1基因。GATA一1是红系造血调控中的一个主要转录因子，能够抑制红
系细胞的增殖和促进红细胞分化，Fli一1属于ets转录因子家族，主要在红系
细胞中表达，在多种红白血病中，由于逆转录病毒的插入而持续激活。它能
够促进红系细胞的增殖而抑制分化。作为红系相关因子，GAI’A一1和Fli一1具
有相互抑制的作用。EDRF是近年来发现的一个红系相关基因，对血红蛋白
珠蛋白链的稳定，减少细胞内沉淀而降低其细胞毒性至关重要。在诱导分化
的HB60一5的细胞中，同样可以见到GATA一1和EDRF的上调和Fli一1的下调。
而经过应用GAI人一1基因和Fli一1基因转染HB60一5细胞，发现GAEA一1可以
上调EDRF而Fli一1可以使之下调。从而证实了NF一EZ是通过升高GAI’A一1
和降低Fli一1进而加强EDRF的表达。
唾
性
r
NF-E2 (nuclear factor erythroid 2) is a basic leucine zipper protein which is belong to CNC transcriptional family. NF-E2 is critical for the globin expression. The binding of NF-E2 to the MARES in the DNase I hypersensitivity site HS2 which is located in the LCR (locus control region) of P globin induce the high expression of 3 globin. There is also NF-E2 binding site in the HS40 site which is the enhancer of a globin. NF-E2 is a heterozimer which is formed by 2 subunit p18 and p45. p28 is a widely expressed protein. p45 subunit is tissue restricted protein which is almost exclusively found only in hematopoeitic processor, erythroid cell, megakyrocyte, granule cell. In addition to the function on the erythroid differentiation, it is also essential for normal platelet production. Targeted disruption of the gene encoding the 45 kDa subunit leads to severe thrombocytopenia but little if any defect in erythropoiesis, indicating that other molecules can compensate p45 's function in red cell maturation in vivo.
However, retroviral integration within the p45 gene has been shown to disrupt erythroid di€erentiation in erythroleukemia cells. In the erythroid cell line CBS, due to the intergration of previrus, one allele p45NF-E2 is inactive and another allele is lost during the development. Indicate the antitumor effect of NF-E2 in the development of the erythroid leukemia induced by the friend virus . Injected the friend virus to p45NF-E2+ new born mice to induce erythroid
leukemia, the p45NF-E2+ mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/- mice were significantly larger than those of +/+ mice. Only the tumors generated from +/-mice gave rise to cell lines, establishment in culture was associated with the loss of the remaining wild-type p45 NFE2 allele in most of the cell lines. Indicate that p45 NFE2 functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia.
In order to clarify the mechanism of the antitumor function of NF-E2 we transfected the p45NF-E2 to CB3 and HB22.2 cell in which the p45NF-E2 is null due to the previrus intergration. Globin expression was recruited after the transfection. The cell growth was much slower in HB22.2 cell transfected with p45NF-E2 compare to the control cell. The Cyclin dependent kinase(CDK) inhibitor p27 was upregulated significantly. But in CB3 cell line there was no change between transfected cell and control cell, the resean maybe due to there is much more gene inactive in CB3 cell than in HB22.2 cell. In HB60-5 cell which was induced erythroid differentiation after the withdraw of SCF in the culter medium. The p45NF-E2 and globin was upregulated gradually, simultaneously, p27 was also upregulated.
p27 can slow down the cell cycle by inhibiting the activation of CDK, conversely, the activated CDK2 can phosphorylated the Threoninel87 of p27 which can be degradated by ubiquitin dependent proteasome. Cyclin Dl plays important role in the degradation of p27. Cyclin Dl is a switch in the cell cycle. While cell external mitosis stimulation cause increasing of Cyclin Dl, p27 assembly Cyclin Dl and CDK4 complexity. The Cyclin D1/CDK4 sequesters p27
and blocks the interaction of p27 and Cyclin E1CDK2. More activated CDK2 causes more degradiation of p27.
In HB22.2 cell the expression of p45NF-E2 leaded to deregulated of Cyclin Dl and CDK2, and the interaction of p27 and CDK2 was more obviously than that in control cells. In HB60-5 cell which was induced erythroid differentiation, the change of cell cycle relative protein is similarly. To demonstrated whether the antitumor effect is dependent on the erythroid differentiation, we transfected p45NF-E2 to COS1 cell which is monkey kidney cell lines. We also got p27 upregulation an Cyclin Dl down regulation, but there is no CDK2 decreasing and the enhanced p27/CDK2 interaction.
To elucidate the genes expression regulated by NF-E2, we use microarray to screen the gene in mice fetus li
编码小鼠p45NF-E2的基因位于友好病毒的一个常见的插入位点Fli-2区域。在友好病毒诱导产生的一些红白血病细胞系中，友好病毒的插入导致一条等位基因失活，同时在肿瘤的形成过程中，另一条等位基因丢失。提示NF-E2可能在红白血病的发生中起到抗癌基因的作用。当应用友好病毒注射p45NF-E2基因敲除杂合子小鼠诱导红白血病时，与野生型小鼠相比发病率升高，只有来源于杂合子的原发肿瘤能够建立细胞系，并且大部分细胞系的建立都伴有另一条等位基因的丢失而导致p45NF-E2的完全失活。进一步确定了NF-E2具有抗癌基因的功能。
吉林人学博1学位论文
呼
心
为了探讨NF一EZ抗肿瘤作用的机制，我们应用p45NF一EZ缺陷的红白血
病细胞cB3和HB22.2作为细胞模型对其功能进行了研究。当外源P45NF一EZ
基因在CB3和HB 22.2中得到表达后，在两种细胞中都获得了血红蛋白的表
达。对肿瘤生长曲线的研究发现，在HB222细胞中，外源基因的表达极大
地抑制了肿瘤细胞的生长。对细胞周期相关蛋白的研究表明，NF一EZ能够通
过升高细胞周期素依赖的蛋白激酶(cDK)的抑制因子p27来发挥抗肿瘤作
用。但CB3细胞中却没有见到抑制肿瘤细胞生长的作用，同样地也没有p27
的改变，考虑可能是由于在CB3细胞中多种细胞缺陷，细胞环境相对不完整
所致。为了证实NF一EZ的抑制肿瘤功能，我们对HB60一5进行诱导分化，随
着诱导时间的延长，P45NF一EZ和血红蛋白的表达逐渐升高，同时也可以见到
p27的逐渐增加。p27作为细胞周期抑制因子，能够对各种CDK进行抑制，
但其主要的靶位则是抑制CDKZ的功能。反之，激活的CDKZ能够使p27第
187位苏氨酸磷酸化，从而被泛素依赖的蛋白酶体降解。在细胞周期的进行
中，cyclin Dl起到“开关”的作用，同时Cyclin Dl对p27的降解过程起到
重要的作用。当细胞受到外来因素的刺激时，首先出现cyclin Dl的升高，
而cyclin Dl与CDK4通过p27的组装作用而形成复合物，同时滞留了p27，
阻止其与Cyclin E/CDKZ复合物的结合而发挥抑制CDKZ的功能。我们检测
T转染外源P45NF一EZ的HB22.2细胞的Cyelin nl及CDK的改变，发现NF一EZ
可以降低Cyclin Dl与CDKZ的蛋白水平，同时应用免疫沉淀的方法研究蛋
白之间的相互作用表明P27与CDKZ的结合增多而发挥抑制作用。同样的在
HB60一5诱导分化的细胞当中，也可以见到Cycin DI和CDKZ同样的改变。
以上这些细胞周期相关蛋白的改变均发生在转录后水平。为了确定NF-EZ对
细胞周期蛋白的调节是否依赖于红系细胞分化，我们将p45NF一E2基因转染
到猴肾脏细胞cosl中，同样地得到了p27和cyclin Dl的改变，但是却没
有CDKZ水平和活性的变化，说明NF一EZ对p27和Cyclin Dl的调节不需要
勺/
口了
吉林人学搏尸尹位论文
造血细胞环境，但是完全发挥抑制细胞周期的作用则需要红系细胞分化参与
其中。
为了进一步寻求NF一EZ在红系造血调控中所发挥的作用，我们引用基因
芯片技术对NF一EZ所调节的基因进行了检测。我们首先检测了14.5天小鼠胚
胎肝脏中基因的变化，发现在p45NF一EZ基因敲除的小鼠胚胎肝脏中，与野
生型对照组相比，没有血红蛋白表达的差异，Northem Blot检测也证明了这
一点。从基因芯片的结果我们知道，在体内NF一EZ能够通过调节铁蛋白轻链
1及timeless同源基因而发挥影响铁代谢和生物节律的功能。在转基因细胞的
基因芯片检测中，我们发现NF一EZ能够上调G户a’A一1和EDRF基因，同时下
调Fli一1基因。GATA一1是红系造血调控中的一个主要转录因子，能够抑制红
系细胞的增殖和促进红细胞分化，Fli一1属于ets转录因子家族，主要在红系
细胞中表达，在多种红白血病中，由于逆转录病毒的插入而持续激活。它能
够促进红系细胞的增殖而抑制分化。作为红系相关因子，GAI’A一1和Fli一1具
有相互抑制的作用。EDRF是近年来发现的一个红系相关基因，对血红蛋白
珠蛋白链的稳定，减少细胞内沉淀而降低其细胞毒性至关重要。在诱导分化
的HB60一5的细胞中，同样可以见到GATA一1和EDRF的上调和Fli一1的下调。
而经过应用GAI人一1基因和Fli一1基因转染HB60一5细胞，发现GAEA一1可以
上调EDRF而Fli一1可以使之下调。从而证实了NF一EZ是通过升高GAI’A一1
和降低Fli一1进而加强EDRF的表达。
唾
性
r
NF-E2 (nuclear factor erythroid 2) is a basic leucine zipper protein which is belong to CNC transcriptional family. NF-E2 is critical for the globin expression. The binding of NF-E2 to the MARES in the DNase I hypersensitivity site HS2 which is located in the LCR (locus control region) of P globin induce the high expression of 3 globin. There is also NF-E2 binding site in the HS40 site which is the enhancer of a globin. NF-E2 is a heterozimer which is formed by 2 subunit p18 and p45. p28 is a widely expressed protein. p45 subunit is tissue restricted protein which is almost exclusively found only in hematopoeitic processor, erythroid cell, megakyrocyte, granule cell. In addition to the function on the erythroid differentiation, it is also essential for normal platelet production. Targeted disruption of the gene encoding the 45 kDa subunit leads to severe thrombocytopenia but little if any defect in erythropoiesis, indicating that other molecules can compensate p45 's function in red cell maturation in vivo.
However, retroviral integration within the p45 gene has been shown to disrupt erythroid di€erentiation in erythroleukemia cells. In the erythroid cell line CBS, due to the intergration of previrus, one allele p45NF-E2 is inactive and another allele is lost during the development. Indicate the antitumor effect of NF-E2 in the development of the erythroid leukemia induced by the friend virus . Injected the friend virus to p45NF-E2+ new born mice to induce erythroid
leukemia, the p45NF-E2+ mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/- mice were significantly larger than those of +/+ mice. Only the tumors generated from +/-mice gave rise to cell lines, establishment in culture was associated with the loss of the remaining wild-type p45 NFE2 allele in most of the cell lines. Indicate that p45 NFE2 functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia.
In order to clarify the mechanism of the antitumor function of NF-E2 we transfected the p45NF-E2 to CB3 and HB22.2 cell in which the p45NF-E2 is null due to the previrus intergration. Globin expression was recruited after the transfection. The cell growth was much slower in HB22.2 cell transfected with p45NF-E2 compare to the control cell. The Cyclin dependent kinase(CDK) inhibitor p27 was upregulated significantly. But in CB3 cell line there was no change between transfected cell and control cell, the resean maybe due to there is much more gene inactive in CB3 cell than in HB22.2 cell. In HB60-5 cell which was induced erythroid differentiation after the withdraw of SCF in the culter medium. The p45NF-E2 and globin was upregulated gradually, simultaneously, p27 was also upregulated.
p27 can slow down the cell cycle by inhibiting the activation of CDK, conversely, the activated CDK2 can phosphorylated the Threoninel87 of p27 which can be degradated by ubiquitin dependent proteasome. Cyclin Dl plays important role in the degradation of p27. Cyclin Dl is a switch in the cell cycle. While cell external mitosis stimulation cause increasing of Cyclin Dl, p27 assembly Cyclin Dl and CDK4 complexity. The Cyclin D1/CDK4 sequesters p27
and blocks the interaction of p27 and Cyclin E1CDK2. More activated CDK2 causes more degradiation of p27.
In HB22.2 cell the expression of p45NF-E2 leaded to deregulated of Cyclin Dl and CDK2, and the interaction of p27 and CDK2 was more obviously than that in control cells. In HB60-5 cell which was induced erythroid differentiation, the change of cell cycle relative protein is similarly. To demonstrated whether the antitumor effect is dependent on the erythroid differentiation, we transfected p45NF-E2 to COS1 cell which is monkey kidney cell lines. We also got p27 upregulation an Cyclin Dl down regulation, but there is no CDK2 decreasing and the enhanced p27/CDK2 interaction.
To elucidate the genes expression regulated by NF-E2, we use microarray to screen the gene in mice fetus li
引文
1. Mignotte . V. Wall .L ; deBoer . E . Grosveld. Nucleic Acids Res 17. 37-54(1989).
2. Orkin. S.H. Cell 63 , 665-672(1990)
3. Erythroid transcription factor NFE2 is a haematopioetic-specific basic-leucine zipper protein. Nancy c. Andrews, Hediy Erdjument-Bromage, Mark. B. Davidson Nature . Vol 362 22 April 1993.
4. Mignotte V. wall deBoerE, Grosved, F & Romeo. P.H Nucleic Acid Res 17. 37-54 (1989)
5. Philipsen. S. Talbot D; Fraser P &Grosveld , F FMBOJ 9 , 2159-2178(1990)
6. Ney, P.A Sorrentino. B.P. McDonagh. K. Genes Dev 4. 993-1006(1990)
7. Ney, P.A Genes Dev 4. 993-1006(1990)
8. Jarman. A.P. etal Molec Cell. Biol 11 4679-4689
9. Taketani. S. Eur. J .Biochem. 205, 217-222(1992)
10. Nature Vol 367. 10 FeBruray 1994. regulation of transcription by dimerization of erythroid factor NFE2 p45 with small Maf protein.
11. Proc Natl , Acad Sci USA Vao . PP 11488-11492 1993
12. V-Blank. The Maf protein:Regulators of differentiation. Trend Biochem. Sci (1997) ; in press.
13. Onco gene 1997 Apr 24 ; 14(16):1901-10
14. Blood 1997 Jun 1; 89(11):3925-35
15. Genes Cells 1996 Feb;1(2):223-38
16. Oncogene 1997 Feb 20; 14(7):873-7
17. Nol Cell Biol 1995 Apr; 15(4):2180-90
18. Mohler. J. Vani Mech . Dev 34, 3-10(1991)
19. The activation domain of enhancer binding protein p45 NF-E2 interacts with TAF Ⅱ 130 and mediates long-rang activation of the α -and- β -globin gene loci in erythroid cell line. Proc. Natl. Acad. Sci USA V94 PP. 10051-10056 September 1997.
20. WW.Domain-binding Motif within the Activation Domain of the Hematopoietic Transcription Factor NFE2 is Essential for Establishment of a Fissue-specific Histone Modification Pattern. The Joarnal of Biological. Chemistry. Vol. 279. No. 9 Issue of FeberaryPP 7456-7461 2004
21. Multiple region of p45NF-E2 are required for beta-blobin gene expession in erythroid cell. Nucleic Acid Res 1997 Jun 15;25(12):2509-15
22. Moleculor characterization and localization of the human MaFG gene. Blank V, knoll JH , Andrew N.C. Genomic 1997 Aug 15; 44(1):147-9
23. P.A. Ney. N.C. Andrew. SM Jane. purification of human NF-E2 complex:cDNA cloning of the hematoporetic cell specific subunit and evidence for associated partner Molo. Cell . Biol 13 (1993) 5604-5612
24. Exp Hematol 2000 Oct: 28(10):1113-9 Functional characterization of the two alternative promoters of human p45 NFE2. Toki T, Araik , Teruik, KomatsuN.
25. J. Boil Chem. 2000 Apt 7 ; 275(14):10567-76. Regulation of Mouse p45 NF-E2 transcription by an erythroid specific GATA-dependent intronic alternative promoter.
26. J. Boil chem. 1999 Aug 13; 274(33):23491-8. hFOG-2 , a novel zinc finger protein, bind the co-repressor m CtBP2 and modulates GATA-mediated activation. HolmesM, Turner J , Fox A , Chisholm o , Crossley M ,Chong, B
27. Oncogene (2002) 21 , 3368-3376. Transcriptional regulation of erythropoiesis :an affair involung multiple partners. Alan B Cantor and Stuart H Orkin.
28. Tohoku J Expeo Med . 2000. Dec; 192(4):259-73 . Teruik, Takanashi Y.
29. Exp Cell Res 1998 Nov 25; 245(1):186-94. Yamada T , kihara-Negishi F.
30. J Biol Chem, 1998 Feb 27, 273(9):5358-65. regulation of NF-E2 activity in erythroleukemia cell differentiation . Nagai T, Igarashi K
31. L Catanil, N Vianellil, M Amabilel, Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis. Leukemia (2002) 16, 1773 - 1781
32. J. Boil Chem. 2003. May 23; 278(21):19534-40. Epub 2003 March 17. Erythroid gene suppression by NF-KappaB. Liu JJ , Hou SC. ShenCK.
33. Bulger. M. Looping versus linking : toward a model for long distance gene activation . Gene Dev. 1999 13 , 2465-2477
34. Reik , A , Telling, A , 1998. Mol Cell Biol 18, 5992-6000.
35. 1998 Mol. Cell. Biol. 18, 5992-6000. The locus control region is necessary for gene expression in the human β-globin locus but not for the maintenance of an open chromatin structor.
36. 1999. Nature 398 , 344-348 . Effects of altered gene order or orientation of locus control region on humanβ-globin gene expression in mice.
37. Rev. Biochem 57:159-197 1998. nuclerse hypersensitive site in Chromatin.
38. A major positive regulatory region located for upstream of human α -globin gene locus . Gene Dev 1990 4:1558-1601 Higgs , D.R, W.G. Wood.
39. Inamdar NM, Ahn YI, Alam J. The heme-responsive element of the mouse heme oxygenase-1 gene is an extended AP-1 binding site that resembles the recognition sequences for MAF and NF-E2 transcription factors. Biochem Biophys Res Commun. 1996:221:570-576.
40. Each hypersensitive site of humanβ-globin locus control region confer a different development pattern of expression of the globin gene. Genes Dev 1993 7:106-113. Fraser, P , S. Pruzina.
41. A deletion of the human β -gobin locus activation region cause a major alteration in Chromatin Structure and replication across the entire β-gobin locus Genes Dev 1990 4:1637-1649. Forrester , w. c. F, E. Epner.
42. 1990. Synergistic enhancement of globin gene expression by activator protein-1-like proteins . Proc. Natl. Acad . Sci, USA. 87:9000-9004
43. 1992. Nucleic Acids Res 20:237-243. The LCR-like α -globin positive regulatory element function as an enhancer in transiently transfected cells during erythroid differentiation. Pondel , M.D.m. George.
44. Dependence of globin gene expression in mouse erythroleukemia cells on the NFE2 heterodimer . Mol Cell Biol 1995 15:4640-4647 Kotkow KJ, Orkin SH
45. Proc .Natl Acad Sci USA Vol 91 PP:8389-8402 Augerst 1994. Retrovial intergration with the Fli-2 locus result in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukemias : Evidence that NF-E2 is essential for globin expression. Shi-Jiang lu ShelDon Rowan MaRia Rosa Bani.
46. Nuckeic Acid Research 2003 , Vol 31 , Nov4 292-1301. Characterization of human β-globin downstream promoter region KellyM . leach , karen F. vieira.
47. Nature (London) 312, 612-615 1984 Brent , R & Ptashne , M.
48. Mueller-Storm, H.P. Sogo , J.M. 1989 Cell 58, 767-777.
49. Felsenfeld, G (1992) Nature (London)355, 219-224
50. Blood , 1 July 2000 . Volume 96 Number 1 334-339 . Direct interaction of NF-E2 with hypersensitive site 2 of he β -globin locus control region in living cell . E . Camilla Forsberg , Karen M . Downs .
51. Molecular and cellular Biology, Oct 1996 5634-5644. NFE2 disrupts Chromatin stracture at human β -globin locus control Region Hypersensitive site2 in Vitro. Jennifer A . ARMSTRONG , Bevekly M EMERSON.
52. 2000 . Mol cell Bio 20 , 1899-1910. Vignali , M , Hassan.
53. Cell 2000 103 , 263-271. Cheng , P ; Allis .
54. A major role for TATA box in recreitment of Chromatin modifying complxes to a globin genepromoter PNAS June 2003 Vol 100. No12 7009-7014. Chang-yun Gui and Am Rean.
55. 2001 Molecular Cell Vol 8 , 465-471 August 465-471. Distinct Mechanisms Control RNA Polymerase Ⅱ. Recruitment is a Tissue specific locus control Region and a Down stream Promoter kirby D . Johnso , Heather M . Christersen.
56. The Journal of Biological chemistry 2001 Vol 276 No. 14 . issue of April 6 , 10715-10721 . Stimulation of NFE2 DNA Binding by CREB-binding protein
(CBP)-mediated Acetylation. Hsiao-Ling Hung , Arexander Y . kim.
57. 1999. The Journal of Biological Chemistry Vol 274. No. 38, Issue of september 17 26850-26859. Requirement of an EIA-Sensitive coactivator for long-rang Transactivation by the β -globin locus control region E. Camilla Forsberg, kirby Johnson.
58. 2002 Nucleic Acids Research , Vol 30 , No. 7 152-1530. Requirement for utilization of CREB binding protein by hupersensitive site two of the β -globin locus control Region kirby D. Johnson, Jason E. Norton and Emery H. Bresnick.
59. Blood April 2001 Volume 97, number 7 2151-2158. Reduced oxidative stress response in red blood cell form p45 NFE2-deficient mice. Jefferson. Y Chan, Mandy Kwong.
60. Proc Nail Acad Sci USA 1995 Sep 12 ; (19): 8690-4. Erythropoiesis and globin expression in mice lacking the transcriptior factor NFE2. ShivdasaniRA, Orkin SA.
61. Transcription factor NFE2 is Required for platelet Formation independent of the Actions of Thrombopoietin MGDF in Megakarcyte Development. Ramesh A . Shivdasni. Cell Vol 81 , 695-704, June 2 , 1995, 695-704.
62. p45NFE2 regulate expression of thromboxan synthasein megakaryocytes. The EMBO Jownal Vol 16 No 18 5654-5661 1997 Sophie Deveaux , Sylvia Cohen-kancinsky
63. J Biol chem 2002 Jun 21, 277(25):22497-508 Epub 2002 Apr15. Transcriptional control of the human thromboxane synthasegene in vivo and in vitro. YaekashiwaM, Wang LH.
64. Nuclear Factor-erythroid 2 (NFE2) expression in normal and malignant megakayocto.
65. Proc Natl Acad Sci USA. Vol 87, 1332-1336 February 1990 identification and mapping of a common proviral integration site Fli-1 in erythraleukemia cell induced by Friend murine leukemia virus Yaacoo.
66. Retroviral integration with the Fli-2 locus result in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukamia : Evidence the NFE2 is essential for globin expression. Shi - Jianglu. Proc Natl Acad Sci USA.
67. p45 NFE2 is a Negative Regulator of Erythroid Proliferation which contribute to the progression of Friend virus induced Erythroleukemia. Molecular and cellular Biology Jan 2001 , P73-80 . YouJun Li.
68. YOU-JUNLI, IRACHEL R. HIGGINS, I BRIAN J. PAK, p45NFE2 Is a Negative Regulator of Erythroid Proliferation Which Contributes to the Progression of Friend Virus-Induced Erythroleukemias MOLECULAR AND CELLULAR BIOLOGY, Jan. 2001, p.73 - 80
69. British Journal of haematology 2000 , 110, 663-673. Lineage-specific
regulation of cell cycle control gene expression during hematopoietic cell diffrentiation . Yusuk Furukawa et.
70. Blood 15. October 2000, volume 96, number 8 cell cycle exit during termiral erythroid diffrentiation is associated with accumulation of p27kipl and inactivation of K2 kinase FenF. Hsieh.
71. deregulated deragulation of CDK inibitor p27 and maligrant transformation. Seminars in Cancer Biology 13(2003) 41-47. Jonna Bloom , Michele pagano.
72. Hanat B.L. Wang A; Seth , P , and Jetten , A.M (1998) . up-regulation of p27kipl , p21WAF1/CIP and p16 Inka is associated with but not sufficient for induction of squamous murine keratinocytes. Cell Growth Differ , 8 ,203-211.
73. Baldasarre , G. Barone , M.V, Belletti, B, Sandomenico, C. et. (1999). Key role of the cyclin-dependent kinase inhibitor p27kip for embyonal Carcinoma cell survival and diffrentiation . Oncogene 18 6241-6251.
74. Hengst L. Dulic, V, Slingerland, 3、 M, lees , E et al . A cell-regulated inhibator of cyclin-dependent kinase proc Natl Acad Sci USA 91 , 5291-5295.
75. FeroM, Rivkin M , Tasch M, PorterP , Carowe , FirpoE et al. Asyndrome of multi-organ hyperplasia with features of gigantism, tumorigenesis and female sterility in p27kipl-deficient mice . Cell 1996; 85:733-74.
76. Kiyokawa H, KinemanR, Manova-Todorova K etal . Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27kipl Cell 1996; 85:721-32.
77. Park MS, Rosai J, Nguyen HT, Capodiecip. Cordon-Cardo C ,etal p27 and Rb are overlapping pathways suppressing tumorigenesis on mice proc Natl Acad Sci USA 1999; 96:6382-7.
78. Jeannette Philipp-Staheli , shannon R. Payne , Christopher J . Kemp p27kipl:Regulation and function of a haptoinsufficient tumor suppressor and its Misregulation in Cancer, Experimental cell Research 264, 148-168(2001).
79. Deregulated degradation of the cak inhitor p27 and maligrant transformation. Joanna Bloom , Michere Pagano Seminar in Cancer Biology 13(2003)41-47.
80. Millara S .S, Vidal, A, Markus, M;etal. A v-rich element in the 5' untranslated region is necessary for the translation of p27 mRNA. Mol Cell Biol 205947-5959.
81. Russo AA, Jeffrey PD, Patten AK, etal. Crystal steucture of the p27kipl cyclin-dependent kinase inhibitor bound to the cyclin A-CDK2 complex. Nature 1996;382:325-31.
82. Sherff, R. J, Groudine, M, Gordon, M. etal(1997). CyclinE-CDK2 is a regulator of p27kipl . Gene Dev . 11, 1464-1478.
83. Cyclin D1 Serve as a cell cycle regulatory in actively proliferating cells.
Current opinion in cell Biology 2003, 15:158-163.
84. Soos, T.J. Kiyokawa, H, Yan, J. S etal(1996). Formation of p27-CDK complex during the human mitotic cell cycle cell Growth Differ 7,135-146.
85. Kawada M, Yamagoe S, Murakami Y. etal 1997. Induction of p27kipl degradation and an chorage independence by Ras through the Map kinase signaling pathway. Oncogene 15 , 629-637.
86. Yoshio TeraDa, Seiji Inoshita, Osama Nakashima etal. Regulation of cyclin DI expression and cell cycle progression by mitogen-activated protein kinase cascad kidney international Vol 56 , 1258-1261.
87. Graff, J R, Konicek, B. W., Mcmolty, A.M. etal(2000). Increased Akt acticity contributes to prostate cancer progression by dramatically accelerating prorate tumor growth and diminishing p27kipl, increase its protein stability. J . Biol .Chen . 275,25146-25154.
88. Reynisdottrr, I ,and Massague J (1997) . the subcellular location of p15(ink4b) and p27(kipl) coordinate their inhibitory interactions with cdk4 and cdk2 .Genes Dev . 11, 492-503.
89. Jing xiao, Changgong Li, Nian-ling Zhu Timeless in lung morphogenesis Developmental Dynamics 228:82-94.2003
90. Elizabeth C. Theil, Ferritn:at the crossoads of iron and oxygen metabolism Nutrition 2003 1549s
91. Weis, M J, S.H Orkin Gata-1 transcription factor:key regulate of hematopoeisis. Exp. Hematol 1995 22:99-107
92. Marcin Rylski, John J. welch, Ying-yu Che et al. Gata-1-mediated proliferation arrest during erythroid maturation. Molecular and cellular biology 2003 july p5031-5042.
93. Ben-David Y,Giddens E.B. Bernstein A. Pro. Natl. Acad. Sci. USA 1990,87,1332-1336.
94. Denicourt C, Edouard EB ,Rassart E J. virol 73,4439-4442.
95. Bergeron D, Poliquin L, Kozak CA and Rassart E J. virol 1991,65,7-17
96. Delattre O, Zueman J, Plougastel B Nature 1992 359,162-165
97. Amadine HL Truong, Yaacov Ben-David The role of Fli-1 in normal cell function and malignant transformation. Onco(2000) 19,6482-6489.
98. Anthony J. Kihm, Wei Hong et. al An aboundant erythroid protein that stablizaes free α-globin Nature(2002),417(6),13:758-
2. Orkin. S.H. Cell 63 , 665-672(1990)
3. Erythroid transcription factor NFE2 is a haematopioetic-specific basic-leucine zipper protein. Nancy c. Andrews, Hediy Erdjument-Bromage, Mark. B. Davidson Nature . Vol 362 22 April 1993.
4. Mignotte V. wall deBoerE, Grosved, F & Romeo. P.H Nucleic Acid Res 17. 37-54 (1989)
5. Philipsen. S. Talbot D; Fraser P &Grosveld , F FMBOJ 9 , 2159-2178(1990)
6. Ney, P.A Sorrentino. B.P. McDonagh. K. Genes Dev 4. 993-1006(1990)
7. Ney, P.A Genes Dev 4. 993-1006(1990)
8. Jarman. A.P. etal Molec Cell. Biol 11 4679-4689
9. Taketani. S. Eur. J .Biochem. 205, 217-222(1992)
10. Nature Vol 367. 10 FeBruray 1994. regulation of transcription by dimerization of erythroid factor NFE2 p45 with small Maf protein.
11. Proc Natl , Acad Sci USA Vao . PP 11488-11492 1993
12. V-Blank. The Maf protein:Regulators of differentiation. Trend Biochem. Sci (1997) ; in press.
13. Onco gene 1997 Apr 24 ; 14(16):1901-10
14. Blood 1997 Jun 1; 89(11):3925-35
15. Genes Cells 1996 Feb;1(2):223-38
16. Oncogene 1997 Feb 20; 14(7):873-7
17. Nol Cell Biol 1995 Apr; 15(4):2180-90
18. Mohler. J. Vani Mech . Dev 34, 3-10(1991)
19. The activation domain of enhancer binding protein p45 NF-E2 interacts with TAF Ⅱ 130 and mediates long-rang activation of the α -and- β -globin gene loci in erythroid cell line. Proc. Natl. Acad. Sci USA V94 PP. 10051-10056 September 1997.
20. WW.Domain-binding Motif within the Activation Domain of the Hematopoietic Transcription Factor NFE2 is Essential for Establishment of a Fissue-specific Histone Modification Pattern. The Joarnal of Biological. Chemistry. Vol. 279. No. 9 Issue of FeberaryPP 7456-7461 2004
21. Multiple region of p45NF-E2 are required for beta-blobin gene expession in erythroid cell. Nucleic Acid Res 1997 Jun 15;25(12):2509-15
22. Moleculor characterization and localization of the human MaFG gene. Blank V, knoll JH , Andrew N.C. Genomic 1997 Aug 15; 44(1):147-9
23. P.A. Ney. N.C. Andrew. SM Jane. purification of human NF-E2 complex:cDNA cloning of the hematoporetic cell specific subunit and evidence for associated partner Molo. Cell . Biol 13 (1993) 5604-5612
24. Exp Hematol 2000 Oct: 28(10):1113-9 Functional characterization of the two alternative promoters of human p45 NFE2. Toki T, Araik , Teruik, KomatsuN.
25. J. Boil Chem. 2000 Apt 7 ; 275(14):10567-76. Regulation of Mouse p45 NF-E2 transcription by an erythroid specific GATA-dependent intronic alternative promoter.
26. J. Boil chem. 1999 Aug 13; 274(33):23491-8. hFOG-2 , a novel zinc finger protein, bind the co-repressor m CtBP2 and modulates GATA-mediated activation. HolmesM, Turner J , Fox A , Chisholm o , Crossley M ,Chong, B
27. Oncogene (2002) 21 , 3368-3376. Transcriptional regulation of erythropoiesis :an affair involung multiple partners. Alan B Cantor and Stuart H Orkin.
28. Tohoku J Expeo Med . 2000. Dec; 192(4):259-73 . Teruik, Takanashi Y.
29. Exp Cell Res 1998 Nov 25; 245(1):186-94. Yamada T , kihara-Negishi F.
30. J Biol Chem, 1998 Feb 27, 273(9):5358-65. regulation of NF-E2 activity in erythroleukemia cell differentiation . Nagai T, Igarashi K
31. L Catanil, N Vianellil, M Amabilel, Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis. Leukemia (2002) 16, 1773 - 1781
32. J. Boil Chem. 2003. May 23; 278(21):19534-40. Epub 2003 March 17. Erythroid gene suppression by NF-KappaB. Liu JJ , Hou SC. ShenCK.
33. Bulger. M. Looping versus linking : toward a model for long distance gene activation . Gene Dev. 1999 13 , 2465-2477
34. Reik , A , Telling, A , 1998. Mol Cell Biol 18, 5992-6000.
35. 1998 Mol. Cell. Biol. 18, 5992-6000. The locus control region is necessary for gene expression in the human β-globin locus but not for the maintenance of an open chromatin structor.
36. 1999. Nature 398 , 344-348 . Effects of altered gene order or orientation of locus control region on humanβ-globin gene expression in mice.
37. Rev. Biochem 57:159-197 1998. nuclerse hypersensitive site in Chromatin.
38. A major positive regulatory region located for upstream of human α -globin gene locus . Gene Dev 1990 4:1558-1601 Higgs , D.R, W.G. Wood.
39. Inamdar NM, Ahn YI, Alam J. The heme-responsive element of the mouse heme oxygenase-1 gene is an extended AP-1 binding site that resembles the recognition sequences for MAF and NF-E2 transcription factors. Biochem Biophys Res Commun. 1996:221:570-576.
40. Each hypersensitive site of humanβ-globin locus control region confer a different development pattern of expression of the globin gene. Genes Dev 1993 7:106-113. Fraser, P , S. Pruzina.
41. A deletion of the human β -gobin locus activation region cause a major alteration in Chromatin Structure and replication across the entire β-gobin locus Genes Dev 1990 4:1637-1649. Forrester , w. c. F, E. Epner.
42. 1990. Synergistic enhancement of globin gene expression by activator protein-1-like proteins . Proc. Natl. Acad . Sci, USA. 87:9000-9004
43. 1992. Nucleic Acids Res 20:237-243. The LCR-like α -globin positive regulatory element function as an enhancer in transiently transfected cells during erythroid differentiation. Pondel , M.D.m. George.
44. Dependence of globin gene expression in mouse erythroleukemia cells on the NFE2 heterodimer . Mol Cell Biol 1995 15:4640-4647 Kotkow KJ, Orkin SH
45. Proc .Natl Acad Sci USA Vol 91 PP:8389-8402 Augerst 1994. Retrovial intergration with the Fli-2 locus result in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukemias : Evidence that NF-E2 is essential for globin expression. Shi-Jiang lu ShelDon Rowan MaRia Rosa Bani.
46. Nuckeic Acid Research 2003 , Vol 31 , Nov4 292-1301. Characterization of human β-globin downstream promoter region KellyM . leach , karen F. vieira.
47. Nature (London) 312, 612-615 1984 Brent , R & Ptashne , M.
48. Mueller-Storm, H.P. Sogo , J.M. 1989 Cell 58, 767-777.
49. Felsenfeld, G (1992) Nature (London)355, 219-224
50. Blood , 1 July 2000 . Volume 96 Number 1 334-339 . Direct interaction of NF-E2 with hypersensitive site 2 of he β -globin locus control region in living cell . E . Camilla Forsberg , Karen M . Downs .
51. Molecular and cellular Biology, Oct 1996 5634-5644. NFE2 disrupts Chromatin stracture at human β -globin locus control Region Hypersensitive site2 in Vitro. Jennifer A . ARMSTRONG , Bevekly M EMERSON.
52. 2000 . Mol cell Bio 20 , 1899-1910. Vignali , M , Hassan.
53. Cell 2000 103 , 263-271. Cheng , P ; Allis .
54. A major role for TATA box in recreitment of Chromatin modifying complxes to a globin genepromoter PNAS June 2003 Vol 100. No12 7009-7014. Chang-yun Gui and Am Rean.
55. 2001 Molecular Cell Vol 8 , 465-471 August 465-471. Distinct Mechanisms Control RNA Polymerase Ⅱ. Recruitment is a Tissue specific locus control Region and a Down stream Promoter kirby D . Johnso , Heather M . Christersen.
56. The Journal of Biological chemistry 2001 Vol 276 No. 14 . issue of April 6 , 10715-10721 . Stimulation of NFE2 DNA Binding by CREB-binding protein
(CBP)-mediated Acetylation. Hsiao-Ling Hung , Arexander Y . kim.
57. 1999. The Journal of Biological Chemistry Vol 274. No. 38, Issue of september 17 26850-26859. Requirement of an EIA-Sensitive coactivator for long-rang Transactivation by the β -globin locus control region E. Camilla Forsberg, kirby Johnson.
58. 2002 Nucleic Acids Research , Vol 30 , No. 7 152-1530. Requirement for utilization of CREB binding protein by hupersensitive site two of the β -globin locus control Region kirby D. Johnson, Jason E. Norton and Emery H. Bresnick.
59. Blood April 2001 Volume 97, number 7 2151-2158. Reduced oxidative stress response in red blood cell form p45 NFE2-deficient mice. Jefferson. Y Chan, Mandy Kwong.
60. Proc Nail Acad Sci USA 1995 Sep 12 ; (19): 8690-4. Erythropoiesis and globin expression in mice lacking the transcriptior factor NFE2. ShivdasaniRA, Orkin SA.
61. Transcription factor NFE2 is Required for platelet Formation independent of the Actions of Thrombopoietin MGDF in Megakarcyte Development. Ramesh A . Shivdasni. Cell Vol 81 , 695-704, June 2 , 1995, 695-704.
62. p45NFE2 regulate expression of thromboxan synthasein megakaryocytes. The EMBO Jownal Vol 16 No 18 5654-5661 1997 Sophie Deveaux , Sylvia Cohen-kancinsky
63. J Biol chem 2002 Jun 21, 277(25):22497-508 Epub 2002 Apr15. Transcriptional control of the human thromboxane synthasegene in vivo and in vitro. YaekashiwaM, Wang LH.
64. Nuclear Factor-erythroid 2 (NFE2) expression in normal and malignant megakayocto.
65. Proc Natl Acad Sci USA. Vol 87, 1332-1336 February 1990 identification and mapping of a common proviral integration site Fli-1 in erythraleukemia cell induced by Friend murine leukemia virus Yaacoo.
66. Retroviral integration with the Fli-2 locus result in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukamia : Evidence the NFE2 is essential for globin expression. Shi - Jianglu. Proc Natl Acad Sci USA.
67. p45 NFE2 is a Negative Regulator of Erythroid Proliferation which contribute to the progression of Friend virus induced Erythroleukemia. Molecular and cellular Biology Jan 2001 , P73-80 . YouJun Li.
68. YOU-JUNLI, IRACHEL R. HIGGINS, I BRIAN J. PAK, p45NFE2 Is a Negative Regulator of Erythroid Proliferation Which Contributes to the Progression of Friend Virus-Induced Erythroleukemias MOLECULAR AND CELLULAR BIOLOGY, Jan. 2001, p.73 - 80
69. British Journal of haematology 2000 , 110, 663-673. Lineage-specific
regulation of cell cycle control gene expression during hematopoietic cell diffrentiation . Yusuk Furukawa et.
70. Blood 15. October 2000, volume 96, number 8 cell cycle exit during termiral erythroid diffrentiation is associated with accumulation of p27kipl and inactivation of K2 kinase FenF. Hsieh.
71. deregulated deragulation of CDK inibitor p27 and maligrant transformation. Seminars in Cancer Biology 13(2003) 41-47. Jonna Bloom , Michele pagano.
72. Hanat B.L. Wang A; Seth , P , and Jetten , A.M (1998) . up-regulation of p27kipl , p21WAF1/CIP and p16 Inka is associated with but not sufficient for induction of squamous murine keratinocytes. Cell Growth Differ , 8 ,203-211.
73. Baldasarre , G. Barone , M.V, Belletti, B, Sandomenico, C. et. (1999). Key role of the cyclin-dependent kinase inhibitor p27kip for embyonal Carcinoma cell survival and diffrentiation . Oncogene 18 6241-6251.
74. Hengst L. Dulic, V, Slingerland, 3、 M, lees , E et al . A cell-regulated inhibator of cyclin-dependent kinase proc Natl Acad Sci USA 91 , 5291-5295.
75. FeroM, Rivkin M , Tasch M, PorterP , Carowe , FirpoE et al. Asyndrome of multi-organ hyperplasia with features of gigantism, tumorigenesis and female sterility in p27kipl-deficient mice . Cell 1996; 85:733-74.
76. Kiyokawa H, KinemanR, Manova-Todorova K etal . Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27kipl Cell 1996; 85:721-32.
77. Park MS, Rosai J, Nguyen HT, Capodiecip. Cordon-Cardo C ,etal p27 and Rb are overlapping pathways suppressing tumorigenesis on mice proc Natl Acad Sci USA 1999; 96:6382-7.
78. Jeannette Philipp-Staheli , shannon R. Payne , Christopher J . Kemp p27kipl:Regulation and function of a haptoinsufficient tumor suppressor and its Misregulation in Cancer, Experimental cell Research 264, 148-168(2001).
79. Deregulated degradation of the cak inhitor p27 and maligrant transformation. Joanna Bloom , Michere Pagano Seminar in Cancer Biology 13(2003)41-47.
80. Millara S .S, Vidal, A, Markus, M;etal. A v-rich element in the 5' untranslated region is necessary for the translation of p27 mRNA. Mol Cell Biol 205947-5959.
81. Russo AA, Jeffrey PD, Patten AK, etal. Crystal steucture of the p27kipl cyclin-dependent kinase inhibitor bound to the cyclin A-CDK2 complex. Nature 1996;382:325-31.
82. Sherff, R. J, Groudine, M, Gordon, M. etal(1997). CyclinE-CDK2 is a regulator of p27kipl . Gene Dev . 11, 1464-1478.
83. Cyclin D1 Serve as a cell cycle regulatory in actively proliferating cells.
Current opinion in cell Biology 2003, 15:158-163.
84. Soos, T.J. Kiyokawa, H, Yan, J. S etal(1996). Formation of p27-CDK complex during the human mitotic cell cycle cell Growth Differ 7,135-146.
85. Kawada M, Yamagoe S, Murakami Y. etal 1997. Induction of p27kipl degradation and an chorage independence by Ras through the Map kinase signaling pathway. Oncogene 15 , 629-637.
86. Yoshio TeraDa, Seiji Inoshita, Osama Nakashima etal. Regulation of cyclin DI expression and cell cycle progression by mitogen-activated protein kinase cascad kidney international Vol 56 , 1258-1261.
87. Graff, J R, Konicek, B. W., Mcmolty, A.M. etal(2000). Increased Akt acticity contributes to prostate cancer progression by dramatically accelerating prorate tumor growth and diminishing p27kipl, increase its protein stability. J . Biol .Chen . 275,25146-25154.
88. Reynisdottrr, I ,and Massague J (1997) . the subcellular location of p15(ink4b) and p27(kipl) coordinate their inhibitory interactions with cdk4 and cdk2 .Genes Dev . 11, 492-503.
89. Jing xiao, Changgong Li, Nian-ling Zhu Timeless in lung morphogenesis Developmental Dynamics 228:82-94.2003
90. Elizabeth C. Theil, Ferritn:at the crossoads of iron and oxygen metabolism Nutrition 2003 1549s
91. Weis, M J, S.H Orkin Gata-1 transcription factor:key regulate of hematopoeisis. Exp. Hematol 1995 22:99-107
92. Marcin Rylski, John J. welch, Ying-yu Che et al. Gata-1-mediated proliferation arrest during erythroid maturation. Molecular and cellular biology 2003 july p5031-5042.
93. Ben-David Y,Giddens E.B. Bernstein A. Pro. Natl. Acad. Sci. USA 1990,87,1332-1336.
94. Denicourt C, Edouard EB ,Rassart E J. virol 73,4439-4442.
95. Bergeron D, Poliquin L, Kozak CA and Rassart E J. virol 1991,65,7-17
96. Delattre O, Zueman J, Plougastel B Nature 1992 359,162-165
97. Amadine HL Truong, Yaacov Ben-David The role of Fli-1 in normal cell function and malignant transformation. Onco(2000) 19,6482-6489.
98. Anthony J. Kihm, Wei Hong et. al An aboundant erythroid protein that stablizaes free α-globin Nature(2002),417(6),13:758-