跳到主要內容

臺灣博碩士論文加值系統

(3.236.68.118) 您好!臺灣時間:2021/08/04 20:42
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林子暘
研究生(外文):Tzu-Yang Lin
論文名稱:Abl藉由Abi磷酸化Cdc2並調控其在DNA損害下G2-M檢查點之功能
論文名稱(外文):Abi Enhances Abl-mediated Cdc2 Phosphorylation and Inactivation for DNA Damage G2-M Checkpoint
指導教授:周文剛
指導教授(外文):Wen-Gang Chou
學位類別:博士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:英文
論文頁數:88
中文關鍵詞:AblAbiCdc2Bcr-AblDNA損害G2-M 檢查點慢性骨髓性白血症
外文關鍵詞:AblAbiCdc2Bcr-AblDNA damageG2-M checkpointchronic myelogenous leukemia
相關次數:
  • 被引用被引用:0
  • 點閱點閱:115
  • 評分評分:
  • 下載下載:13
  • 收藏至我的研究室書目清單書目收藏:0
Abl為一種非受體的酪氨酸蛋白激脢,通常藉由聯結蛋白而與其受質結合,進而在不同的生理刺激下調控各種功能,包括細胞骨架的重整、細胞生長、及細胞凋亡。Abi蛋白家族最早是因為此蛋白質會與Abl互相結合而被發現並分離出來,其功能可能跟調控致癌型Abl所引起的細胞轉型及癌化能力有關。在本篇論文中,我們利用酵母菌雙雜交法篩選Abi的結合蛋白,並鑑定出Cdc2是一個新穎的Abi結合蛋白。在本研究中我們想探討Abi在連結Abl和Cdc2的關係中所扮演的角色。我們發現這三者能在果蠅及哺乳類動物細胞中以複合體形式存在,在細胞中大量表現Abi時能加強Abl 與Cdc2間的結合,顯示Abi是一聯結蛋白,藉此連結來增強Abl 和Cdc2的交互作用。另外,Abi能促進Abl磷酸化Cdc2的第十五個氨基酸 (Y15),並導致Cdc2活性的減弱。我們也發現在果蠅細胞同時表現Abl 及Abi能抑制細胞生長。更進一步,在帶有Bcr-Abl (癌化型Abl) 基因的細胞中,若利用STI571抑制Bcr-Abl的激脢活性或是以RNA干擾術來降低Bcr-Abl蛋白質的生成時,這種細胞在游離輻射的處理下所引起Cdc2 Y15的磷酸化程度及G2-M細胞週期的停滯程度會降低。如此的結果指出,Bcr-Abl可能直接或間接藉由Abi蛋白質的連結來調控DNA傷害所引起Cdc2磷酸化及其活性的抑制。但是,在非Bcr-Abl的細胞中,c-Abl似乎在調控Cdc2及細胞週期上只扮演一小部分的功能。此外,由於Abl 及Abi都已知在肌動蛋白絲的重組上扮演功能,因而我們也探討Cdc2在細胞中的位置並發現Cdc2會位在富含肌動蛋白絲的lamellipodia上,並且和Abl 、Abi同時位在相類似的細胞結構上。總結來說,我們認為DNA傷害所導致Cdc2活性在Bcr-Abl細胞中受到抑制,以及Cdc2在肌動蛋白絲的重組過程中移動至lamellipodia之機制可能與Abl及Abi有關聯。
Abl is a non-receptor tyrosine kinase, which is frequently coupled by adaptor proteins to interact with its substrates for the regulation of cytoskeleton rearrangement, cell growth, and apoptosis in response to a variety of biological stimuli. The Abl-interactor (Abi) family members were first reported as Abl adaptors involved in the regulation of oncogenic Abl transforming activity. In the present study, we have used a yeast two-hybrid screen to identify Cdc2 as a novel Abi-binding protein. This finding led us to investigate the role of Abi in linking Abl and Cdc2. These three proteins formed tri-complex in Drosophila and mammalian cells. Expressing Abi in cells greatly enhanced the formation of Abl-Cdc2 complex, suggesting Abi functions as an adaptor protein facilitating the binding between Abl and Cdc2. We showed that Abi promoted Abl-mediated phosphorylation of Cdc2 at tyrosine 15 and inactivation of kinase activity of Cdc2. Coexpression of Abl and Abi in Drosophila S2 cells led to suppression of cell growth. Furthermore, we showed that Bcr-Abl-positive cells exhibited abrogated radiation-induced Cdc2-Y15 phosphorylation and G2-M arrest as Bcr-Abl kinase activity was blocked by STI571 or protein expression was suppressed by siRNA. This result is consistent with the fact that inhibitory phosphorylation at Y15 of Cdc2 triggers the G2-M arrest in response to DNA damage. Nonetheless, in Bcr-Abl-negative cells, c-Abl appears to be redundant in modulating Cdc2 for checkpoint control. Since both Abl and Abi are also involved in actin dynamics, we investigated the subcellular localization of Cdc2 and, surprisingly, found that it was recruited to the lamellipodia, colocalizing with Abl and Abi in actin-rich bundles. Together, the data suggest that inhibition of Cdc2 kinase for G2-M DNA damage checkpoint in Bcr-Abl cells and the recruitment of Cdc2 to lamellipodia for actin dynamics are associated with Abl and Abi proteins.
ABSTRACT III
中文摘要 IV
INTRODUCTION 1
MATERIALS AND METHODS 5
Yeast two-hybrid 5
Cell culture 5
Establishments of stable cell lines 6
Antibodies 6
Plasmids construction 7
Transient transfection and immunoblotting 7
Small interfering RNA (siRNA) treatment 8
GST pull-downs and immunoprecipitation 9
In vitro phosphorylation assay 9
Cell cycle checkpoint assay 9
Immunostaining 10
Mass spectrometry analysis 10
Cell fractionation 11
Statistical Analysis 11
RESULTS 12
Abi is a novel Cdc2 interactor 12
Cdc2 interacts with Abi in Drosophila S2 cells 13
The amino terminal domain of Abi is essential for binding to Cdc2 13
Abi acts as a physical bridge between Abl and Cdc2 14
Cdc2 is a novel substrate of Abl 15
Disruption of Abi-Cdc2 or Abi-Abl interaction abolishes Abl-mediated phosphorylation of Cdc2 16
Abi enhances Cdc2 inactivation by Abl 17
Tyr15 of Cdc2 is a Abl phosphorylation site 17
Overexpression of Abl and Abi suppresses cell proliferation 18
The interaction between Abi and Cdc2 is evolutionarily conserved 18
Abl regulates IR-induced Cdc2 Y15 phosphorylation and G2 arrest in Bcr-Abl-positive cells 19
Both cytoplasmic and nuclear Cdc2 in K562 cells are Y15 phosphorylated in response to IR treatment 20
RNAi-mediated knockdown of Bcr-Abl impairs IR-induced Cdc2-pY15 and G2-M arrest 21
STI571 does not reduce IR-induced Cdc2 inhibition and G2-M arrest in Bcr-Abl-negative cells 22
IR-induced DNA-damage still initiates Cdc2-pY15 and G2 arrest in fibroblasts lacking c-Abl 22
No cooperative role of c-Abl and BRCA1 on DNA damage G2 checkpoint 23
Colocalization of Abl, Abi, and Cdc2 to the motile lamellipodia regions 24
DISCUSSION 27
FUTURE PROSPECTS 32
To investigate direct functional link between Bcr-Abl and Cdc2 in IR-induced G2-M arrest 32
To study the role of Abl-Abi-Cdc2 in cytoskeleton dynamics 33
REFERENCES 35
FIGURES 47
APPENDIX 87
1. Baskaran, R., Wood, L. D., Whitaker, L. L., Canman, C. E., Morgan, S. E., Xu, Y., Barlow, C., Baltimore, D., Wynshaw-Boris, A., Kastan, M. B., and Wang, J. Y. (1997). Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516-519.

2. Bedi, A., Barber, J. P., Bedi, G. C., el-Deiry, W. S., Sidransky, D., Vala, M. S., Akhtar, A. J., Hilton, J., and Jones, R. J. (1995). BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood 86, 1148-1158.

3. Ben-Neriah, Y., Daley, G. Q., Mes-Masson, A. M., Witte, O. N., and Baltimore, D. (1986). The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 233, 212-214.

4. Bershadsky, A. D., Ivanova, O. Y., Lyass, L. A., Pletyushkina, O. Y., Vasiliev, J. M., and Gelfand, I. M. (1990). Cytoskeletal reorganizations responsible for the phorbol ester-induced formation of cytoplasmic processes: possible involvement of intermediate filaments. Proc Natl Acad Sci U S A 87, 1884-1888.

5. Bi, S., Hughes, T., Bungey, J., Chase, A., de Fabritiis, P., and Goldman, J. M. (1992). p53 in chronic myeloid leukemia cell lines. Leukemia 6, 839-842.

6. Biesova, Z., Piccoli, C., and Wong, W. T. (1997). Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Oncogene 14, 233-241.

7. Bogdan, S., and Klambt, C. (2003). Kette regulates actin dynamics and genetically interacts with Wave and Wasp. Development 130, 4427-4437.

8. Buchdunger, E., Zimmermann, J., Mett, H., Meyer, T., Muller, M., Druker, B. J., and Lydon, N. B. (1996). Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56, 100-104.

9. Burton, E. A., Plattner, R., and Pendergast, A. M. (2003). Abl tyrosine kinases are required for infection by Shigella flexneri. Embo J 22, 5471-5479.

10. Clark, S. S., McLaughlin, J., Timmons, M., Pendergast, A. M., Ben-Neriah, Y., Dow, L. W., Crist, W., Rovera, G., Smith, S. D., and Witte, O. N. (1988). Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science 239, 775-777.

11. Dai, Z., and Pendergast, A. (1995). Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes Dev. 9, 2569-2582.

12. Daley, G. Q., and Baltimore, D. (1988). Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A 85, 9312-9316.

13. Daley, G. Q., McLaughlin, J., Witte, O. N., and Baltimore, D. (1987). The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science 237, 532-535.

14. Davis, R. L., Konopka, J. B., and Witte, O. N. (1985). Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties. Mol Cell Biol 5, 204-213.

15. Deininger, M. W., Goldman, J. M., and Melo, J. V. (2000). The molecular biology of chronic myeloid leukemia. Blood 96, 3343-3356.

16. Deutsch, E., Dugray, A., AbdulKarim, B., Marangoni, E., Maggiorella, L., Vaganay, S., M'Kacher, R., Rasy, S. D., Eschwege, F., Vainchenker, W., Turhan, A. G., and Bourhis, J. (2001). BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood 97, 2084-2090.

17. Deutsch, E., Jarrousse, S., Buet, D., Dugray, A., Bonnet, M. L., Vozenin-Brotons, M. C., Guilhot, F., Turhan, A. G., Feunteun, J., and Bourhis, J. (2003). Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells. Blood 101, 4583-4588.

18. Dierov, J., Dierova, R., and Carroll, M. (2004). BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint. Cancer Cell 5, 275-285.

19. Downey, G. P., Chan, C. K., Lea, P., Takai, A., and Grinstein, S. (1992). Phorbol ester-induced actin assembly in neutrophils: role of protein kinase C. J Cell Biol 116, 695-706.

20. Echarri, A., Lai, M. J., Robinson, M. R., and Pendergast, A. M. (2004). Abl interactor 1 (Abi-1) wave-binding and SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodium localization, and wave-1 levels. Mol Cell Biol 24, 4979-4993.

21. Fan, P. D., and Goff, S. P. (2000). Abl interactor 1 binds to sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases. Mol Cell Biol 20, 7591-7601.

22. Ferris, D. K., White, G. A., Kelvin, D. J., Copeland, T. D., Li, C. C., and Longo, D. L. (1991). p34cdc2 is physically associated with and phosphorylated by a cdc2-specific tyrosine kinase. Cell Growth Differ 2, 343-349.

23. Flynn, D. C. (2001). Adaptor proteins. Oncogene 20, 6270-6272.

24. Foray, N., Marot, D., Randrianarison, V., Venezia, N. D., Picard, D., Perricaudet, M., Favaudon, V., and Jeggo, P. (2002). Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Mol Cell Biol 22, 4020-4032.

25. Frasca, F., Vigneri, P., Vella, V., Vigneri, R., and Wang, J. Y. (2001). Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to Hepatocyte Growth Factor. Oncogene 20, 3845-3856.

26. Gallagher, R., Collins, S., Trujillo, J., McCredie, K., Ahearn, M., Tsai, S., Metzgar, R., Aulakh, G., Ting, R., Ruscetti, F., and Gallo, R. (1979). Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood 54, 713-733.

27. Groffen, J., Stephenson, J. R., Heisterkamp, N., Bartram, C., de Klein, A., and Grosveld, G. (1984). The human c-abl oncogene in the Philadelphia translocation. J Cell Physiol Suppl 3, 179-191.

28. Heisterkamp, N., Stam, K., Groffen, J., de Klein, A., and Grosveld, G. (1985). Structural organization of the bcr gene and its role in the Ph' translocation. Nature 315, 758-761.

29. Ichigotani, Y., Yokozaki, S., Fukuda, Y., Hamaguchi, M., and Matsuda, S. (2002). Forced expression of NESH suppresses motility and metastatic dissemination of malignant cells. Cancer Res 62, 2215-2219.

30. Ikeguchi, A., Yang, H. Y., Gao, G., and Goff, S. P. (2001). Inhibition of v-Abl transformation in 3T3 cells overexpressing different forms of the Abelson interactor protein Abi-1. Oncogene 20, 4926-4934.

31. Juang, J.-L., and Hoffmann, F. M. (1999). Drosophila Abelson interacting protein (dAbi) is a positive regulator of Abelson tyrosine kinase activity. Oncogene 18, 5138-5147.

32. Kain, K. H., and Klemke, R. L. (2001). Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk-CAS complexes. J Biol Chem 276, 16185-16192.

33. Kao, G. D., McKenna, W. G., and Muschel, R. J. (1999). p34(Cdc2) kinase activity is excluded from the nucleus during the radiation-induced G(2) arrest in HeLa cells. J Biol Chem 274, 34779-34784.

34. Kelliher, M. A., McLaughlin, J., Witte, O. N., and Rosenberg, N. (1990). Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A 87, 6649-6653.

35. Kharbanda, S., Ren, R., Pandey, P., Shafman, T. D., Feller, S. M., Weichselbaum, R. R., and Kufe, D. W. (1995). Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376, 785-788.

36. Kipreos, E. T., and Wang, J. Y. (1990). Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. Science 248, 217-220.

37. Klein, E., Ben-Bassat, H., Neumann, H., Ralph, P., Zeuthen, J., Polliack, A., and Vanky, F. (1976). Properties of the K562 cell line, derived from a patient with chronic myeloid leukemia. Int J Cancer 18, 421-431.

38. Kunda, P., Craig, G., Dominguez, V., and Baum, B. (2003). Abi, Sra1, and Kette control the stability and localization of SCAR/WAVE to regulate the formation of actin-based protrusions. Curr Biol 13, 1867-1875.

39. Law, J. C., Ritke, M. K., Yalowich, J. C., Leder, G. H., and Ferrell, R. E. (1993). Mutational inactivation of the p53 gene in the human erythroid leukemic K562 cell line. Leuk Res 17, 1045-1050.

40. Lee, D. F., Chen, C. C., Hsu, T. A., and Juang, J. L. (2000). A baculovirus superinfection system: efficient vehicle for gene transfer into Drosophila S2 cells. J Virol 74, 11873-11880.

41. Lewis, J. M., Baskaran, R., Taagepera, S., Schwartz, M. A., and Wang, J. Y. (1996). Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc Natl Acad Sci U S A 93, 15174-15179.

42. Liu, F., Rothblum-Oviatt, C., Ryan, C. E., and Piwnica-Worms, H. (1999). Overproduction of human Myt1 kinase induces a G2 cell cycle delay by interfering with the intracellular trafficking of Cdc2-cyclin B1 complexes. Mol Cell Biol 19, 5113-5123.

43. Lock, R. B., and Ross, W. E. (1990). Inhibition of p34cdc2 kinase activity by etoposide or irradiation as a mechanism of G2 arrest in Chinese hamster ovary cells. Cancer Res 50, 3761-3766.

44. Lou, Z., Chini, C. C., Minter-Dykhouse, K., and Chen, J. (2003). Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem 278, 13599-13602.

45. Lugo, T. G., Pendergast, A. M., Muller, A. J., and Witte, O. N. (1990). Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247, 1079-1082.

46. Lugo, T. G., and Witte, O. N. (1989). The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol 9, 1263-1270.

47. Manes, T., Zheng, D. Q., Tognin, S., Woodard, A. S., Marchisio, P. C., and Languino, L. R. (2003). Alpha(v)beta3 integrin expression up-regulates cdc2, which modulates cell migration. J Cell Biol 161, 817-826.

48. Mayer, B. J. (2001). SH3 domains: complexity in moderation. J Cell Sci 114, 1253-1263.

49. McLaughlin, J., Chianese, E., and Witte, O. N. (1987). In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A 84, 6558-6562.

50. McWhirter, J. R., and Wang, J. Y. (1993). An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. Embo J 12, 1533-1546.

51. Miyazaki, K., Matsuda, S., Ichigotani, Y., Takenouchi, Y., Hayashi, K., Fukuda, Y., Nimura, Y., and Hamaguchi, M. (2000). Isolation and characterization of a novel human gene (NESH) which encodes a putative signaling molecule similar to e3B1 protein. Biochim Biophys Acta 1493, 237-241.

52. Morgan, D. O. (1995). Principles of CDK regulation. Nature 374, 131-134.

53. Nagar, B., Hantschel, O., Young, M. A., Scheffzek, K., Veach, D., Bornmann, W., Clarkson, B., Superti-Furga, G., and Kuriyan, J. (2003). Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112, 859-871.

54. Nebreda, A. R., Gannon, J. V., and Hunt, T. (1995). Newly synthesized protein(s) must associate with p34cdc2 to activate MAP kinase and MPF during progesterone-induced maturation of Xenopus oocytes. Embo J 14, 5597-5607.

55. Nishii, K., Kabarowski, J. H., Gibbons, D. L., Griffiths, S. D., Titley, I., Wiedemann, L. M., and Greaves, M. F. (1996). ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. Oncogene 13, 2225-2234.

56. Nurse, P. (1997). Checkpoint pathways come of age. Cell 91, 865-867.

57. O'Connell, M. J., Raleigh, J. M., Verkade, H. M., and Nurse, P. (1997). Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. Embo J 16, 545-554.

58. O'Connell, M. J., Walworth, N. C., and Carr, A. M. (2000). The G2-phase DNA-damage checkpoint. Trends Cell Biol 10, 296-303.

59. Ogura, M., Morishima, Y., Ohno, R., Kato, Y., Hirabayashi, N., Nagura, H., and Saito, H. (1985). Establishment of a novel human megakaryoblastic leukemia cell line, MEG-01, with positive Philadelphia chromosome. Blood 66, 1384-1392.

60. Pendergast, A. M. (2002). The Abl family kinases: mechanisms of regulation and signaling. Adv Cancer Res 85, 51-100.

61. Pendergast, A. M., Muller, A. J., Havlik, M. H., Clark, R., McCormick, F., and Witte, O. N. (1991). Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor. Proc Natl Acad Sci U S A 88, 5927-5931.

62. Pierce, A., Spooncer, E., Wooley, S., Dive, C., Francis, J. M., Miyan, J., Owen-Lynch, P. J., Dexter, T. M., and Whetton, A. D. (2000). Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. Oncogene 19, 5487-5497.

63. Plattner, R., Kadlec, L., DeMali, K. A., Kazlauskas, A., and Pendergast, A. M. (1999). c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 13, 2400-2411.

64. Plattner, R., Koleske, A. J., Kazlauskas, A., and Pendergast, A. M. (2004). Bidirectional signaling links the Abelson kinases to the platelet-derived growth factor receptor. Mol Cell Biol 24, 2573-2583.

65. Pluk, H., Dorey, K., and Superti-Furga, G. (2002). Autoinhibition of c-Abl. Cell 108, 247-259.

66. Raitano, A. B., Whang, Y. E., and Sawyers, C. L. (1997). Signal transduction by wild-type and leukemogenic Abl proteins. Biochim Biophys Acta 1333, F201-F216.

67. Raleigh, J. M., and O'Connell, M. J. (2000). The G(2) DNA damage checkpoint targets both Wee1 and Cdc25. J Cell Sci 113 ( Pt 10), 1727-1736.

68. Ramet, M., Manfruelli, P., Pearson, A., Mathey-Prevot, B., and Ezekowitz, R. A. (2002). Functional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Nature 416, 644-648.

69. Ramet, M., Pearson, A., Manfruelli, P., Li, X., Koziel, H., Gobel, V., Chung, E., Krieger, M., and Ezekowitz, R. A. (2001). Drosophila scavenger receptor CI is a pattern recognition receptor for bacteria. Immunity 15, 1027-1038.

70. Rhind, N., and Russell, P. (2001). Roles of the mitotic inhibitors Wee1 and Mik1 in the G(2) DNA damage and replication checkpoints. Mol Cell Biol 21, 1499-1508.

71. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D., and Hall, A. (1992). The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401-410.

72. Roder, K., Hung, M. S., Lee, T. L., Lin, T. Y., Xiao, H., Isobe, K. I., Juang, J. L., and Shen, C. J. (2000). Transcriptional repression by Drosophila methyl-CpG-binding proteins. Mol Cell Biol 20, 7401-7409.

73. Rogers, S. L., Rogers, G. C., Sharp, D. J., and Vale, R. D. (2002). Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle. J Cell Biol 158, 873-884.

74. Rogers, S. L., Wiedemann, U., Stuurman, N., and Vale, R. D. (2003). Molecular requirements for actin-based lamella formation in Drosophila S2 cells. J Cell Biol 162, 1079-1088.

75. Rowley, J. D. (1973). Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290-293.

76. Salgia, R., Li, J. L., Ewaniuk, D. S., Pear, W., Pisick, E., Burky, S. A., Ernst, T., Sattler, M., Chen, L. B., and Griffin, J. D. (1997). BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest 100, 46-57.

77. Sattler, M., and Salgia, R. (1997). Activation of hematopoietic growth factor signal transduction pathways by the human oncogene BCR/ABL. Cytokine Growth Factor Rev 8, 63-79.

78. Sattler, M., Verma, S., Shrikhande, G., Byrne, C. H., Pride, Y. B., Winkler, T., Greenfield, E. A., Salgia, R., and Griffin, J. D. (2000). The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 275, 24273-24278.

79. Scherr, M., Battmer, K., Winkler, T., Heidenreich, O., Ganser, A., and Eder, M. (2003). Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood 101, 1566-1569.

80. Schneider, I. (1972). Cell lines derived from late embryonic stages of Drosophila melanogaster. J Embryol Exp Morphol 27, 353-365.

81. Scita, G., Nordstrom, J., Carbone, R., Tenca, P., Giardina, G., Gutkind, S., Bjarnegard, M., Betsholtz, C., and Di Fiore, P. P. (1999). EPS8 and E3B1 transduce signals from Ras to Rac. Nature 401, 290-293.

82. Shafman, T., Khanna, K. K., Kedar, P., Spring, K., Kozlov, S., Yen, T., Hobson, K., Gatei, M., Zhang, N., Watters, D., Egerton, M., Shiloh, Y., Kharbanda, S., Kufe, D., and Lavin, M. F. (1997). Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387, 520-523.

83. Shi, Y., Alin, K., and Goff, S. (1995). Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Genes Dev. 9, 2583-2597.

84. Slupianek, A., Hoser, G., Majsterek, I., Bronisz, A., Malecki, M., Blasiak, J., Fishel, R., and Skorski, T. (2002). Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 22, 4189-4201.

85. Small, J. V., Stradal, T., Vignal, E., and Rottner, K. (2002). The lamellipodium: where motility begins. Trends Cell Biol 12, 112-120.

86. Steffen, A., Rottner, K., Ehinger, J., Innocenti, M., Scita, G., Wehland, J., and Stradal, T. E. (2004). Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation. Embo J.

87. Stiewe, T., Parssanedjad, K., Esche, H., Opalka, B., and Putzer, B. M. (2000). E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents. Cancer Res 60, 3957-3964.

88. Stradal, T., Courtney, K. D., Rottner, K., Hahne, P., Small, J. V., and Pendergast, A. M. (2001). The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia. Curr Biol 11, 891-895.

89. Sun, X., Majumder, P., Shioya, H., Wu, F., Kumar, S., Weichselbaum, R., Kharbanda, S., and Kufe, D. (2000). Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. J Biol Chem 275, 17237-17240.

90. Tan, M., Jing, T., Lan, K. H., Neal, C. L., Li, P., Lee, S., Fang, D., Nagata, Y., Liu, J., Arlinghaus, R., Hung, M. C., and Yu, D. (2002). Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell 9, 993-1004.

91. Tani, K., Sato, S., Sukezane, T., Kojima, H., Hirose, H., Hanafusa, H., and Shishido, T. (2003). Abl interactor 1 promotes tyrosine 296 phosphorylation of mammalian enabled (Mena) by c-Abl kinase. J Biol Chem 278, 21685-21692.

92. Taylor, W. R., and Stark, G. R. (2001). Regulation of the G2/M transition by p53. Oncogene 20, 1803-1815.

93. Topaly, J., Fruehauf, S., Ho, A. D., and Zeller, W. J. (2002). Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning. Br J Cancer 86, 1487-1493.

94. Trotta, R., Vignudelli, T., Candini, O., Intine, R. V., Pecorari, L., Guerzoni, C., Santilli, G., Byrom, M. W., Goldoni, S., Ford, L. P., Caligiuri, M. A., Maraia, R. J., Perrotti, D., and Calabretta, B. (2003). BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 3, 145-160.

95. Van Etten, R. A. (1999). Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 9, 179-186.

96. Vandenberg, C. J., Gergely, F., Ong, C. Y., Pace, P., Mallery, D. L., Hiom, K., and Patel, K. J. (2003). BRCA1-independent ubiquitination of FANCD2. Mol Cell 12, 247-254.

97. Vigneri, P., and Wang, J. Y. (2001). Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 7, 228-234.

98. Wang, B., Mysliwiec, T., Krainc, D., Jensen, R. A., Sonoda, G., Testa, J. R., Golemis, E. A., and Kruh, G. D. (1996). Identification of ArgBP1, an Arg protein tyrosine kinase binding protein that is the human homologue of a CNS-specific Xenopus gene. Oncogene 12, 1921-1929.

99. Wang, J. Y. (2000). Regulation of cell death by the Abl tyrosine kinase. Oncogene 19, 5643-5650.

100. Wohlbold, L., van der Kuip, H., Miething, C., Vornlocher, H. P., Knabbe, C., Duyster, J., and Aulitzky, W. E. (2003). Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 102, 2236-2239.

101. Woodring, P. J., Hunter, T., and Wang, J. Y. (2001). Inhibition of c-Abl tyrosine kinase activity by filamentous actin. J Biol Chem 276, 27104-27110.

102. Woodring, P. J., Hunter, T., and Wang, J. Y. (2003). Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases. J Cell Sci 116, 2613-2626.

103. Xu, B., Kim, S. T., Lim, D. S., and Kastan, M. B. (2002). Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol Cell Biol 22, 1049-1059.

104. Yamane, K., Chen, J., and Kinsella, T. J. (2003). Both DNA topoisomerase II-binding protein 1 and BRCA1 regulate the G2-M cell cycle checkpoint. Cancer Res 63, 3049-3053.

105. Yarden, R. I., Pardo-Reoyo, S., Sgagias, M., Cowan, K. H., and Brody, L. C. (2002). BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 30, 285-289.

106. Young, J. C., and Witte, O. N. (1988). Selective transformation of primitive lymphoid cells by the BCR/ABL oncogene expressed in long-term lymphoid or myeloid cultures. Mol Cell Biol 8, 4079-4087.

107. Zhu, J., and Wang, J. Y. (2004). Death by Abl: a matter of location. Curr Top Dev Biol 59, 165-192.

108. Zou, X., and Calame, K. (1999). Signaling pathways activated by oncogenic forms of Abl tyrosine kinase. J Biol Chem 274, 18141-18144.

109. Zukerberg, L. R., Patrick, G. N., Nikolic, M., Humbert, S., Wu, C. L., Lanier, L. M., Gertler, F. B., Vidal, M., Van Etten, R. A., and Tsai, L. H. (2000). Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26, 633-646.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top