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研究生:黃琇雯
研究生(外文):Xiu-Wen Huang
論文名稱:HTm4在造血細胞分化過程中扮演的角色
論文名稱(外文):The Role of HTm4 in Haematopoietic Cell Differentiation
指導教授:柯順龍
指導教授(外文):Jon, J.L. Ko
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:64
中文關鍵詞:HTm4細胞分化
外文關鍵詞:HTm4cell differentiation
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HTm4是一個造血細胞系特有的細胞週期調節因子。在造血細胞中的表現受到高度調控。在造血細胞的分化過程中,CD19自B細胞系早期開始表現,並持續至後期。以此作為標記,HTm4在B細胞系的表現時期似乎與CD19一致;以CD11b作為髓系細胞系標記,HTm4表現於部分髓系細胞系;以CD3作為T細胞系標記,無法偵測到HTm4的表現。
為了研究HTm4在造血細胞的分化過程中的表現與可能造成的影響,我們計畫建立一個具有HTm4+/EGFP或是HTm4Floxed/EGFP基因型的小鼠胚胎幹細胞株。前者可以幫助我們觀察HTm4的表現。在HTm4+/EGFP細胞株中,EGFP等同於HTm4的表現,因此我們可以誘導幹細胞分化成的所有的造血細胞,再觀察細胞中HTm4的表現。在本篇論文中,我們建立單套HTm4染色體的胚胎幹細胞株(HTm4+/EGFP),篩選出具有正確基因型的clone的機率約為1/300。我們誘導這個胚胎幹細胞分化向B 細胞系,並偵測HTm4與CD19的表現。到目前為止,我們發現與人類造血幹細胞誘導分化的結果相比較,誘導小鼠胚胎幹細胞分化為B細胞的過程中,HTm4可能不會在所有表現CD19的B細胞群中表現。接下來,我們會繼續建立HTm4Floxed/EGFP基因型的小鼠胚胎幹細胞株。
先前的研究結果證實過量或降低HTm4的表現均會抑制細胞週期進行,然而確切的細胞週期停滯位置仍不清楚。為了確定細胞週期的停滯位置,我們以serum starvation與thymidine同步化HTm4穩定抑制細胞株。以serum starvation將細胞同步化後,細胞週期會停滯在G0時期,重新進行細胞週期時,HTm4穩定抑制細胞與K562並沒有差異;然而使用thymidine將細胞同步化後,細胞週期停滯在G1/S時期,重新進行細胞週期時,相較於對照組與K562細胞,HTm4穩定抑制細胞的細胞週期會出現明顯的延遲,延遲現象約24小時後消失。因此我們認為HTm4作用在G1/S時期,且作用位置在thymidine使細胞週期停滯的位置之後。由於p27Kip1與CDK2及cyclin E發生交互作用的時間是在G1/S時期,因此我們認為p27Kip1可能與HTm4共同調節G1/S時期的進行,降低HTm4的表現可能增強p27Kip1與cyclin E-CDK2複合物的交互作用,導致細胞週期進行發生延遲。我們想知道在HTm4穩定抑制細胞中,p27Kip1與cyclin E-CDK2產生的交互作用是否會比控制組與K562高,因此我們使用細胞核萃取與免疫沉澱的方式進行分析。到目前為止,資料不具一致性。未來我們可能使用p27Kip1穩定抑制細胞評估HTm4表現降低可能產生的影響。
已知細胞週期停滯會影響紅血球分化。因此我們想知道HTm4表現降低導致的細胞週期延遲是否會與紅血球分化有關。我們使用濃度為1�嵱的Ara-C誘導細胞分化,發現所有細胞株被Ara-C誘導分化為紅血球的比例相同,但在誘導分化的48-96小時,HTm4穩定抑制細胞株有較多的細胞進入紅血球晚期。我們的實驗結果顯示在正常環境下,HTm4可能調控細胞進入紅血球分化的時間。
HTm4 is a hematopoietic-specific cell-cycle regulator. Its expression in hematopoietic cells is highly regulated. In the cascade of hematopoietic differentiation, HTm4 is detected consistently in B cell lineages with CD19+ phenotype, in some subpopulations but not all of myelocytic lineages with CD11b+ phenotype, and none in cells with CD3+ marker, which is considered T cell lineage specific.
To study the expression and influences of HTm4 in the differentiation of hematopoietic cells, we set out to establish murine embryonic stem (ES) cells with either HTm4+/EGFP or HTm4Floxed/EGFP phenotype. The former will aid us in the detection of HTm4, as signified by the co-expression of EGFP, expression in all hematopoietic cells derived from ES cells under induction of differentiation. In this study, we established haploid ES cell (HTm4+/EGFP), at a frequency of 1/300 ES clones analyzed. The ES cell (HTm4+/EGFP) had been induced to differentiate along the B cell lineage, and the expression of HTm4 examined simultaneously with that of CD19. So far, we found that the expression of HTm4 may not in all CD19+ B cell population, in contrast to our previous observation derived from the differentiation of human hematopoistic stem cells. Work also in progress is the procurement of ES (HTm4Floxed/EGFP) cells.
It is established that the overexpression or reduction of HTm4 would inhibit the cell cycle progression, though the point of this blockade is still unknown. To ascertain the stated point of blockade, we analyzed HTm4-knockdown K562 cells synchronized by either serum starvation or thymidine treatment. Cells synchronized by serum starvation, G0 phase blockade, failed to show any effect of HTm4 knockdown, while that with thymidine, G1-S phase blockade, showed prominent cell-cycle delay in HTm4 knockdown cells. This delay lasted for about 24 hours, in comparision to that of the control and parental line. It seems that HTm4 is functioning at G1/S transition, and probably, after the point of blockade by thymidine. Since p27Kip1 interacts with cdk2 and cyclin E that is also functioning in the G1/S transit, it likely coordinates with HTm4 in the regulation of cell cycle progression at G1/S transition. The reduction of HTm4 might enhance the interaction between p27Kip1 and CyclinE-CDK2 complexes, and subsequently delay cell-cycle progression. We have tried to acertain if the amount of p27Kip1 in the cyclinE-CDK 2 is higher in HTm4 knockdown cell than that of the control and parental line through fractionation and immunoprecipitation. Thus far, the data are inconsistent. Our alternative approach is to evaluate HTm4 knockdown effect in p27Kip1 knockdown cells.
Cell-cycle arrest is known to affect erythrocytic differentiation. We set out to evaluate if the cell-cycle retardation caused by HTm4 knockdown also pertinent to erythrocytic differentiation. Employing Ara-C (1 μM) induction system, we showed that at 48 to 96 hr post induction HTm4 knockdown cells gave rise to more erythrocytes in late to terminal differentiation stage than that of the control and partental line, although the overall efficacy for the induction of erythroid differentiation remained the same for all groups. Our data suggested that under normal condition, HTm4 might participate in the temporal regulation of erythroid differentiation.
英文摘要………………………………………………………………… 4
中文摘要………………………………………………………………… 5
緒論……………………………………………………………………… 6
1.1 總論………………………………………………………………… 6
1.2 HTm4………………………………………………………………… 7
1.3 Genetic manipulation of embryonic stem cells…………… 8
1.4 K562 Human erythromyeloblastoid leukemia cell line…… 9
1.5 Cell cycle progression…………………………………………10
1.6 Erythropoiesis……………………………………………………12
1.7 研究目標……………………………………………………………13
實驗材料與方法…………………………………………………………16
2.1 細胞培養……………………………………………………………16
2.2小鼠胚胎幹細胞中的基因標的(gene targeting) ………………17
2.3小鼠胚胎幹細胞基因體DNA (genomic DNA)的製備………………17
2.4基因型定型(genotyping) …………………………………………18
2.5誘導小鼠胚胎幹細胞往B淋巴細胞分化……………………………19
2.6 Total RNA的萃取 …………………………………………………20
2.7反轉錄酵素聚合酶連鎖反應(RT-PCR) ……………………………20
2.8細胞生長速率的計數 ………………………………………………21
2.9細胞的同步化(synchronization)…………………………………21
2.10 Propidium iodide staining……………………………………22
2.11誘導細胞分化成紅血球……………………………………………23
2.12 Benzidine stain assay…………………………………………23
2.13細胞核萃取物的製備(Nuclear extraction)……………………23
2.14蛋白質定量(Bio-Rad Protein Assay) …………………………24
2.15免疫沉澱(Immunoprecipitation) ………………………………24
2.16西方墨點分析(Western blot)……………………………………24
實驗結果…………………………………………………………………26
3.1基因標的(gene targeting)及基因型定型(genotyping) ………26
3.2 HTm4於小鼠胚胎幹細胞往B淋巴細胞分化過程中的表現情形 …26
3.3確認HTm4及Luciferase穩定抑制細胞株的HTm4抑制效果 ………28
3.4 HTm4參與細胞週期的作用點………………………………………28
3.5 HTm4表現抑制導致細胞生長速率降低的可能機制………………29
3.6抑制HTm4表現促進Ara-C誘導之K562細胞分化……………………30
討論與未來計畫…………………………………………………………32
參考文獻…………………………………………………………………40
附圖及附表………………………………………………………………45
Figure 1 預期篩選出老鼠胚胎幹細胞的基因型(HTm4+/EGFP) ……45
Figure 2 HTm4 EGFP/+標的載體組成示意圖…………………………46
Figure 3 HTm4基因型定型 (genotyping)–homologous recombination…47
Figure 4 ESC/OP9 coculture system誘導小鼠胚胎幹細胞往B淋巴細胞分化過程中細胞型態變化與HTm4表現情形…………………… 48
Figure 5 ESC/OP9 coculture system誘導HTm4+/EGFP小鼠胚胎幹細胞往B淋巴細胞分化過程中細胞型態變化與HTm4表現情形………49
Figure 6 分析ESC/OP9 coculture system誘導HTm4+/EGFP小鼠胚胎幹細胞往B淋巴細胞分化過程中HTm4與CD19的表現情形………51
Figure 7 確認K562建立的HTm4穩定抑制細胞株的HTm4抑制效果… 52
Figure 8 確認抑制HTm4表現導致細胞生長速率降低的效果……… 53
Figure 9 HTm4的存在與否對於細胞週期進行的影響……………… 54
Figure 10 K562細胞核萃取物進行免疫沉澱的西方墨點分析………57
Figure 11 HTm4的存在與否對於K562內Myc表現的影響……………59
Figure 12 降低HTm4表現對細胞分化成紅血球的影響 ……………60
Figure 13 Floxed HTm4 標的載體組成示意圖 ……………………62
Figure 14 預期篩選出老鼠胚胎幹細胞的基因型(HTm4 floxed/EGFP)…63
Table I The sequences and locations of primers…………… 64
1. Metcalf, D., The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature, 1989. 339(6219): p. 27-30.
2. Ferrari, F., S. Bortoluzzi, A. Coppe, D. Basso, S. Bicciato, R. Zini, C. Gemelli, G.A. Danieli, and S. Ferrari, Genomic expression during human myelopoiesis. BMC Genomics, 2007. 8: p. 264.
3. Adra, C.N., J.M. Lelias, H. Kobayashi, M. Kaghad, P. Morrison, J.D. Rowley, and B. Lim, Cloning of the cDNA for a hematopoietic cell-specific protein related to CD20 and the beta subunit of the high-affinity IgE receptor: evidence for a family of proteins with four membrane-spanning regions. Proc Natl Acad Sci U S A, 1994. 91(21): p. 10178-82.
4. Donato, J.L., J. Ko, J.L. Kutok, T. Cheng, T. Shirakawa, X.Q. Mao, D. Beach, D.T. Scadden, M.H. Sayegh, and C.N. Adra, Human HTm4 is a hematopoietic cell cycle regulator. J Clin Invest, 2002. 109(1): p. 51-8.
5. 蕭詩立, HTm4在細胞分化過程中扮演的角色. 碩士論文, 2008.
6. Hulett, M.D., E. Pagler, and J.R. Hornby, Cloning and characterization of a mouse homologue of the human haematopoietic cell-specific four-transmembrane gene HTm4. Immunol Cell Biol, 2001. 79(4): p. 345-9.
7. Liang, Y. and T.F. Tedder, Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics, 2001. 72(2): p. 119-27.
8. Ishibashi, K., M. Suzuki, S. Sasaki, and M. Imai, Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and beta subunit of the high-affinity IgE receptor. Gene, 2001. 264(1): p. 87-93.
9. Liang, Y., T.R. Buckley, L. Tu, S.D. Langdon, and T.F. Tedder, Structural organization of the human MS4A gene cluster on Chromosome 11q12. Immunogenetics, 2001. 53(5): p. 357-68.
10. Bubien, J.K., L.J. Zhou, P.D. Bell, R.A. Frizzell, and T.F. Tedder, Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol, 1993. 121(5): p. 1121-32.
11. Clark, E.A. and P.J. Lane, Regulation of human B-cell activation and adhesion. Annu Rev Immunol, 1991. 9: p. 97-127.
12. Leveille, C., A.L.-D. R, and W. Mourad, CD20 is physically and functionally coupled to MHC class II and CD40 on human B cell lines. Eur J Immunol, 1999. 29(1): p. 65-74.
13. Kurosaki, T., I. Gander, U. Wirthmueller, and J.V. Ravetch, The beta subunit of the Fc epsilon RI is associated with the Fc gamma RIII on mast cells. J Exp Med, 1992. 175(2): p. 447-51.
14. Chinami, M., Y. Yano, X. Yang, S. Salahuddin, K. Moriyama, M. Shiroishi, H. Turner, T. Shirakawa, and C.N. Adra, Binding of HTm4 to cyclin-dependent kinase (Cdk)-associated phosphatase (KAP).Cdk2.cyclin A complex enhances the phosphatase activity of KAP, dissociates cyclin A, and facilitates KAP dephosphorylation of Cdk2. J Biol Chem, 2005. 280(17): p. 17235-42.
15. Kennedy, M. and G.M. Keller, Hematopoietic commitment of ES cells in culture. Methods Enzymol, 2003. 365: p. 39-59.
16. Sung, Y.H., J. Song, and H.W. Lee, Functional genomics approach using mice. J Biochem Mol Biol, 2004. 37(1): p. 122-32.
17. Wobus, A.M. and K.R. Boheler, Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev, 2005. 85(2): p. 635-78.
18. Sauer, B. and N. Henderson, Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A, 1988. 85(14): p. 5166-70.
19. Trinh, K.R. and S.L. Morrison, Site-specific and directional gene replacement mediated by Cre recombinase. J Immunol Methods, 2000. 244(1-2): p. 185-93.
20. Koeffler, H.P. and D.W. Golde, Human myeloid leukemia cell lines: a review. Blood, 1980. 56(3): p. 344-50.
21. Vermeulen, K., D.R. Van Bockstaele, and Z.N. Berneman, The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif, 2003. 36(3): p. 131-49.
22. Seth P. Lerner, C.N.S., Textbook of Bladder cancer. 2006.
23. Morgan, D.O., Principles of CDK regulation. Nature, 1995. 374(6518): p. 131-4.
24. van den Heuvel, S., Cell-cycle regulation. WormBook, 2005: p. 1-16.
25. Blomen, V.A. and J. Boonstra, Cell fate determination during G1 phase progression. Cell Mol Life Sci, 2007. 64(23): p. 3084-104.
26. Poon, R.Y. and T. Hunter, Dephosphorylation of Cdk2 Thr160 by the cyclin-dependent kinase-interacting phosphatase KAP in the absence of cyclin. Science, 1995. 270(5233): p. 90-3.
27. Johnson, D.G. and C.L. Walker, Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol, 1999. 39: p. 295-312.
28. LaBaer, J., M.D. Garrett, L.F. Stevenson, J.M. Slingerland, C. Sandhu, H.S. Chou, A. Fattaey, and E. Harlow, New functional activities for the p21 family of CDK inhibitors. Genes Dev, 1997. 11(7): p. 847-62.
29. Buttitta, L.A. and B.A. Edgar, Mechanisms controlling cell cycle exit upon terminal differentiation. Curr Opin Cell Biol, 2007. 19(6): p. 697-704.
30. Murate, T., S. Saga, T. Hotta, H. Asano, T. Ito, K. Kato, K. Tsushita, T. Kinoshita, A. Ichikawa, S. Yoshida, and et al., The close relationship between DNA replication and the selection of differentiation lineages of human erythroleukemia cell lines K562, HEL, and TF1 into either erythroid or megakaryocytic lineages. Exp Cell Res, 1993. 208(1): p. 35-43.
31. Hsieh, F.F., L.A. Barnett, W.F. Green, K. Freedman, I. Matushansky, A.I. Skoultchi, and L.L. Kelley, Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27(Kip1) and inactivation of cdk2 kinase. Blood, 2000. 96(8): p. 2746-54.
32. Nakagawa, M., J.L. Oliva, D. Kothapalli, A. Fournier, R.K. Assoian, and M.G. Kazanietz, Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21. J Biol Chem, 2005. 280(40): p. 33926-34.
33. Cheng, T., N. Rodrigues, H. Shen, Y. Yang, D. Dombkowski, M. Sykes, and D.T. Scadden, Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science, 2000. 287(5459): p. 1804-8.
34. Cheng, T., N. Rodrigues, D. Dombkowski, S. Stier, and D.T. Scadden, Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nat Med, 2000. 6(11): p. 1235-40.
35. Taniguchi, T., H. Endo, N. Chikatsu, K. Uchimaru, S. Asano, T. Fujita, T. Nakahata, and T. Motokura, Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase inhibitors during human hematopoiesis. Blood, 1999. 93(12): p. 4167-78.
36. Durand, B., M.L. Fero, J.M. Roberts, and M.C. Raff, p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation. Curr Biol, 1998. 8(8): p. 431-40.
37. Peter Klinken, S., Red blood cells. Int J Biochem Cell Biol, 2002. 34(12): p. 1513-8.
38. Koury, M.J., S.T. Sawyer, and S.J. Brandt, New insights into erythropoiesis. Curr Opin Hematol, 2002. 9(2): p. 93-100.
39. Kwon, Y.H., A. Jovanovic, M.S. Serfas, H. Kiyokawa, and A.L. Tyner, P21 functions to maintain quiescence of p27-deficient hepatocytes. J Biol Chem, 2002. 277(44): p. 41417-22.
40. Denicourt, C. and S.F. Dowdy, Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev, 2004. 18(8): p. 851-5.
41. Kitajima, K., M. Tanaka, J. Zheng, E. Sakai-Ogawa, and T. Nakano, In vitro differentiation of mouse embryonic stem cells to hematopoietic cells on an OP9 stromal cell monolayer. Methods Enzymol, 2003. 365: p. 72-83.
42. Cho, S.K., T.D. Webber, J.R. Carlyle, T. Nakano, S.M. Lewis, and J.C. Zuniga-Pflucker, Functional characterization of B lymphocytes generated in vitro from embryonic stem cells. Proc Natl Acad Sci U S A, 1999. 96(17): p. 9797-802.
43. Kim, S., R.N. La Motte-Mohs, D. Rudolph, J.C. Zuniga-Pflucker, and T.W. Mak, The role of nuclear factor-kappaB essential modulator (NEMO) in B cell development and survival. Proc Natl Acad Sci U S A, 2003. 100(3): p. 1203-8.
44. Cho, S.K. and J.C. Zuniga-Pflucker, Development of lymphoid lineages from embryonic stem cells in vitro. Methods Enzymol, 2003. 365: p. 158-69.
45. 簡秀娟, HTm4於B細胞分化過程中的表現情形及HTm4 knockdown對於髓系細胞分化的影響. 2008.
46. Wanda, P.E. and M.M. Walker, Hemoglobin induction by Ara-C in human erythroleukemic cells (K562) is cell-cycle dependent. Leuk Res, 1989. 13(8): p. 683-8.
47. Nagasawa, T., Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol, 2006. 6(2): p. 107-16.
48. Oster, S.K., C.S. Ho, E.L. Soucie, and L.Z. Penn, The myc oncogene: MarvelouslY Complex. Adv Cancer Res, 2002. 84: p. 81-154.
49. Yang, W., J. Shen, M. Wu, M. Arsura, M. FitzGerald, Z. Suldan, D.W. Kim, C.S. Hofmann, S. Pianetti, R. Romieu-Mourez, L.P. Freedman, and G.E. Sonenshein, Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene, 2001. 20(14): p. 1688-702.
50. Acosta, J.C., N. Ferrandiz, G. Bretones, V. Torrano, R. Blanco, C. Richard, B. O'Connell, J. Sedivy, M.D. Delgado, and J. Leon, Myc inhibits p27-induced erythroid differentiation of leukemia cells by repressing erythroid master genes without reversing p27-mediated cell cycle arrest. Mol Cell Biol, 2008. 28(24): p. 7286-95.
51. Luisi-DeLuca, C., T. Mitchell, D. Spriggs, and D.W. Kufe, Induction of terminal differentiation in human K562 erythroleukemia cells by arabinofuranosylcytosine. J Clin Invest, 1984. 74(3): p. 821-7.
52. Pardee, A.B., A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A, 1974. 71(4): p. 1286-90.
53. Gallo, J.H., J.V. Ordonez, G.E. Brown, and J.R. Testa, Synchronization of human leukemic cells: relevance for high-resolution chromosome banding. Hum Genet, 1984. 66(2-3): p. 220-4.
54. Danthinne, X., K. Aoki, A.L. Kurachi, G.J. Nabel, and E.G. Nabel, Combination gene delivery of the cell cycle inhibitor p27 with thymidine kinase enhances prodrug cytotoxicity. J Virol, 1998. 72(11): p. 9201-7.
55. Russo, A.A., P.D. Jeffrey, A.K. Patten, J. Massague, and N.P. Pavletich, Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature, 1996. 382(6589): p. 325-31.
56. Kikuchi, J., Y. Furukawa, S. Iwase, Y. Terui, M. Nakamura, S. Kitagawa, M. Kitagawa, N. Komatsu, and Y. Miura, Polyploidization and functional maturation are two distinct processes during megakaryocytic differentiation: involvement of cyclin-dependent kinase inhibitor p21 in polyploidization. Blood, 1997. 89(11): p. 3980-90.
57. Wu, H., M. Wade, L. Krall, J. Grisham, Y. Xiong, and T. Van Dyke, Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Genes Dev, 1996. 10(3): p. 245-60.
58. Fisher, J.W., S. Koury, T. Ducey, and S. Mendel, Erythropoietin production by interstitial cells of hypoxic monkey kidneys. Br J Haematol, 1996. 95(1): p. 27-32.
59. Zhu, H. and H.F. Bunn, Oxygen sensing and signaling: impact on the regulation of physiologically important genes. Respir Physiol, 1999. 115(2): p. 239-47.
60. Eckardt, K.U. and A. Kurtz, Regulation of erythropoietin production. Eur J Clin Invest, 2005. 35 Suppl 3: p. 13-9.
61. Huang, Y., K.M. Du, Z.H. Xue, H. Yan, D. Li, W. Liu, Z. Chen, Q. Zhao, J.H. Tong, Y.S. Zhu, and G.Q. Chen, Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1alpha. Leukemia, 2003. 17(11): p. 2065-73.
62. Mikami, M., Y. Sadahira, A. Haga, T. Otsuki, H. Wada, and T. Sugihara, Hypoxia-inducible factor-1 drives the motility of the erythroid progenitor cell line, UT-7/Epo, via autocrine motility factor. Exp Hematol, 2005. 33(5): p. 531-41.
63. Harrison, J.S., P. Rameshwar, V. Chang, and P. Bandari, Oxygen saturation in the bone marrow of healthy volunteers. Blood, 2002. 99(1): p. 394.
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