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. 1997 May;17(5):2933–2943. doi: 10.1128/mcb.17.5.2933

Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAF1/Cip1) by STAT5.

I Matsumura 1, J Ishikawa 1, K Nakajima 1, K Oritani 1, Y Tomiyama 1, J Miyagawa 1, T Kato 1, H Miyazaki 1, Y Matsuzawa 1, Y Kanakura 1
PMCID: PMC232145  PMID: 9111365

Abstract

Although thrombopoietin (TPO) is known to play a fundamental role in both megakaryopoiesis and thrombopoiesis, the molecular mechanism of TPO-induced megakaryocytic differentiation is not known. In a human megakaryoblastic leukemia cell line, CMK, that showed some degree of megakaryocytic differentiation after culture with TPO, the cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/Cip1), but not p27(Kip1), p16(INK4A), p15(INK4B), or p18(INK4C), was found to be upregulated in an immediately early response to TPO. The expression of p21 was found to be sustained over a period of 5 days by treatment with TPO in large polyploid cells that developed in response to TPO, but not in small undifferentiated cells, indicating a close correlation between the ligand-induced differentiation and p21 induction in CMK cells. To examine potential roles of Cdk inhibitors in megakaryocytic differentiation, CMK cells were transfected with the p21, p27, or p16 gene, together with a marker gene, beta-galactosidase, and were cultured with medium alone for 5 days. The ectopic expression of p21 or p27 but not of p16 led to induction of megakaryocytic differentiation of CMK cells. Overexpression of the N-terminal domain (amino acids [aa] 1 to 75) of p21 was sufficient to induce megakaryocytic differentiation, whereas that of the C-terminal domain (aa 76 to 164) had little or no effect on morphological features. Furthermore, we found that although TPO induced tyrosine phosphorylation of both STAT3 and STAT5 in CMK cells, only STAT5 showed binding activities to potential STAT-binding sites that locate in the promoter region of p21 gene (p21-SIE sites), thereby leading to transactivation of p21. These results suggested that p21 induction, possibly mediated through activated STAT5, could play an important role in TPO-induced megakaryocytic differentiation.

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Selected References

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  1. Biggs J. R., Kudlow J. E., Kraft A. S. The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. J Biol Chem. 1996 Jan 12;271(2):901–906. doi: 10.1074/jbc.271.2.901. [DOI] [PubMed] [Google Scholar]
  2. Bloch A. Dynamics of interaction between DNA-specific antitumor agents and serum-contained cytokines in the initiation of ML-1 human myeloblastic leukemia cell differentiation. Leukemia. 1993 Aug;7(8):1219–1224. [PubMed] [Google Scholar]
  3. Brugarolas J., Chandrasekaran C., Gordon J. I., Beach D., Jacks T., Hannon G. J. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995 Oct 12;377(6549):552–557. doi: 10.1038/377552a0. [DOI] [PubMed] [Google Scholar]
  4. Chan F. K., Zhang J., Cheng L., Shapiro D. N., Winoto A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol. 1995 May;15(5):2682–2688. doi: 10.1128/mcb.15.5.2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen J., Jackson P. K., Kirschner M. W., Dutta A. Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature. 1995 Mar 23;374(6520):386–388. doi: 10.1038/374386a0. [DOI] [PubMed] [Google Scholar]
  6. Chin Y. E., Kitagawa M., Su W. C., You Z. H., Iwamoto Y., Fu X. Y. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996 May 3;272(5262):719–722. doi: 10.1126/science.272.5262.719. [DOI] [PubMed] [Google Scholar]
  7. Datto M. B., Li Y., Panus J. F., Howe D. J., Xiong Y., Wang X. F. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5545–5549. doi: 10.1073/pnas.92.12.5545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deng C., Zhang P., Harper J. W., Elledge S. J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995 Aug 25;82(4):675–684. doi: 10.1016/0092-8674(95)90039-x. [DOI] [PubMed] [Google Scholar]
  9. Farese A. M., Hunt P., Boone T., MacVittie T. J. Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates. Blood. 1995 Jul 1;86(1):54–59. [PubMed] [Google Scholar]
  10. García P., Calés C. Endoreplication in megakaryoblastic cell lines is accompanied by sustained expression of G1/S cyclins and downregulation of cdc25C. Oncogene. 1996 Aug 15;13(4):695–703. [PubMed] [Google Scholar]
  11. Gouilleux F., Pallard C., Dusanter-Fourt I., Wakao H., Haldosen L. A., Norstedt G., Levy D., Groner B. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. EMBO J. 1995 May 1;14(9):2005–2013. doi: 10.1002/j.1460-2075.1995.tb07192.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gu Y., Turck C. W., Morgan D. O. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature. 1993 Dec 16;366(6456):707–710. doi: 10.1038/366707a0. [DOI] [PubMed] [Google Scholar]
  13. Guadagno T. M., Newport J. W. Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell. 1996 Jan 12;84(1):73–82. doi: 10.1016/s0092-8674(00)80994-0. [DOI] [PubMed] [Google Scholar]
  14. Guan K. L., Jenkins C. W., Li Y., Nichols M. A., Wu X., O'Keefe C. L., Matera A. G., Xiong Y. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 1994 Dec 15;8(24):2939–2952. doi: 10.1101/gad.8.24.2939. [DOI] [PubMed] [Google Scholar]
  15. Gurney A. L., Carver-Moore K., de Sauvage F. J., Moore M. W. Thrombocytopenia in c-mpl-deficient mice. Science. 1994 Sep 2;265(5177):1445–1447. doi: 10.1126/science.8073287. [DOI] [PubMed] [Google Scholar]
  16. Gurney A. L., Wong S. C., Henzel W. J., de Sauvage F. J. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5292–5296. doi: 10.1073/pnas.92.12.5292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Halevy O., Novitch B. G., Spicer D. B., Skapek S. X., Rhee J., Hannon G. J., Beach D., Lassar A. B. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science. 1995 Feb 17;267(5200):1018–1021. doi: 10.1126/science.7863327. [DOI] [PubMed] [Google Scholar]
  18. Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
  19. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  20. Hirai H., Roussel M. F., Kato J. Y., Ashmun R. A., Sherr C. J. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol. 1995 May;15(5):2672–2681. doi: 10.1128/mcb.15.5.2672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ihle J. N. Cytokine receptor signalling. Nature. 1995 Oct 19;377(6550):591–594. doi: 10.1038/377591a0. [DOI] [PubMed] [Google Scholar]
  22. Ihle J. N. STATs: signal transducers and activators of transcription. Cell. 1996 Feb 9;84(3):331–334. doi: 10.1016/s0092-8674(00)81277-5. [DOI] [PubMed] [Google Scholar]
  23. Jiang H., Lin J., Su Z. Z., Collart F. R., Huberman E., Fisher P. B. Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF1/CIP1, expression in the absence of p53. Oncogene. 1994 Nov;9(11):3397–3406. [PubMed] [Google Scholar]
  24. Johnson P., Chung S., Benchimol S. Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin. Mol Cell Biol. 1993 Mar;13(3):1456–1463. doi: 10.1128/mcb.13.3.1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kaushansky K., Lok S., Holly R. D., Broudy V. C., Lin N., Bailey M. C., Forstrom J. W., Buddle M. M., Oort P. J., Hagen F. S. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994 Jun 16;369(6481):568–571. doi: 10.1038/369568a0. [DOI] [PubMed] [Google Scholar]
  26. Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood. 1995 Jul 15;86(2):419–431. [PubMed] [Google Scholar]
  27. Lee M. H., Reynisdóttir I., Massagué J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995 Mar 15;9(6):639–649. doi: 10.1101/gad.9.6.639. [DOI] [PubMed] [Google Scholar]
  28. Lew D. J., Decker T., Strehlow I., Darnell J. E. Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons. Mol Cell Biol. 1991 Jan;11(1):182–191. doi: 10.1128/mcb.11.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Liu M., Lee M. H., Cohen M., Bommakanti M., Freedman L. P. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 1996 Jan 15;10(2):142–153. doi: 10.1101/gad.10.2.142. [DOI] [PubMed] [Google Scholar]
  30. Luo Y., Hurwitz J., Massagué J. Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature. 1995 May 11;375(6527):159–161. doi: 10.1038/375159a0. [DOI] [PubMed] [Google Scholar]
  31. Macleod K. F., Sherry N., Hannon G., Beach D., Tokino T., Kinzler K., Vogelstein B., Jacks T. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995 Apr 15;9(8):935–944. doi: 10.1101/gad.9.8.935. [DOI] [PubMed] [Google Scholar]
  32. Matsumura I., Kanakura Y., Kato T., Ikeda H., Horikawa Y., Ishikawa J., Kitayama H., Nishiura T., Tomiyama Y., Miyazaki H. The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells. Blood. 1996 Oct 15;88(8):3074–3082. [PubMed] [Google Scholar]
  33. Matsumura I., Kanakura Y., Kato T., Ikeda H., Ishikawa J., Horikawa Y., Hashimoto K., Moriyama Y., Tsujimura T., Nishiura T. Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin. Blood. 1995 Jul 15;86(2):703–709. [PubMed] [Google Scholar]
  34. Matsuoka S., Edwards M. C., Bai C., Parker S., Zhang P., Baldini A., Harper J. W., Elledge S. J. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 1995 Mar 15;9(6):650–662. doi: 10.1101/gad.9.6.650. [DOI] [PubMed] [Google Scholar]
  35. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
  36. Missero C., Calautti E., Eckner R., Chin J., Tsai L. H., Livingston D. M., Dotto G. P. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5451–5455. doi: 10.1073/pnas.92.12.5451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Morella K. K., Bruno E., Kumaki S., Lai C. F., Fu J., Wang H. M., Murray L., Hoffman R., Timour M., Bénit L. Signal transduction by the receptors for thrombopoietin (c-mpL) and interleukin-3 in hematopoietic and nonhematopoietic cells. Blood. 1995 Jul 15;86(2):557–571. [PubMed] [Google Scholar]
  38. Mu S. X., Xia M., Elliott G., Bogenberger J., Swift S., Bennett L., Lappinga D. L., Hecht R., Lee R., Saris C. J. Megakaryocyte growth and development factor and interleukin-3 induce patterns of protein-tyrosine phosphorylation that correlate with dominant differentiation over proliferation of mpl-transfected 32D cells. Blood. 1995 Dec 15;86(12):4532–4543. [PubMed] [Google Scholar]
  39. Nakajima K., Kusafuka T., Takeda T., Fujitani Y., Nakae K., Hirano T. Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. Mol Cell Biol. 1993 May;13(5):3027–3041. doi: 10.1128/mcb.13.5.3027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nakajima K., Yamanaka Y., Nakae K., Kojima H., Ichiba M., Kiuchi N., Kitaoka T., Fukada T., Hibi M., Hirano T. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996 Jul 15;15(14):3651–3658. [PMC free article] [PubMed] [Google Scholar]
  41. Nakanishi M., Robetorye R. S., Adami G. R., Pereira-Smith O. M., Smith J. R. Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1. EMBO J. 1995 Feb 1;14(3):555–563. doi: 10.1002/j.1460-2075.1995.tb07031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Noda A., Ning Y., Venable S. F., Pereira-Smith O. M., Smith J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90–98. doi: 10.1006/excr.1994.1063. [DOI] [PubMed] [Google Scholar]
  43. Pallard C., Gouilleux F., Bénit L., Cocault L., Souyri M., Levy D., Groner B., Gisselbrecht S., Dusanter-Fourt I. Thrombopoietin activates a STAT5-like factor in hematopoietic cells. EMBO J. 1995 Jun 15;14(12):2847–2856. doi: 10.1002/j.1460-2075.1995.tb07284.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Parker S. B., Eichele G., Zhang P., Rawls A., Sands A. T., Bradley A., Olson E. N., Harper J. W., Elledge S. J. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science. 1995 Feb 17;267(5200):1024–1027. doi: 10.1126/science.7863329. [DOI] [PubMed] [Google Scholar]
  45. Polyak K., Lee M. H., Erdjument-Bromage H., Koff A., Roberts J. M., Tempst P., Massagué J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994 Jul 15;78(1):59–66. doi: 10.1016/0092-8674(94)90572-x. [DOI] [PubMed] [Google Scholar]
  46. Porteu F., Rouyez M. C., Cocault L., Bénit L., Charon M., Picard F., Gisselbrecht S., Souyri M., Dusanter-Fourt I. Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin. Mol Cell Biol. 1996 May;16(5):2473–2482. doi: 10.1128/mcb.16.5.2473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sadowski H. B., Gilman M. Z. Cell-free activation of a DNA-binding protein by epidermal growth factor. Nature. 1993 Mar 4;362(6415):79–83. doi: 10.1038/362079a0. [DOI] [PubMed] [Google Scholar]
  48. Sato T., Fuse A., Eguchi M., Hayashi Y., Ryo R., Adachi M., Kishimoto Y., Teramura M., Mizoguchi H., Shima Y. Establishment of a human leukaemic cell line (CMK) with megakaryocytic characteristics from a Down's syndrome patient with acute megakaryoblastic leukaemia. Br J Haematol. 1989 Jun;72(2):184–190. doi: 10.1111/j.1365-2141.1989.tb07681.x. [DOI] [PubMed] [Google Scholar]
  49. Schwaller J., Koeffler H. P., Niklaus G., Loetscher P., Nagel S., Fey M. F., Tobler A. Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. J Clin Invest. 1995 Mar;95(3):973–979. doi: 10.1172/JCI117806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  51. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  52. Sugahara H., Kanakura Y., Furitsu T., Ishihara K., Oritani K., Ikeda H., Kitayama H., Ishikawa J., Hashimoto K., Kanayama Y. Induction of programmed cell death in human hematopoietic cell lines by fibronectin via its interaction with very late antigen 5. J Exp Med. 1994 Jun 1;179(6):1757–1766. doi: 10.1084/jem.179.6.1757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sugimoto K., Toyoshima H., Sakai R., Miyagawa K., Hagiwara K., Ishikawa F., Takaku F., Yazaki Y., Hirai H. Frequent mutations in the p53 gene in human myeloid leukemia cell lines. Blood. 1992 May 1;79(9):2378–2383. [PubMed] [Google Scholar]
  54. Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. doi: 10.1016/0092-8674(94)90573-8. [DOI] [PubMed] [Google Scholar]
  55. Vigon I., Mornon J. P., Cocault L., Mitjavila M. T., Tambourin P., Gisselbrecht S., Souyri M. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5640–5644. doi: 10.1073/pnas.89.12.5640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Waga S., Hannon G. J., Beach D., Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994 Jun 16;369(6481):574–578. doi: 10.1038/369574a0. [DOI] [PubMed] [Google Scholar]
  57. Wakao H., Harada N., Kitamura T., Mui A. L., Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J. 1995 Jun 1;14(11):2527–2535. doi: 10.1002/j.1460-2075.1995.tb07250.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wegenka U. M., Buschmann J., Lütticken C., Heinrich P. C., Horn F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol. 1993 Jan;13(1):276–288. doi: 10.1128/mcb.13.1.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yamanaka Y., Nakajima K., Fukada T., Hibi M., Hirano T. Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. EMBO J. 1996 Apr 1;15(7):1557–1565. [PMC free article] [PubMed] [Google Scholar]
  60. de Sauvage F. J., Carver-Moore K., Luoh S. M., Ryan A., Dowd M., Eaton D. L., Moore M. W. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996 Feb 1;183(2):651–656. doi: 10.1084/jem.183.2.651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. de Sauvage F. J., Hass P. E., Spencer S. D., Malloy B. E., Gurney A. L., Spencer S. A., Darbonne W. C., Henzel W. J., Wong S. C., Kuang W. J. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994 Jun 16;369(6481):533–538. doi: 10.1038/369533a0. [DOI] [PubMed] [Google Scholar]
  62. el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
  63. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

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