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Volumn 27, Issue 43, 2008, Pages 5706-5716

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

Author keywords

Cell death; DAPK2; E2F1; KLF6; Sp1; Transcription

Indexed keywords

DEATH ASSOCIATED PROTEIN KINASE; DEATH ASSOCIATED PROTEIN KINASE 2; KRUPPEL LIKE FACTOR 6; MITHRAMYCIN; MITHRAMYCIN A; TRANSCRIPTION FACTOR E2F1; TRANSCRIPTION FACTOR SP1; UNCLASSIFIED DRUG;

EID: 52949111324     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2008.179     Document Type: Article
Times cited : (32)

References (50)
  • 1
    • 0025730640 scopus 로고
    • A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian-cells
    • Andrews NC, Faller DV. (1991). A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian-cells. Nucleic Acids Res 19: 2499.
    • (1991) Nucleic Acids Res , vol.19 , pp. 2499
    • Andrews, N.C.1    Faller, D.V.2
  • 2
    • 0742324404 scopus 로고    scopus 로고
    • Life and death decisions by E2F-1
    • Bell LA, Ryan KM. (2003). Life and death decisions by E2F-1. Cell Death Differ 11: 137-142.
    • (2003) Cell Death Differ , vol.11 , pp. 137-142
    • Bell, L.A.1    Ryan, K.M.2
  • 3
    • 33746359639 scopus 로고    scopus 로고
    • The death-associated kinases: Structure, function, and beyond
    • Bialik S, Kimchi A. (2006). The death-associated kinases: structure, function, and beyond. Ann Rev Biochem 75: 189-210.
    • (2006) Ann Rev Biochem , vol.75 , pp. 189-210
    • Bialik, S.1    Kimchi, A.2
  • 4
    • 0035860820 scopus 로고    scopus 로고
    • Kruppel-like factors: Three fingers in many pies
    • Bieker JJ. (2001). Kruppel-like factors: three fingers in many pies. J Biol Chem 276: 34355-34358.
    • (2001) J Biol Chem , vol.276 , pp. 34355-34358
    • Bieker, J.J.1
  • 5
    • 0034929708 scopus 로고    scopus 로고
    • Sp1 and Kruppel-like factor family of transcription factors in cell growth regulation and cancer
    • Black AR, Black JD, Azizkhan-Clifford J. (2001). Sp1 and Kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188: 143-160.
    • (2001) J Cell Physiol , vol.188 , pp. 143-160
    • Black, A.R.1    Black, J.D.2    Azizkhan-Clifford, J.3
  • 6
    • 0025221436 scopus 로고
    • Transcriptional initiation is controlled by upstream Gc-box Interactions in a tataa-less promoter
    • Blake MC, Jambou RC, Swick AG, Kahn JW, Azizkhan JC. (1990). Transcriptional initiation is controlled by upstream Gc-box Interactions in a tataa-less promoter. Mol Cell Biol 10: 6632-6641.
    • (1990) Mol Cell Biol , vol.10 , pp. 6632-6641
    • Blake, M.C.1    Jambou, R.C.2    Swick, A.G.3    Kahn, J.W.4    Azizkhan, J.C.5
  • 7
    • 0036893431 scopus 로고    scopus 로고
    • Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: Their potential role in the response to vascular injury
    • Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M et al. (2002). Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100: 4001-4010.
    • (2002) Blood , vol.100 , pp. 4001-4010
    • Botella, L.M.1    Sanchez-Elsner, T.2    Sanz-Rodriguez, F.3    Kojima, S.4    Shimada, J.5    Guerrero-Esteo, M.6
  • 8
    • 33645500652 scopus 로고    scopus 로고
    • Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1
    • Britschgi C, Rizzi M, Grob TJ, Tschan MP, Hugli B, Reddy VA et al. (2006). Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. Oncogene 25: 2030-2039.
    • (2006) Oncogene , vol.25 , pp. 2030-2039
    • Britschgi, C.1    Rizzi, M.2    Grob, T.J.3    Tschan, M.P.4    Hugli, B.5    Reddy, V.A.6
  • 10
    • 33845624653 scopus 로고    scopus 로고
    • Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer
    • Christoph F, Kempkensteffen C, Weikert S, Kollermann J, Krause H, Miller K et al. (2006). Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br J Cancer 95: 1701-1707.
    • (2006) Br J Cancer , vol.95 , pp. 1701-1707
    • Christoph, F.1    Kempkensteffen, C.2    Weikert, S.3    Kollermann, J.4    Krause, H.5    Miller, K.6
  • 11
    • 33750920705 scopus 로고    scopus 로고
    • Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis
    • DeGregori J, Johnson DG. (2006). Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr Mol Med 6: 739-748.
    • (2006) Curr Mol Med , vol.6 , pp. 739-748
    • DeGregori, J.1    Johnson, D.G.2
  • 12
    • 23744507860 scopus 로고    scopus 로고
    • E2F1 is crucial for E2F-dependent apoptosis
    • Denchi EL, Helin K. (2005). E2F1 is crucial for E2F-dependent apoptosis. EMBO Rep 6: 661-667.
    • (2005) EMBO Rep , vol.6 , pp. 661-667
    • Denchi, E.L.1    Helin, K.2
  • 13
    • 33745725772 scopus 로고    scopus 로고
    • Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination
    • Difeo A, Narla G, Hirshfeld J, Camacho-Vanegas O, Narla J, Rose SL et al. (2006). Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination. Clin Cancer Res 12: 3730-3739.
    • (2006) Clin Cancer Res , vol.12 , pp. 3730-3739
    • Difeo, A.1    Narla, G.2    Hirshfeld, J.3    Camacho-Vanegas, O.4    Narla, J.5    Rose, S.L.6
  • 15
  • 16
    • 1542305653 scopus 로고    scopus 로고
    • Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis
    • Hershko T, Ginsberg D. (2004). Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 279: 8627-8634.
    • (2004) J Biol Chem , vol.279 , pp. 8627-8634
    • Hershko, T.1    Ginsberg, D.2
  • 17
    • 0033960235 scopus 로고    scopus 로고
    • Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis
    • Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A. (2000). Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol Cell Biol 20: 1044-1054.
    • (2000) Mol Cell Biol , vol.20 , pp. 1044-1054
    • Inbal, B.1    Shani, G.2    Cohen, O.3    Kissil, J.L.4    Kimchi, A.5
  • 19
    • 2542521484 scopus 로고    scopus 로고
    • Kruppel-Like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells
    • Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O et al. (2004). Kruppel-Like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Cancer Res 64: 3838-3843.
    • (2004) Cancer Res , vol.64 , pp. 3838-3843
    • Ito, G.1    Uchiyama, M.2    Kondo, M.3    Mori, S.4    Usami, N.5    Maeda, O.6
  • 20
    • 0029926303 scopus 로고    scopus 로고
    • Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F
    • Karlseder J, Rotheneder H, Wintersberger E. (1996). Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol Cell Biol 16: 1659-1667.
    • (1996) Mol Cell Biol , vol.16 , pp. 1659-1667
    • Karlseder, J.1    Rotheneder, H.2    Wintersberger, E.3
  • 21
    • 0033564351 scopus 로고    scopus 로고
    • Hypermethylation of the DAP-Kinase CpG island is a common alteration in B-cell malignancies
    • Katzenellenbogen RA, Baylin SB, Herman JG. (1999). Hypermethylation of the DAP-Kinase CpG island is a common alteration in B-cell malignancies. Blood 93: 4347-4353.
    • (1999) Blood , vol.93 , pp. 4347-4353
    • Katzenellenbogen, R.A.1    Baylin, S.B.2    Herman, J.G.3
  • 22
    • 0032509217 scopus 로고    scopus 로고
    • Transcriptional activation of transforming growth factor beta 1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1 - potential mechanisms for autocrine fibrogenesis in response to injury
    • Kim Y, Ratziu V, Choi SG, Lalazar A, Theiss G, Dang Q et al. (1998). Transcriptional activation of transforming growth factor beta 1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1 - potential mechanisms for autocrine fibrogenesis in response to injury. J Biol Chem 273: 33750-33758.
    • (1998) J Biol Chem , vol.273 , pp. 33750-33758
    • Kim, Y.1    Ratziu, V.2    Choi, S.G.3    Lalazar, A.4    Theiss, G.5    Dang, Q.6
  • 23
    • 0027980124 scopus 로고
    • Start site selection at the tata-less carbamoyl-phosphate synthase (glutamine-hydrolyzing) aspartate carbamoyltransferase dihydroorotase promoter
    • Kollmar R, Sukow KA, Sponagle SK, Farnham PJ. (1994). Start site selection at the tata-less carbamoyl-phosphate synthase (glutamine-hydrolyzing) aspartate carbamoyltransferase dihydroorotase promoter. J Biol Chem 269: 2252-2257.
    • (1994) J Biol Chem , vol.269 , pp. 2252-2257
    • Kollmar, R.1    Sukow, K.A.2    Sponagle, S.K.3    Farnham, P.J.4
  • 24
    • 11244325724 scopus 로고    scopus 로고
    • Inhibition of p53-mediated transcriptional responses by mithramycin A
    • Koutsodontis G, Kardassis D. (2004). Inhibition of p53-mediated transcriptional responses by mithramycin A. Oncogene 23: 9190-9200.
    • (2004) Oncogene , vol.23 , pp. 9190-9200
    • Koutsodontis, G.1    Kardassis, D.2
  • 25
    • 1242339706 scopus 로고    scopus 로고
    • E2F and Sp1/Sp3 synergize but are not sufficient to activate the MYCN gene in neuroblastomas
    • Kramps C, Strieder V, Sapetschnig A, Suske G, Lutz W. (2004). E2F and Sp1/Sp3 synergize but are not sufficient to activate the MYCN gene in neuroblastomas. J Biol Chem 279: 5110-5117.
    • (2004) J Biol Chem , vol.279 , pp. 5110-5117
    • Kramps, C.1    Strieder, V.2    Sapetschnig, A.3    Suske, G.4    Lutz, W.5
  • 26
    • 27144524063 scopus 로고    scopus 로고
    • Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation
    • Li D, Yea S, Dolios G, Martignetti JA, Narla G, Wang R et al. (2005). Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation. Cancer Res 65: 9216-9225.
    • (2005) Cancer Res , vol.65 , pp. 9216-9225
    • Li, D.1    Yea, S.2    Dolios, G.3    Martignetti, J.A.4    Narla, G.5    Wang, R.6
  • 27
    • 0029981560 scopus 로고    scopus 로고
    • Cell cycle-regulated association of E2F1 and sp1 is related to their functional interaction
    • Lin SY, Black AR, Kostic D, Pajovic S, Hoover CN, Azizkhan JC. (1996). Cell cycle-regulated association of E2F1 and sp1 is related to their functional interaction. Mol Cell Biol 16: 1668-1675.
    • (1996) Mol Cell Biol , vol.16 , pp. 1668-1675
    • Lin, S.Y.1    Black, A.R.2    Kostic, D.3    Pajovic, S.4    Hoover, C.N.5    Azizkhan, J.C.6
  • 28
    • 0035893756 scopus 로고    scopus 로고
    • Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features
    • Maruyama R, Toyooka S, Toyooka KO, Harada K, Virmani AK, Zochbauer-Muller S et al. (2001). Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. Cancer Res 61: 8659-8663.
    • (2001) Cancer Res , vol.61 , pp. 8659-8663
    • Maruyama, R.1    Toyooka, S.2    Toyooka, K.O.3    Harada, K.4    Virmani, A.K.5    Zochbauer-Muller, S.6
  • 31
    • 0035252592 scopus 로고    scopus 로고
    • E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis
    • Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E et al. (2001). E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev 15: 267-285.
    • (2001) Genes Dev , vol.15 , pp. 267-285
    • Muller, H.1    Bracken, A.P.2    Vernell, R.3    Moroni, M.C.4    Christians, F.5    Grassilli, E.6
  • 32
    • 0037377699 scopus 로고    scopus 로고
    • Kruppel cripples prostate cancer - KLF6 progress and prospects
    • Narla G, Friedman SL, Martignetti JA. (2003). Kruppel cripples prostate cancer - KLF6 progress and prospects. Am J Pathol 162: 1047-1052.
    • (2003) Am J Pathol , vol.162 , pp. 1047-1052
    • Narla, G.1    Friedman, S.L.2    Martignetti, J.A.3
  • 33
  • 34
    • 0036297530 scopus 로고    scopus 로고
    • Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors
    • Parisi T, Pollice A, Di Cristofano A, Calabro V, La Mantia G. (2002). Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors. Biochem Biophys Res Commun 291: 1138-1145.
    • (2002) Biochem Biophys Res Commun , vol.291 , pp. 1138-1145
    • Parisi, T.1    Pollice, A.2    Di Cristofano, A.3    Calabro, V.4    La Mantia, G.5
  • 35
    • 0037716527 scopus 로고    scopus 로고
    • Modulation of Sp1-dependent transcription by a cis-acting E2F element in dhfr promoter
    • Park KK, Rue SW, Lee IS, Kim HC, Lee IK, Ahn JD et al. (2003). Modulation of Sp1-dependent transcription by a cis-acting E2F element in dhfr promoter. Biochem Biophys Res Commun 306: 239-243.
    • (2003) Biochem Biophys Res Commun , vol.306 , pp. 239-243
    • Park, K.K.1    Rue, S.W.2    Lee, I.S.3    Kim, H.C.4    Lee, I.K.5    Ahn, J.D.6
  • 36
    • 34247882638 scopus 로고    scopus 로고
    • E2F1 death pathways as targets for cancer therapy
    • Putzer BM. (2007). E2F1 death pathways as targets for cancer therapy. J Cell Mol Med 11: 239-251.
    • (2007) J Cell Mol Med , vol.11 , pp. 239-251
    • Putzer, B.M.1
  • 37
    • 0037706860 scopus 로고    scopus 로고
    • The Bcr kinase downregulates ras signaling by phosphorylating AF-6 and binding to its PDZ domain
    • Radziwill G, Erdmann RA, Margelisch U, Moelling K. (2003). The Bcr kinase downregulates ras signaling by phosphorylating AF-6 and binding to its PDZ domain. Mol Cell Biol 23: 4663-4672.
    • (2003) Mol Cell Biol , vol.23 , pp. 4663-4672
    • Radziwill, G.1    Erdmann, R.A.2    Margelisch, U.3    Moelling, K.4
  • 38
    • 11144357280 scopus 로고    scopus 로고
    • Kruppel-Like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer
    • Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S et al. (2004). Kruppel-Like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology 126: 1090-1103.
    • (2004) Gastroenterology , vol.126 , pp. 1090-1103
    • Reeves, H.L.1    Narla, G.2    Ogunbiyi, O.3    Haq, A.I.4    Katz, A.5    Benzeno, S.6
  • 39
    • 34249696951 scopus 로고    scopus 로고
    • The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells
    • Rizzi M, Tschan MP, Britschgi C, Britschgi A, Hugli B, Grob TJ et al. (2007). The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells. J Leukoc Biol 81: 1599-1608.
    • (2007) J Leukoc Biol , vol.81 , pp. 1599-1608
    • Rizzi, M.1    Tschan, M.P.2    Britschgi, C.3    Britschgi, A.4    Hugli, B.5    Grob, T.J.6
  • 40
    • 0031771497 scopus 로고    scopus 로고
    • The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53
    • Robertson KD, Jones PA. (1998). The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol Cell Biol 18: 6457-6473.
    • (1998) Mol Cell Biol , vol.18 , pp. 6457-6473
    • Robertson, K.D.1    Jones, P.A.2
  • 41
    • 0037020686 scopus 로고    scopus 로고
    • The DAP-kinase family of proteins: Study of a novel group of calcium-regulated death-promoting kinases
    • Shohat G, Shani G, Eisenstein M, Kimchi A. (2002). The DAP-kinase family of proteins: study of a novel group of calcium-regulated death-promoting kinases. Biochim Biophys Acta (BBA) - Prot Proteom 1600: 45-50.
    • (2002) Biochim Biophys Acta (BBA) - Prot Proteom , vol.1600 , pp. 45-50
    • Shohat, G.1    Shani, G.2    Eisenstein, M.3    Kimchi, A.4
  • 42
    • 8844286089 scopus 로고    scopus 로고
    • A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function
    • Slavin DA, Koritschoner NP, Prieto CC, Lopez-Diaz FJ, Chatton B, Bocco JL. (2004). A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function. Oncogene 23: 8196-8205.
    • (2004) Oncogene , vol.23 , pp. 8196-8205
    • Slavin, D.A.1    Koritschoner, N.P.2    Prieto, C.C.3    Lopez-Diaz, F.J.4    Chatton, B.5    Bocco, J.L.6
  • 43
    • 17144371344 scopus 로고    scopus 로고
    • A novel mitochondrial protein DIPmediat es E2F1-induced apoptosis independently of p53
    • Stanelle J, Tu-Rapp H, Putzer BM. (2005). A novel mitochondrial protein DIPmediat es E2F1-induced apoptosis independently of p53. Cell Death Differ 12: 347-357.
    • (2005) Cell Death Differ , vol.12 , pp. 347-357
    • Stanelle, J.1    Tu-Rapp, H.2    Putzer, B.M.3
  • 44
    • 0032866999 scopus 로고    scopus 로고
    • The Sp-family of transcription factors
    • Suske G. (1999). The Sp-family of transcription factors. Gene 238: 291-300.
    • (1999) Gene , vol.238 , pp. 291-300
    • Suske, G.1
  • 45
    • 20144368777 scopus 로고    scopus 로고
    • Vascular implications of the Kruppel-like family of transcription factors
    • Suzuki T, Aizawa K, Matsumura T, Nagai R. (2005). Vascular implications of the Kruppel-like family of transcription factors. Arterioscler Thromb Vasc Biol 25: 1135-1141.
    • (2005) Arterioscler Thromb Vasc Biol , vol.25 , pp. 1135-1141
    • Suzuki, T.1    Aizawa, K.2    Matsumura, T.3    Nagai, R.4
  • 46
    • 0242384942 scopus 로고    scopus 로고
    • Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns
    • Tschan MP, Fischer KM, Fung VS, Pirnia F, Borner MM, Fey MF et al. (2003). Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns. J Biol Chem 278: 42750-42760.
    • (2003) J Biol Chem , vol.278 , pp. 42750-42760
    • Tschan, M.P.1    Fischer, K.M.2    Fung, V.S.3    Pirnia, F.4    Borner, M.M.5    Fey, M.F.6
  • 47
    • 0033137330 scopus 로고    scopus 로고
    • Mammalian Kruppel-like transcription factors: More than just a pretty finger
    • Turner J, Crossley M. (1999). Mammalian Kruppel-like transcription factors: more than just a pretty finger. Trends Biochem Sci 24: 236-241.
    • (1999) Trends Biochem Sci , vol.24 , pp. 236-241
    • Turner, J.1    Crossley, M.2
  • 48
    • 0942276838 scopus 로고    scopus 로고
    • Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes
    • Voso MT, Scardocci A, Guidi F, Zini G, Di Mario A, Pagano L et al. (2004). Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes. Blood 103: 698-700.
    • (2004) Blood , vol.103 , pp. 698-700
    • Voso, M.T.1    Scardocci, A.2    Guidi, F.3    Zini, G.4    Di Mario, A.5    Pagano, L.6
  • 49
    • 33645925293 scopus 로고    scopus 로고
    • Novel link between E2F1 and Smac/DIABLO: Proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1
    • Xie W, Jiang P, Miao L, Zhao Y, Zhimin Z, Qing L et al. (2006). Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1. Nucleic Acids Res 34: 2046-2055.
    • (2006) Nucleic Acids Res , vol.34 , pp. 2046-2055
    • Xie, W.1    Jiang, P.2    Miao, L.3    Zhao, Y.4    Zhimin, Z.5    Qing, L.6


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