메뉴 건너뛰기




Volumn 24, Issue 22, 2013, Pages 3496-3510

Bves and NDRG4 regulate Directional epicardial cell migration through autocrine extracellular matrix deposition

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD VESSEL EPICARDIAL SUBSTANCE PROTEIN; CELL PROTEIN; FIBRONECTIN; N MYC DOWNSTREAM REGULATED GENE 4 PROTEIN; UNCLASSIFIED DRUG;

EID: 84888257749     PISSN: 10591524     EISSN: 19394586     Source Type: Journal    
DOI: 10.1091/mbc.E12-07-0539     Document Type: Article
Times cited : (41)

References (56)
  • 1
    • 0036168145 scopus 로고    scopus 로고
    • Mouse Pop1 is required for muscle regeneration in adult skeletal muscle
    • DOI 10.1128/MCB.22.5.1504-1512.2002
    • Andrée B, Fileige A, Arnold HH, Brand T (2002). Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Mol Cell Biol 22, 1504-1512. (Pubitemid 34150786)
    • (2002) Molecular and Cellular Biology , vol.22 , Issue.5 , pp. 1504-1512
    • Andree, B.1    Fleige, A.2    Arnold, H.-H.3    Brand, T.4
  • 3
    • 0020459571 scopus 로고
    • Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro
    • DOI 10.1083/jcb.95.3.763
    • Bader D, Masaki T, Fischman DA (1982). Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J Cell Biol 95, 763-770. (Pubitemid 13186099)
    • (1982) Journal of Cell Biology , vol.95 , Issue.3 , pp. 763-770
    • Bader, D.1    Masaki, T.2    Fischman, D.A.3
  • 4
    • 33748157549 scopus 로고    scopus 로고
    • Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease)
    • DOI 10.1002/glia.20386
    • Berger P, Niemann A, Suter U (2006). Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease). Glia 54, 243-257. (Pubitemid 44316230)
    • (2006) GLIA , vol.54 , Issue.4 , pp. 243-257
    • Berger, P.1    Niemann, A.2    Suter, U.3
  • 5
    • 77953023276 scopus 로고    scopus 로고
    • NDRG2 is one of novel intrinsic factors for regulation of IL-10 production in human myeloid cell
    • Choi S-C et al. (2010). NDRG2 is one of novel intrinsic factors for regulation of IL-10 production in human myeloid cell. Biochem Biophys Res Commun 396, 684-690.
    • (2010) Biochem Biophys Res Commun , vol.396 , pp. 684-690
    • Choi, S.-C.1
  • 6
    • 80053586217 scopus 로고    scopus 로고
    • Application of small organic molecules reveals cooperative TGFbeta and BMP regulation of mesothelial cell behaviors
    • Cross EE, Thomason RT, Martinez M, Hopkins CR, Hong CC, Bader DM (2011). Application of small organic molecules reveals cooperative TGFbeta and BMP regulation of mesothelial cell behaviors. ACS Chem Biol 6, 952-961.
    • (2011) ACS Chem Biol , vol.6 , pp. 952-961
    • Cross, E.E.1    Thomason, R.T.2    Martinez, M.3    Hopkins, C.R.4    Hong, C.C.5    Bader, D.M.6
  • 7
    • 0037164867 scopus 로고    scopus 로고
    • The fibronectin-binding integrins α5β1 and αvβ3 differentially modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis
    • DOI 10.1083/jcb.200205014
    • Danen E H J (2002). The fibronectin-binding integrins alpha5beta1 and alphavbeta3 differentially modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis. J Cell Biol 159, 1071-1086. (Pubitemid 36055761)
    • (2002) Journal of Cell Biology , vol.159 , Issue.6 , pp. 1071-1086
    • Danen, E.H.J.1    Sonneveld, P.2    Brakebusch, C.3    Fassler, R.4    Sonnenberg, A.5
  • 9
    • 84855966245 scopus 로고    scopus 로고
    • Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression
    • Dozynkiewicz MA et al. (2011). Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev Cell 22, 131-145.
    • (2011) Dev Cell , vol.22 , pp. 131-145
    • Dozynkiewicz, M.A.1
  • 11
    • 84857119014 scopus 로고    scopus 로고
    • Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice
    • Froese A et al. (2012). Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest 122, 1119-1130.
    • (2012) J Clin Invest , vol.122 , pp. 1119-1130
    • Froese, A.1
  • 14
    • 21244491489 scopus 로고    scopus 로고
    • Directional persistence of EGF-induced cell migration is associated with stabilization of lamellipodial protrusions
    • DOI 10.1529/biophysj.104.047365
    • Harms BD, Bassi GM, Horwitz AR, Lauffenburger DA (2005). Directional persistence of EGF-induced cell migration is associated with stabilization of lamellipodial protrusions. Biophys J 88, 1479-1488. (Pubitemid 40975974)
    • (2005) Biophysical Journal , vol.88 , Issue.2 , pp. 1479-1488
    • Harms, B.D.1    Bassi, G.M.2    Horwitz, A.R.3    Lauffenburger, D.A.4
  • 16
    • 33644874395 scopus 로고    scopus 로고
    • Utilizing the split-ubiquitin membrane yeast two-hybrid system to identify protein-protein interactions of integral membrane proteins
    • Iyer K, Bürkle L, Auerbach D, Thaminy S, Dinkel M, Engels K, Stagljar I (2005). Utilizing the split-ubiquitin membrane yeast two-hybrid system to identify protein-protein interactions of integral membrane proteins. Sci STKE 2005, p13.
    • (2005) Sci STKE 2005 , pp. 13
    • Iyer, K.1    Bürkle, L.2    Auerbach, D.3    Thaminy, S.4    Dinkel, M.5    Engels, K.6    Stagljar, I.7
  • 18
    • 0028927288 scopus 로고
    • Cell surface glycoconjugates and the extracellular matrix of the developing mouse embryo epicardium
    • Kalman F, Viragh S, Modis L (1995). Cell surface glycoconjugates and the extracellular matrix of the developing mouse embryo epicardium. Anat Embryol (Berl) 191, 451-464.
    • (1995) Anat Embryol (Berl) , vol.191 , pp. 451-464
    • Kalman, F.1    Viragh, S.2    Modis, L.3
  • 19
    • 48249090849 scopus 로고    scopus 로고
    • Identification of a novel intracellular interaction domain essential for Bves function
    • Kawaguchi M, Hager HA, Wada A, Koyama T, Chang MS, Bader DM (2008). Identification of a novel intracellular interaction domain essential for Bves function. PLOS ONE 3, e2261.
    • (2008) PLOS ONE , vol.3
    • Kawaguchi, M.1    Hager, H.A.2    Wada, A.3    Koyama, T.4    Chang, M.S.5    Bader, D.M.6
  • 20
    • 77956282908 scopus 로고    scopus 로고
    • Frequent silencing of Popeye domain-containing genes, BVES and POPDC3, is associated with promoter hypermethylation in gastric cancer
    • Kim M et al. (2010). Frequent silencing of Popeye domain-containing genes, BVES and POPDC3, is associated with promoter hypermethylation in gastric cancer. Carcinogenesis 31, 1685-1693.
    • (2010) Carcinogenesis , vol.31 , pp. 1685-1693
    • Kim, M.1
  • 21
    • 79954631619 scopus 로고    scopus 로고
    • Ndrg1 in development and maintenance of the myelin sheath
    • King R H M et al. (2011). Ndrg1 in development and maintenance of the myelin sheath. Neurobiol Dis 42, 368-380.
    • (2011) Neurobiol Dis , vol.42 , pp. 368-380
    • King, R.H.M.1
  • 22
    • 0031602193 scopus 로고    scopus 로고
    • Synthesis and screening of peptide libraries on continuous cellulose membrane supports
    • Kramer A, Schneider-Mergener J (1998). Synthesis and screening of peptide libraries on continuous cellulose membrane supports. Methods Mol Biol 87, 25-39.
    • (1998) Methods Mol Biol , vol.87 , pp. 25-39
    • Kramer, A.1    Schneider-Mergener, J.2
  • 23
    • 0028952534 scopus 로고
    • Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice
    • Kwee L, Baldwin HS, Shen HM, Stewart CL, Buck C, Buck CA, Labow MA (1995). Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 121, 489-503.
    • (1995) Development , vol.121 , pp. 489-503
    • Kwee, L.1    Baldwin, H.S.2    Shen, H.M.3    Stewart, C.L.4    Buck, C.5    Buck, C.A.6    Labow, M.A.7
  • 24
    • 33846622087 scopus 로고    scopus 로고
    • Blood vessel/epicardial substance (bves) expression, essential for embryonic development, is down regulated by Grk/EFGR signalling
    • DOI 10.1387/ijdb.052108sl
    • Lin S, Zhao D, Bownes M (2007). Blood vessel/epicardial substance (Bves) expression, essential for embryonic development, is down regulated by Grk/EFGR signalling. Int J Dev Biol 51, 37-44. (Pubitemid 46182039)
    • (2007) International Journal of Developmental Biology , vol.51 , Issue.1 , pp. 37-44
    • Lin, S.1    Zhao, D.2    Bownes, M.3
  • 25
    • 77954902702 scopus 로고    scopus 로고
    • Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
    • Lobert VH, Brech A, Pedersen NM, Wesche J, Oppelt A, Malerød L, Stenmark H (2010). Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes. Dev Cell 19, 148-159.
    • (2010) Dev Cell , vol.19 , pp. 148-159
    • Lobert, V.H.1    Brech, A.2    Pedersen, N.M.3    Wesche, J.4    Oppelt, A.5    Malerød, L.6    Stenmark, H.7
  • 26
    • 80052249995 scopus 로고    scopus 로고
    • Temporal characteristics of vesicular fusion in astrocytes: Examination of synaptobrevin 2-laden vesicles at single vesicle resolution
    • Malarkey EB, Parpura V (2011). Temporal characteristics of vesicular fusion in astrocytes: examination of synaptobrevin 2-laden vesicles at single vesicle resolution. J Physiol 589, 4271-4300.
    • (2011) J Physiol , vol.589 , pp. 4271-4300
    • Malarkey, E.B.1    Parpura, V.2
  • 27
    • 0014602211 scopus 로고
    • Embryonic development of the heart. II. Formation of the epicardium
    • Manasek FJ (1969). Embryonic development of the heart. II. Formation of the epicardium. J Embryol Exp Morphol 22, 333-348.
    • (1969) J Embryol Exp Morphol , vol.22 , pp. 333-348
    • Manasek, F.J.1
  • 28
    • 67649635452 scopus 로고    scopus 로고
    • N-Myc downstream-regulated gene 4 (NDRG4): A candidate tumor suppressor gene and potential biomarker for colorectal cancer
    • Melotte V et al. (2009). N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 101, 916-927.
    • (2009) J Natl Cancer Inst , vol.101 , pp. 916-927
    • Melotte, V.1
  • 30
    • 0042635694 scopus 로고    scopus 로고
    • Evidence for an extracellular matrix bridge guiding proepicardial cell migration to the myocardium of chick embryos
    • DOI 10.1002/dvdy.10335
    • Nahirney P, Mikawa T, Fischman D (2003). Evidence for an extracellular matrix bridge guiding proepicardial cell migration to the myocardium of chick embryos. Dev Dyn 227, 511-523. (Pubitemid 36951075)
    • (2003) Developmental Dynamics , vol.227 , Issue.4 , pp. 511-523
    • Nahirney, P.C.1    Mikawa, T.2    Fischman, D.A.3
  • 31
    • 2442444286 scopus 로고    scopus 로고
    • The ABCA1 transporter modulates late endocytic trafficking: Insights from the correction of the genetic defect in Tangier disease
    • Neufield EB et al. (2004). The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease. J Biol Chem 279, 15571-15578.
    • (2004) J Biol Chem , vol.279 , pp. 15571-15578
    • Neufield, E.B.1
  • 32
    • 0037765996 scopus 로고    scopus 로고
    • A novel homocysteine-responsive gene, smap8, modulates mitogenesis in rat vascular smooth muscle cells
    • DOI 10.1046/j.1432-1033.2003.03626.x
    • Nishimoto S, Tawara J, Toyoda H, Kitamura K, Komurasaki T (2003). A novel homocysteine-responsive gene, smap8, modulates mitogenesis in rat vascular smooth muscle cells. Eur J Biochem 270, 2521-2531. (Pubitemid 36647978)
    • (2003) European Journal of Biochemistry , vol.270 , Issue.11 , pp. 2521-2531
    • Nishimoto, S.1    Tawara, J.2    Toyoda, H.3    Kitamura, K.4    Komurasaki, T.5
  • 33
    • 0037197680 scopus 로고    scopus 로고
    • Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells
    • DOI 10.1016/S0165-3806(02)00300-0, PII S0165380602003000
    • Ohki T, Hongo S, Nakada N, Maeda A, Takeda M (2002). Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells. Brain Res Dev Brain Res 135, 55-63. (Pubitemid 34442489)
    • (2002) Developmental Brain Research , vol.135 , Issue.1-2 , pp. 55-63
    • Ohki, T.1    Hongo, S.2    Nakada, N.3    Maeda, A.4    Takeda, M.5
  • 34
    • 1942422199 scopus 로고    scopus 로고
    • Ndrg1-Deficient Mice Exhibit a Progressive Demyelinating Disorder of Peripheral Nerves
    • DOI 10.1128/MCB.24.9.3949-3956.2004
    • Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T (2004). Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves. Mol Cell Biol 24, 3949-3956. (Pubitemid 38496172)
    • (2004) Molecular and Cellular Biology , vol.24 , Issue.9 , pp. 3949-3956
    • Okuda, T.1    Higashi, Y.2    Kokame, K.3    Tanaka, C.4    Kondoh, H.5    Miyata, T.6
  • 35
    • 27844557346 scopus 로고    scopus 로고
    • Bves modulates epithelial integrity through an interaction at the tight junction
    • DOI 10.1242/jcs.02588
    • Osler ME, Chang MS, Bader DM (2005). Bves modulates epithelial integrity through an interaction at the tight junction. J Cell Sci 118, 4667-4678. (Pubitemid 41646377)
    • (2005) Journal of Cell Science , vol.118 , Issue.20 , pp. 4667-4678
    • Osler, M.E.1    Chang, M.S.2    Bader, D.M.3
  • 37
    • 43049125844 scopus 로고    scopus 로고
    • Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish
    • Qu X, Jia H, Garrity DM, Tompkins K, Batts L, Appel B, Zhong T P, Baldwin HS (2008). Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev Biol 317, 486-496.
    • (2008) Dev Biol , vol.317 , pp. 486-496
    • Qu, X.1    Jia, H.2    Garrity, D.M.3    Tompkins, K.4    Batts, L.5    Appel, B.6    Zhong, T.P.7    Baldwin, H.S.8
  • 38
    • 0036184953 scopus 로고    scopus 로고
    • Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family
    • DOI 10.1023/A:1017934810825
    • Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F (2002). Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem 229, 35-44. (Pubitemid 34187673)
    • (2002) Molecular and Cellular Biochemistry , vol.229 , Issue.1-2 , pp. 35-44
    • Qu, X.1    Zhai, Y.2    Wei, H.3    Zhang, C.4    Xing, G.5    Yu, Y.6    He, F.7
  • 39
    • 0033136016 scopus 로고    scopus 로고
    • Bves: A novel gene expressed during coronary blood vessel development
    • DOI 10.1006/dbio.1999.9246
    • Reese DE, Zavaljevski M, Streiff NL, Bader D (1999). Bves: A novel gene expressed during coronary blood vessel development. Dev Biol 209, 159-171. (Pubitemid 29194320)
    • (1999) Developmental Biology , vol.209 , Issue.1 , pp. 159-171
    • Reese, D.E.1    Zavaljevski, M.2    Streiff, N.L.3    Bader, D.4
  • 40
    • 3242891755 scopus 로고    scopus 로고
    • Bves is expressed in the epithelial components of the retina, lens, and cornea
    • DOI 10.1167/iovs.04-0013
    • Ripley AN, Chang MS, Bader DM (2004). Bves is expressed in the epithelial components of the retina, lens, and cornea. Invest Ophthalmol Vis Sci 45, 2475-2483. (Pubitemid 38998839)
    • (2004) Investigative Ophthalmology and Visual Science , vol.45 , Issue.8 , pp. 2475-2483
    • Ripley, A.N.1    Chang, M.S.2    Bader, D.M.3
  • 44
    • 69949175903 scopus 로고    scopus 로고
    • NDRG4 is required for cell cycle progression and survival in glioblastoma cells
    • Schilling SH et al. (2009). NDRG4 is required for cell cycle progression and survival in glioblastoma cells. J Biol Chem 284, 25160-25169.
    • (2009) J Biol Chem , vol.284 , pp. 25160-25169
    • Schilling, S.H.1
  • 45
    • 0037182578 scopus 로고    scopus 로고
    • Dual functions of α4β1 integrin in epicardial development: Initial migration and long-term attachment
    • DOI 10.1083/jcb.200203075
    • Sengbusch JK, He W, Pinco KA, Yang JT (2002). Dual functions of [alpha]4[beta]1 integrin in epicardial development: initial migration and long-term attachment. J Cell Biol 157, 873-882. (Pubitemid 34847824)
    • (2002) Journal of Cell Biology , vol.157 , Issue.5 , pp. 873-882
    • Sengbusch, J.K.1    He, W.2    Pinco, K.A.3    Yang, J.T.4
  • 46
    • 33646875328 scopus 로고    scopus 로고
    • Characterization of Bves expression during mouse development using newly generated immunoreagents
    • DOI 10.1002/dvdy.20739
    • Smith T, Bader D (2006). Characterization of Bves expression during mouse development using newly generated immunoreagents. Dev Dyn 235, 1701-1708. (Pubitemid 43787972)
    • (2006) Developmental Dynamics , vol.235 , Issue.6 , pp. 1701-1708
    • Smith, T.K.1    Bader, D.M.2
  • 48
    • 80052821897 scopus 로고    scopus 로고
    • Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion
    • Sung BH, Zhu X, Kaverina I, Weaver A M (2011). Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr Biol 21, 1460-1469.
    • (2011) Curr Biol , vol.21 , pp. 1460-1469
    • Sung, B.H.1    Zhu, X.2    Kaverina, I.3    Weaver, A.M.4
  • 50
    • 0034949329 scopus 로고    scopus 로고
    • Bves: Prototype of a new class of cell adhesion molecules expressed during coronary artery development
    • Wada AM, Reese DE, Bader DM (2001). Bves: prototype of a new class of cell adhesion molecules expressed during coronary artery development. Development 128, 2085-2093. (Pubitemid 32600469)
    • (2001) Development , vol.128 , Issue.11 , pp. 2085-2093
    • Wada, A.M.1    Reese, D.E.2    Bader, D.M.3
  • 51
    • 0037459362 scopus 로고    scopus 로고
    • Epicardial/mesothelial cell line retains vasculogenic potential of embryonic epicardium
    • DOI 10.1161/01.RES.0000060484.11032.0B
    • Wada AM, Smith TK, Osler ME, Reese DE, Bader DM (2003). Epicardial/mesothelial cell line retains vasculogenic potential of embryonic epicardium. Circ Res 92, 525-531. (Pubitemid 36368665)
    • (2003) Circulation Research , vol.92 , Issue.5 , pp. 525-531
    • Wada, A.M.1    Smith, T.K.2    Osler, M.E.3    Reese, D.E.4    Bader, D.M.5
  • 52
    • 67651040754 scopus 로고    scopus 로고
    • Identification and action of N-myc downstream regulated gene 4 A2 in rat pancreas
    • Wang JF, Hill DJ (2009). Identification and action of N-myc downstream regulated gene 4 A2 in rat pancreas. J Endocrinol 201, 15-25.
    • (2009) J Endocrinol , vol.201 , pp. 15-25
    • Wang, J.F.1    Hill, D.J.2
  • 53
    • 80053421216 scopus 로고    scopus 로고
    • BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma
    • Williams CS et al. (2011). BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. J Clin Invest 121, 4056-4069.
    • (2011) J Clin Invest , vol.121 , pp. 4056-4069
    • Williams, C.S.1
  • 54
    • 79960416729 scopus 로고    scopus 로고
    • NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia
    • Yamamoto H, Kokame K, Okuda T, Nakajo Y, Yanamoto H, Miyata T (2011). NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia. J Biol Chem 286, 26158-26165.
    • (2011) J Biol Chem , vol.286 , pp. 26158-26165
    • Yamamoto, H.1    Kokame, K.2    Okuda, T.3    Nakajo, Y.4    Yanamoto, H.5    Miyata, T.6
  • 55
    • 0028955748 scopus 로고
    • Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development
    • Yang JT, Rayburn H, Hynes RO (1995). Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 121, 549-560.
    • (1995) Development , vol.121 , pp. 549-560
    • Yang, J.T.1    Rayburn, H.2    Hynes, R.O.3
  • 56
    • 0035307347 scopus 로고    scopus 로고
    • Characterization of the human NDRG gene family: A newly identified member, NDRG4, is specifically expressed in brain and heart
    • DOI 10.1006/geno.2000.6496
    • Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T (2001). Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73, 86-97. (Pubitemid 32382390)
    • (2001) Genomics , vol.73 , Issue.1 , pp. 86-97
    • Zhou, R.-H.1    Kokame, K.2    Tsukamoto, Y.3    Yutani, C.4    Kato, H.5    Miyata, T.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.