메뉴 건너뛰기




Volumn 18, Issue 5 A, 1998, Pages 3139-3152

Growth inhibition induced by Ro 31-8220 and Calphostin C in human glioblastoma cell lines is associated with apoptosis and inhibition of CDC2 kinase

Author keywords

Bcl 2; Chemotherapy; p53; PKC

Indexed keywords

2 [1 (3 AMIDINOTHIOPROPYL) 1H INDOL 3 YL] 3 (1 METHYL 1H INDOL 3 YL)MALEIMIDE; CALPHOSTIN C; DNA FRAGMENT; HISTONE H1; PROTEIN BCL 2; PROTEIN KINASE C; PROTEIN KINASE C INHIBITOR; PROTEIN P53;

EID: 0031762618     PISSN: 02507005     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article
Times cited : (30)

References (67)
  • 1
    • 0027954657 scopus 로고
    • Long-term Survival in patients with malignant astrocytoma
    • Salcman M, Scholtz H, Kaplan RS and Kulik S: Long-term Survival in patients with malignant astrocytoma. Neurosurgery 34: 213-220, 1994.
    • (1994) Neurosurgery , vol.34 , pp. 213-220
    • Salcman, M.1    Scholtz, H.2    Kaplan, R.S.3    Kulik, S.4
  • 2
    • 0019218802 scopus 로고
    • Survival in glioblastoma: Historical perspective
    • Salcman M: Survival in glioblastoma: historical perspective. Neurosurgery 7: 435-439, 1980.
    • (1980) Neurosurgery , vol.7 , pp. 435-439
    • Salcman, M.1
  • 3
    • 0027308823 scopus 로고
    • Long term survival in patients with glioblastoma multiforme
    • Chandler KL, Prados MD, Malec M and Wilson CB: Long term survival in patients with glioblastoma multiforme. Neurosurgery 32: 716-720, 1993.
    • (1993) Neurosurgery , vol.32 , pp. 716-720
    • Chandler, K.L.1    Prados, M.D.2    Malec, M.3    Wilson, C.B.4
  • 4
    • 0027969295 scopus 로고
    • High dose chemotherapy for the treatment of malignant brain tumors
    • Petersdorf SH and Livingston RB: High dose chemotherapy for the treatment of malignant brain tumors. J Neuro-Oncol 20: 155-163, 1994.
    • (1994) J Neuro-Oncol , vol.20 , pp. 155-163
    • Petersdorf, S.H.1    Livingston, R.B.2
  • 6
    • 0021227676 scopus 로고
    • The role of protein kinase C in cell surface signal transduction and tumour promotion
    • Nishizuka Y: The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308: 693-698, 1984.
    • (1984) Nature , vol.308 , pp. 693-698
    • Nishizuka, Y.1
  • 7
    • 0023052241 scopus 로고
    • Studies and perspectives of protein kinase C
    • Nishizuka Y: Studies and perspectives of protein kinase C. Science 233: 305-312, 1986.
    • (1986) Science , vol.233 , pp. 305-312
    • Nishizuka, Y.1
  • 8
    • 0023764824 scopus 로고
    • The molecular heterogeneity of protein kinase C and its implications for cellular regulation
    • Nishizuka Y: The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334: 661-665, 1988.
    • (1988) Nature , vol.334 , pp. 661-665
    • Nishizuka, Y.1
  • 11
    • 0027978538 scopus 로고
    • Protein kinase C and mammary cell differentiation: Involvement of protein kinase Ca in the induction of ß-casein expression
    • Marte BM, Meyer T, Stabel S, Standke GJR, Jaken S, Fabbro D and Hynes NE: Protein kinase C and mammary cell differentiation: Involvement of protein kinase Ca in the induction of ß-casein expression. Cell Growth Diff 5: 239-247, 1994.
    • (1994) Cell Growth Diff , vol.5 , pp. 239-247
    • Marte, B.M.1    Meyer, T.2    Stabel, S.3    Standke, G.J.R.4    Jaken, S.5    Fabbro, D.6    Hynes, N.E.7
  • 14
    • 0024550448 scopus 로고
    • Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C
    • Kobayashi E, Nakano H, Morimoto M and Tamaoki T: Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochem Biophys Res Comm 159: 548-553, 1989.
    • (1989) Biochem Biophys Res Comm , vol.159 , pp. 548-553
    • Kobayashi, E.1    Nakano, H.2    Morimoto, M.3    Tamaoki, T.4
  • 18
    • 0028956550 scopus 로고
    • Regulators of cell death
    • Korsmeyer SJ: Regulators of cell death. TIG 11: 101-103, 1995.
    • (1995) TIG , vol.11 , pp. 101-103
    • Korsmeyer, S.J.1
  • 19
    • 0028072523 scopus 로고
    • DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by bcl-2
    • Strasser A, Harris AW, Jacks T and Cory S: DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by bcl-2. Cell 79: 329-339, 1994.
    • (1994) Cell , vol.79 , pp. 329-339
    • Strasser, A.1    Harris, A.W.2    Jacks, T.3    Cory, S.4
  • 20
    • 0027451668 scopus 로고
    • p53-dependent apoptosis modulates the cytotoxicity of anticancer agents
    • Lowe SW, Ruley HE, Jacks T and Housman DE: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967, 1993.
    • (1993) Cell , vol.74 , pp. 957-967
    • Lowe, S.W.1    Ruley, H.E.2    Jacks, T.3    Housman, D.E.4
  • 22
    • 0027318202 scopus 로고
    • Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53
    • Ramqvist T, Magnusson KP, Wang Y, Szekely L, Klein G and Wiman KG: Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. Oncogene 8: 1495-1500, 1993.
    • (1993) Oncogene , vol.8 , pp. 1495-1500
    • Ramqvist, T.1    Magnusson, K.P.2    Wang, Y.3    Szekely, L.4    Klein, G.5    Wiman, K.G.6
  • 24
    • 0028071555 scopus 로고
    • Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis
    • Greenblatt MS, Bennett WP, Hollstein M and Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855-4878, 1994.
    • (1994) Cancer Res , vol.54 , pp. 4855-4878
    • Greenblatt, M.S.1    Bennett, W.P.2    Hollstein, M.3    Harris, C.C.4
  • 26
    • 0027938209 scopus 로고
    • Cyclins and Cancer II: Cyclin D and CDK inhibitors come of age
    • Hunter T and Pines J: Cyclins and Cancer II: Cyclin D and CDK inhibitors come of age. Cell 79: 573-582, 1994.
    • (1994) Cell , vol.79 , pp. 573-582
    • Hunter, T.1    Pines, J.2
  • 27
    • 0027742184 scopus 로고
    • Distinct roles for cyclin-dependent kinases in cell-cycle control
    • van den Heuvel S and Harlow E: Distinct roles for cyclin-dependent kinases in cell-cycle control. Science 262: 2050-2054, 1993.
    • (1993) Science , vol.262 , pp. 2050-2054
    • Van Den Heuvel, S.1    Harlow, E.2
  • 29
    • 0029065342 scopus 로고
    • Single-step procedure for labeling DNA strand breaks with fluorescein- or BODIPY-conjugated deoxynucleotides: Detection of apoptosis and bromodeoxyuridine incorporation
    • Li X, Traganos F, Melamed MR and Darzynkiewicz Z: Single-step procedure for labeling DNA strand breaks with fluorescein- or BODIPY-conjugated deoxynucleotides: detection of apoptosis and bromodeoxyuridine incorporation. Cytometry 20: 172-180, 1995.
    • (1995) Cytometry , vol.20 , pp. 172-180
    • Li, X.1    Traganos, F.2    Melamed, M.R.3    Darzynkiewicz, Z.4
  • 33
    • 0025732215 scopus 로고
    • Mutational hotspot in the p53 gene in human hepatocellular carcinomas
    • Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ and Harris CC: Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350: 427-428, 1991.
    • (1991) Nature , vol.350 , pp. 427-428
    • Hsu, I.C.1    Metcalf, R.A.2    Sun, T.3    Welsh, J.A.4    Wang, N.J.5    Harris, C.C.6
  • 35
    • 0028227197 scopus 로고
    • A novel inhibitor of cyclin-cdk activity detected in transforming growth factor ß-arrested epithelial cells
    • Slingerland JM, Hengst L, Pan CH, Alexander D, Stampfer MR and Reed SI: A novel inhibitor of cyclin-cdk activity detected in transforming growth factor ß-arrested epithelial cells. Mol Cell Biol 14: 3683-3694, 1994.
    • (1994) Mol Cell Biol , vol.14 , pp. 3683-3694
    • Slingerland, J.M.1    Hengst, L.2    Pan, C.H.3    Alexander, D.4    Stampfer, M.R.5    Reed, S.I.6
  • 36
    • 0027983669 scopus 로고
    • Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations
    • Cho Y, Gorina S, Jeffrey PD and Pavletich NP: Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265: 346-355, 1994.
    • (1994) Science , vol.265 , pp. 346-355
    • Cho, Y.1    Gorina, S.2    Jeffrey, P.D.3    Pavletich, N.P.4
  • 37
    • 0027956867 scopus 로고
    • X-rays strikep53 again
    • Vogelstein B and Kinzler KW: X-rays strikep53 again. Nature 370: 174-175, 1994.
    • (1994) Nature , vol.370 , pp. 174-175
    • Vogelstein, B.1    Kinzler, K.W.2
  • 38
    • 0023709002 scopus 로고
    • A variation in the structure of the protein-coding region of the human p53 gene
    • Buchman VL, Chumakov PM, Ninkina NN, Samarina OP and Georgiev GP: A variation in the structure of the protein-coding region of the human p53 gene. Gene 70: 245-252, 1988.
    • (1988) Gene , vol.70 , pp. 245-252
    • Buchman, V.L.1    Chumakov, P.M.2    Ninkina, N.N.3    Samarina, O.P.4    Georgiev, G.P.5
  • 39
    • 0028037048 scopus 로고
    • Antisense expression of protein kinase Cα inhibits the growth and tumorigenicity of human glioblastoma cells
    • Ahmad S, Mineta T, Martuza RL and Glazer RI: Antisense expression of protein kinase Cα inhibits the growth and tumorigenicity of human glioblastoma cells. Neurosurgery 35: 904-909, 1994.
    • (1994) Neurosurgery , vol.35 , pp. 904-909
    • Ahmad, S.1    Mineta, T.2    Martuza, R.L.3    Glazer, R.I.4
  • 40
    • 0029565732 scopus 로고
    • Apoptosis of human glioma cells in response to calphostin C, a specific protein kinase C inhibitor
    • Ikemoto H, TaniE, Matsumoto T, Nakano A, Furuzama J: Apoptosis of human glioma cells in response to calphostin C, a specific protein kinase C inhibitor. J Neurosurg 84: 1008-1016, 1995.
    • (1995) J Neurosurg , vol.84 , pp. 1008-1016
    • Ikemoto, H.1    Tani, E.2    Matsumoto, T.3    Nakano, A.4    Furuzama, J.5
  • 41
    • 0029022737 scopus 로고
    • Human interleukin-3 receptor modulates bcl-2 mRNA and protein levels through protein kinase C in TF-1 cells
    • Rinaudo MS, Su K, Falk LA, Haldar S and Mufson RA: Human interleukin-3 receptor modulates bcl-2 mRNA and protein levels through protein kinase C in TF-1 cells. Blood 86: 80-88, 1995.
    • (1995) Blood , vol.86 , pp. 80-88
    • Rinaudo, M.S.1    Su, K.2    Falk, L.A.3    Haldar, S.4    Mufson, R.A.5
  • 42
    • 0028053592 scopus 로고
    • Apoptosis of vascular smooth muscle cells-protein kinase C and oncoprotein bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells
    • Leszczynski D, Zhao Y, Luokkamaeki M and Foegh ML: Apoptosis of vascular smooth muscle cells-protein kinase C and oncoprotein bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells. Am J Pathol 145: 1265-1270, 1994.
    • (1994) Am J Pathol , vol.145 , pp. 1265-1270
    • Leszczynski, D.1    Zhao, Y.2    Luokkamaeki, M.3    Foegh, M.L.4
  • 43
    • 0029131820 scopus 로고
    • Bryostatin 1 induces apoptosis and augments inhibitory effects of vincristine in human diffuse large cell lymphoma
    • Mohammad RM, Diwakaran H, Maki A, Emara MA, Pettit GR, Redman B and Al-Katib A: Bryostatin 1 induces apoptosis and augments inhibitory effects of vincristine in human diffuse large cell lymphoma. Leuk Res 19: 667-673, 1995.
    • (1995) Leuk Res , vol.19 , pp. 667-673
    • Mohammad, R.M.1    Diwakaran, H.2    Maki, A.3    Emara, M.A.4    Pettit, G.R.5    Redman, B.6    Al-Katib, A.7
  • 45
    • 0024402595 scopus 로고
    • Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that stimulate protein kinase C
    • McConkey DJ, Hartzell P, Jondal M and Orrenius S: Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that stimulate protein kinase C. J Biol Chem 264: 13399-13402, 1989.
    • (1989) J Biol Chem , vol.264 , pp. 13399-13402
    • McConkey, D.J.1    Hartzell, P.2    Jondal, M.3    Orrenius, S.4
  • 46
    • 0024445085 scopus 로고
    • Phorbol esters inhibit apoptosis in IL-2 dependent T lymphocytes
    • Rodriguez-Tarduchy G and Lopez-Rivas A: Phorbol esters inhibit apoptosis in IL-2 dependent T lymphocytes. Biochem Biophys Res Comm 164: 1069-1075, 1989.
    • (1989) Biochem Biophys Res Comm , vol.164 , pp. 1069-1075
    • Rodriguez-Tarduchy, G.1    Lopez-Rivas, A.2
  • 47
    • 0028302712 scopus 로고
    • Protein kinase C mediates basic fibroblasts growth factor protection of endothelial cells against radiation-induced apoptosis
    • Haimovitz-Friedman A, Balaban N, McLoughlin M, Ehleiter D, Michaeli J, Vlodavsky I and Fuks Z: Protein kinase C mediates basic fibroblasts growth factor protection of endothelial cells against radiation-induced apoptosis. Cancer Res 54: 2591-2597, 1994.
    • (1994) Cancer Res , vol.54 , pp. 2591-2597
    • Haimovitz-Friedman, A.1    Balaban, N.2    McLoughlin, M.3    Ehleiter, D.4    Michaeli, J.5    Vlodavsky, I.6    Fuks, Z.7
  • 48
    • 0028316195 scopus 로고
    • Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C
    • Jarvis WD, Turner AJ, Povirk LF, Traylor RS and Grant S: Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C. Cancer Res 54: 1707-1714, 1994.
    • (1994) Cancer Res , vol.54 , pp. 1707-1714
    • Jarvis, W.D.1    Turner, A.J.2    Povirk, L.F.3    Traylor, R.S.4    Grant, S.5
  • 50
    • 0030572696 scopus 로고    scopus 로고
    • The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C
    • Diaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L and Moscat J: The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86: 777-786, 1996.
    • (1996) Cell , vol.86 , pp. 777-786
    • Diaz-Meco, M.T.1    Municio, M.M.2    Frutos, S.3    Sanchez, P.4    Lozano, J.5    Sanz, L.6    Moscat, J.7
  • 51
    • 0025266685 scopus 로고
    • Activation in vitro of NF-κB by phosphorylation of its inhibitor IKB
    • Ghosh S and Baltimore D: Activation in vitro of NF-κB by phosphorylation of its inhibitor IKB. Nature 344: 678-682, 1990.
    • (1990) Nature , vol.344 , pp. 678-682
    • Ghosh, S.1    Baltimore, D.2
  • 52
    • 0028006556 scopus 로고
    • Mechanism of expression and role in transcriptional control of the proto-oncogene NF-κB-2/LYT-10
    • Chang C-C, Zhang J, Lombardi L, Neri A and Dalla-Favera R: Mechanism of expression and role in transcriptional control of the proto-oncogene NF-κB-2/LYT-10. Oncogene 9: 923-933, 1994.
    • (1994) Oncogene , vol.9 , pp. 923-933
    • Chang, C.-C.1    Zhang, J.2    Lombardi, L.3    Neri, A.4    Dalla-Favera, R.5
  • 53
    • 0029976817 scopus 로고    scopus 로고
    • An essential role for NF-κB in preventing TNF-α-induced cell death
    • Beg AA and Baltimore D: An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274: 782-784, 1996.
    • (1996) Science , vol.274 , pp. 782-784
    • Beg, A.A.1    Baltimore, D.2
  • 54
    • 0029858387 scopus 로고    scopus 로고
    • TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB
    • Wang C-Y, Mayo MW and Baldwin AS: TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274: 784-787, 1996.
    • (1996) Science , vol.274 , pp. 784-787
    • Wang, C.-Y.1    Mayo, M.W.2    Baldwin, A.S.3
  • 56
    • 0028967267 scopus 로고
    • Role of a ubiquitin-conjugated enzyme in degradation of S- and M-phase cyclins
    • Seufert W, Futcher B and Jentsch S: Role of a ubiquitin-conjugated enzyme in degradation of S- and M-phase cyclins. Nature 373: 78-81, 1995.
    • (1995) Nature , vol.373 , pp. 78-81
    • Seufert, W.1    Futcher, B.2    Jentsch, S.3
  • 57
    • 0028967267 scopus 로고
    • Role of a ubiquitin-conjugated enzyme in degradation of S- and M-phase cyclins
    • Seufert W. Fulcher B and Jentsch S: Role of a ubiquitin-conjugated enzyme in degradation of S- and M-phase cyclins. Nature 373: 78-81, 1995.
    • (1995) Nature , vol.373 , pp. 78-81
    • Seufert, W.1    Fulcher, B.2    Jentsch, S.3
  • 59
    • 0028873880 scopus 로고
    • Unscheduled activation of cyclin Bl/cdc2 kinase in human promyelocytic leukemia cell line HL60 cells undergoing apoptosis induced by DNA damage
    • Shimizu T, O'Connor PM, Kohn KW and Pommier Y: Unscheduled activation of cyclin Bl/cdc2 kinase in human promyelocytic leukemia cell line HL60 cells undergoing apoptosis induced by DNA damage. Cancer Res 55: 228-231, 1995.
    • (1995) Cancer Res , vol.55 , pp. 228-231
    • Shimizu, T.1    O'Connor, P.M.2    Kohn, K.W.3    Pommier, Y.4
  • 61
    • 0029661896 scopus 로고    scopus 로고
    • cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1ß-converting enzyme- related proteases
    • cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1ß-converting enzyme- related proteases. Cancer Res 56: 4551-4555, 1996.
    • (1996) Cancer Res , vol.56 , pp. 4551-4555
    • Yao, S.-L.1    McKenna, K.A.2    Sharkis, S.J.3    Bedi, A.4
  • 62
    • 0027217084 scopus 로고
    • Apoptotic death in epithelial cells: Cleavage of DNA of 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation
    • Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR and Sikorska M: Apoptotic death in epithelial cells: cleavage of DNA of 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 12: 3679-3684, 1993.
    • (1993) EMBO J , vol.12 , pp. 3679-3684
    • Oberhammer, F.1    Wilson, J.W.2    Dive, C.3    Morris, I.D.4    Hickman, J.A.5    Wakeling, A.E.6    Walker, P.R.7    Sikorska, M.8
  • 63
    • 0028263376 scopus 로고
    • Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA
    • Ormerod MG, O'Neill CF, Robertson D and Harrap KR: Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA. Exp Cell Res 277; 231-237, 1994.
    • (1994) Exp Cell Res , vol.277 , pp. 231-237
    • Ormerod, M.G.1    O'Neill, C.F.2    Robertson, D.3    Harrap, K.R.4
  • 64
    • 0029084479 scopus 로고
    • Apoptosis of a fibrosarcoma induced by protein-free culture involves DNA cleavage to large fragments but not internucleosomal fragmentation
    • Watanabe H, Kanbe K, Shinozalci T, Hoshino H and Chigira M: Apoptosis of a fibrosarcoma induced by protein-free culture involves DNA cleavage to large fragments but not internucleosomal fragmentation. Int J Cancer 62: 191-198, 1995.
    • (1995) Int J Cancer , vol.62 , pp. 191-198
    • Watanabe, H.1    Kanbe, K.2    Shinozalci, T.3    Hoshino, H.4    Chigira, M.5
  • 65
    • 0025317569 scopus 로고
    • Periodicity of DNA folding in higher order chromatin structures
    • Filipski J, Leblanc J, Youdale T, Sikorska M and Walker PR: Periodicity of DNA folding in higher order chromatin structures. EMBO J 9: 1319-1327, 1990.
    • (1990) EMBO J , vol.9 , pp. 1319-1327
    • Filipski, J.1    Leblanc, J.2    Youdale, T.3    Sikorska, M.4    Walker, P.R.5
  • 66
    • 43949172708 scopus 로고
    • Phagocyte recognition of cells undergoing apoptosis
    • Savill J, Fadok V, Henson P and Haslett C: Phagocyte recognition of cells undergoing apoptosis. Immunol Today 14: 131-136, 1993.
    • (1993) Immunol Today , vol.14 , pp. 131-136
    • Savill, J.1    Fadok, V.2    Henson, P.3    Haslett, C.4
  • 67
    • 0021926813 scopus 로고
    • Macrophage recognition of cells undergoing programmed cell death (apoptosis)
    • Duvall E, Wyllie AH and Morris RG: Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunol 56: 351-358, 1985.
    • (1985) Immunol , vol.56 , pp. 351-358
    • Duvall, E.1    Wyllie, A.H.2    Morris, R.G.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.