메뉴 건너뛰기




Volumn 178, Issue 3, 2011, Pages 1059-1068

NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo

Author keywords

[No Author keywords available]

Indexed keywords

CELL RECEPTOR; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; I KAPPA B KINASE; I KAPPA B KINASE GAMMA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; INTERLEUKIN 10; INTERLEUKIN 12P70; INTERLEUKIN 13; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; MACROPHAGE INFLAMMATORY PROTEIN 2; MONOCYTE CHEMOTACTIC PROTEIN 1; PEPTIDE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

EID: 79952763971     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.1016/j.ajpath.2010.12.009     Document Type: Article
Times cited : (66)

References (65)
  • 1
    • 0030665384 scopus 로고    scopus 로고
    • Biology of cachexia
    • Tisdale MJ: Biology of cachexia. J Natl Cancer Inst 1997, 89:1763-1773
    • (1997) J Natl Cancer Inst , vol.89 , pp. 1763-1773
    • Tisdale, M.J.1
  • 2
    • 0016167138 scopus 로고
    • Proceedings: Causes of death in cancer patients
    • Inagaki J, Rodriguez V, Bodey GP: Proceedings: causes of death in cancer patients. Cancer 1974, 33:568-573
    • (1974) Cancer , vol.33 , pp. 568-573
    • Inagaki, J.1    Rodriguez, V.2    Bodey, G.P.3
  • 3
    • 0036830917 scopus 로고    scopus 로고
    • Cachexia in cancer patients
    • Tisdale MJ: Cachexia in cancer patients. Nat Rev Cancer 2002, 2:862-871
    • (2002) Nat Rev Cancer , vol.2 , pp. 862-871
    • Tisdale, M.J.1
  • 4
    • 0016696542 scopus 로고
    • Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure
    • Corbett TH, Griswold DP Jr., Roberts BJ, Peckham JC, Schabel FM Jr.: Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 1975, 35:2434-2439
    • (1975) Cancer Res , vol.35 , pp. 2434-2439
    • Corbett, T.H.1    Griswold Jr., D.P.2    Roberts, B.J.3    Peckham, J.C.4    Schabel Jr., F.M.5
  • 6
    • 10544222015 scopus 로고    scopus 로고
    • Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways
    • DOI 10.1002/(SICI)1097-0215(19961127)68:5<637::AID-IJC14>3.0.CO;2-Z
    • Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H, Monden M: Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways. Int J Cancer 1996, 68:637-643 (Pubitemid 26414526)
    • (1996) International Journal of Cancer , vol.68 , Issue.5 , pp. 637-643
    • Fujlta, J.1    Tsujinaka, T.2    Yano, M.3    Eoisui, C.4    Saito, H.5    Katsume, A.6    Akamatsu, K.-I.7    Ohsugi, Y.8    Shiozaki, H.9    Monden, M.10
  • 8
    • 67650724069 scopus 로고    scopus 로고
    • Regulation and function of NF-kappaB transcription factors in the immune system
    • Vallabhapurapu S, Karin M: Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009, 27:693-733
    • (2009) Annu Rev Immunol , vol.27 , pp. 693-733
    • Vallabhapurapu, S.1    Karin, M.2
  • 9
    • 59649104233 scopus 로고    scopus 로고
    • The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy
    • Van Gammeren D, Damrauer JS, Jackman RW, Kandarian SC: The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy. FASEB J 2009, 23:362-370
    • (2009) FASEB J , vol.23 , pp. 362-370
    • Van Gammeren, D.1    Damrauer, J.S.2    Jackman, R.W.3    Kandarian, S.C.4
  • 11
    • 61749103068 scopus 로고    scopus 로고
    • Catabolic mediators of cancer cachexia
    • Tisdale MJ: Catabolic mediators of cancer cachexia. Curr Opin Support Palliat Care 2008, 2:256-2561
    • (2008) Curr Opin Support Palliat Care , vol.2 , pp. 256-2561
    • Tisdale, M.J.1
  • 12
    • 67649982995 scopus 로고    scopus 로고
    • Mechanisms of cancer cachexia
    • Tisdale MJ: Mechanisms of cancer cachexia. Physiol Rev 2009, 89:381-410
    • (2009) Physiol Rev , vol.89 , pp. 381-410
    • Tisdale, M.J.1
  • 16
    • 33845697226 scopus 로고    scopus 로고
    • Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway
    • DOI 10.1101/gad.412606
    • Schwarzkopf M, Coletti D, Sassoon D, Marazzi G: Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway. Genes Dev 2006, 20:3440-3452 (Pubitemid 44969161)
    • (2006) Genes and Development , vol.20 , Issue.24 , pp. 3440-3452
    • Schwarzkopf, M.1    Coletti, D.2    Sassoon, D.3    Marazzi, G.4
  • 18
    • 2942599476 scopus 로고    scopus 로고
    • Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma
    • DOI 10.1002/nur.20019
    • McCarthy DO, Whitney P, Hitt A, Al-Majid S: Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma. Res Nurs Health 2004, 27:174-184 (Pubitemid 38748290)
    • (2004) Research in Nursing and Health , vol.27 , Issue.3 , pp. 174-184
    • McCarthy, D.O.1    Whitney, P.2    Hitt, A.3    Al-Majid, S.4
  • 22
    • 0035225284 scopus 로고    scopus 로고
    • Cancer-induced fatigue and skeletal muscle wasting: The role of exercise
    • al-Majid S, McCarthy DO: Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs 2001, 2:186-197
    • (2001) Biol Res Nurs , vol.2 , pp. 186-197
    • Al-Majid, S.1    McCarthy, D.O.2
  • 24
    • 0027196193 scopus 로고
    • Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor
    • Strassmann G, Masui Y, Chizzonite R, Fong M: Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor J Immunol 1993, 150:2341-2345
    • (1993) J Immunol , vol.150 , pp. 2341-2345
    • Strassmann, G.1    Masui, Y.2    Chizzonite, R.3    Fong, M.4
  • 26
    • 33947522846 scopus 로고    scopus 로고
    • Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo
    • DOI 10.1161/01.RES.0000259559.48597.32, PII 0000301220070302000005
    • Willis MS, Ike C, Li L, Wang DZ, Glass DJ, Patterson C: Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo. Circ Res 2007, 100:456-459 (Pubitemid 46673255)
    • (2007) Circulation Research , vol.100 , Issue.4 , pp. 456-459
    • Willis, M.S.1    Ike, C.2    Li, L.3    Wang, D.-Z.4    Glass, D.J.5    Patterson, C.6
  • 28
    • 36049026136 scopus 로고    scopus 로고
    • Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
    • DOI 10.1172/JCI31757
    • Li HH, Willis MS, Lockyer P, Miller N, McDonough H, Glass DJ, Patterson C: Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. J Clin Invest 2007, 117:3211-3223 (Pubitemid 350096979)
    • (2007) Journal of Clinical Investigation , vol.117 , Issue.11 , pp. 3211-3223
    • Li, H.-H.1    Willis, M.S.2    Lockyer, P.3    Miller, N.4    McDonough, H.5    Glass, D.J.6    Patterson, C.7
  • 30
    • 38549102037 scopus 로고    scopus 로고
    • Cytokines and myocardial dysfunction: State of the art
    • El-Menyar AA: Cytokines and myocardial dysfunction: state of the art. J Card Fail 2008, 14:61-74
    • (2008) J Card Fail , vol.14 , pp. 61-74
    • El-Menyar, A.A.1
  • 32
    • 33846966331 scopus 로고    scopus 로고
    • Differences between pathological and physiological cardiac hypertrophy: Novel therapeutic strategies to treat heart failure
    • McMullen JR, Jennings GL: Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 2007, 34:255-262
    • (2007) Clin Exp Pharmacol Physiol , vol.34 , pp. 255-262
    • McMullen, J.R.1    Jennings, G.L.2
  • 33
    • 69149111441 scopus 로고    scopus 로고
    • Effect of curcumin on nuclear factor kappaB signaling pathways in human chronic myelogenous K562 leukemia cells
    • Reuter S, Charlet J, Juncker T, Teiten MH, Dicato M, Diederich M: Effect of curcumin on nuclear factor kappaB signaling pathways in human chronic myelogenous K562 leukemia cells. Ann N Y Acad Sci 2009, 1171:436-447
    • (2009) Ann N Y Acad Sci , vol.1171 , pp. 436-447
    • Reuter, S.1    Charlet, J.2    Juncker, T.3    Teiten, M.H.4    Dicato, M.5    Diederich, M.6
  • 34
    • 23944456384 scopus 로고    scopus 로고
    • Skeletal muscle hypertrophy and atrophy signaling pathways
    • Glass DJ: Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 2005, 37:1974-1984
    • (2005) Int J Biochem Cell Biol , vol.37 , pp. 1974-1984
    • Glass, D.J.1
  • 36
    • 77649162855 scopus 로고    scopus 로고
    • Sent to destroy: The ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease
    • Willis MS, Townley-Tilson WH, Kang EY, Homeister JW, Patterson C: Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res 2010, 106:463-478
    • (2010) Circ Res , vol.106 , pp. 463-478
    • Willis, M.S.1    Townley-Tilson, W.H.2    Kang, E.Y.3    Homeister, J.W.4    Patterson, C.5
  • 38
    • 38049174964 scopus 로고    scopus 로고
    • Appetite for destruction: E3 ubiquitin-ligase protection in cardiac disease
    • Willis MS, Schisler JC, Patterson C: Appetite for destruction: e3 ubiquitin-ligase protection in cardiac disease. Future Cardiol 2008, 4:65-75
    • (2008) Future Cardiol , vol.4 , pp. 65-75
    • Willis, M.S.1    Schisler, J.C.2    Patterson, C.3
  • 40
    • 0034284715 scopus 로고    scopus 로고
    • Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex
    • May MJ, D'Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S: Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 2000, 289:1550-1554
    • (2000) Science , vol.289 , pp. 1550-1554
    • May, M.J.1    D'Acquisto, F.2    Madge, L.A.3    Glockner, J.4    Pober, J.S.5    Ghosh, S.6
  • 42
    • 33748528911 scopus 로고    scopus 로고
    • Into the heart: The emerging role of the ubiquitin-proteasome system
    • DOI 10.1016/j.yjmcc.2006.07.015, PII S0022282806007243
    • Willis MS, Patterson C: Into the heart: the emerging role of the ubiquitin-proteasome system. J Mol Cell Cardiol 2006, 41:567-579 (Pubitemid 44374543)
    • (2006) Journal of Molecular and Cellular Cardiology , vol.41 , Issue.4 , pp. 567-579
    • Willis, M.S.1    Patterson, C.2
  • 43
    • 34147131267 scopus 로고    scopus 로고
    • The bitter end: The ubiquitin-proteasome system and cardiac dysfunction
    • DOI 10.1161/CIRCULATIONAHA.106.649863, PII 0000301720070320000019
    • Patterson C, Ike C, Willis PWt, Stouffer GA, Willis MS: The bitter end: the ubiquitin-proteasome system and cardiac dysfunction. Circulation 2007, 115:1456-1463 (Pubitemid 46648383)
    • (2007) Circulation , vol.115 , Issue.11 , pp. 1456-1463
    • Patterson, C.1    Ike, C.2    Willis IV, P.W.3    Stouffer, G.A.4    Willis, M.S.5
  • 45
    • 59449097421 scopus 로고    scopus 로고
    • Build it up-tear it down: Protein quality control in the cardiac sarcomere
    • Willis MS, Schisler JC, Portbury AL, Patterson C: Build it up-tear it down: protein quality control in the cardiac sarcomere. Cardiovasc Res 2009, 81:439-448
    • (2009) Cardiovasc Res , vol.81 , pp. 439-448
    • Willis, M.S.1    Schisler, J.C.2    Portbury, A.L.3    Patterson, C.4
  • 47
    • 56249110920 scopus 로고    scopus 로고
    • Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection
    • Moss NC, Tang RH, Willis M, Stansfield WE, Baldwin AS, Selzman CH: Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection. J Thorac Cardiovasc Surg 2008, 136:1274-1279
    • (2008) J Thorac Cardiovasc Surg , vol.136 , pp. 1274-1279
    • Moss, N.C.1    Tang, R.H.2    Willis, M.3    Stansfield, W.E.4    Baldwin, A.S.5    Selzman, C.H.6
  • 48
    • 60849113987 scopus 로고    scopus 로고
    • Inhibition of the classical NF-kappaB pathway prevents osteoclast bone-resorbing activity
    • Soysa NS, Alles N, Shimokawa H, Jimi E, Aoki K, Ohya K: Inhibition of the classical NF-kappaB pathway prevents osteoclast bone-resorbing activity. J Bone Miner Metab 2009, 27:131-139
    • (2009) J Bone Miner Metab , vol.27 , pp. 131-139
    • Soysa, N.S.1    Alles, N.2    Shimokawa, H.3    Jimi, E.4    Aoki, K.5    Ohya, K.6
  • 49
    • 63749114213 scopus 로고    scopus 로고
    • Cell-permeable Tat-NBD peptide attenuates rat pancreatitis and acinus cell inflammation response
    • Long YM, Chen K, Liu XJ, Xie WR, Wang H: Cell-permeable Tat-NBD peptide attenuates rat pancreatitis and acinus cell inflammation response. World J Gastroenterol 2009, 15:561-569
    • (2009) World J Gastroenterol , vol.15 , pp. 561-569
    • Long, Y.M.1    Chen, K.2    Liu, X.J.3    Xie, W.R.4    Wang, H.5
  • 51
    • 38449110152 scopus 로고    scopus 로고
    • Cutting edge: The IkappaB kinase (IKK) inhibitor. NEMO-binding domain peptide, blocks inflammatory injury in murine colitis
    • Shibata W, Maeda S, Hikiba Y, Yanai A, Ohmae T, Sakamoto K, Nakagawa H, Ogura K, Omata M: Cutting edge: the IkappaB kinase (IKK) inhibitor. NEMO-binding domain peptide, blocks inflammatory injury in murine colitis J Immunol 2007, 179:2681-2685
    • (2007) J Immunol , vol.179 , pp. 2681-2685
    • Shibata, W.1    Maeda, S.2    Hikiba, Y.3    Yanai, A.4    Ohmae, T.5    Sakamoto, K.6    Nakagawa, H.7    Ogura, K.8    Omata, M.9
  • 52
    • 70350545937 scopus 로고    scopus 로고
    • Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation
    • Tas SW, Vervoordeldonk MJ, Hajji N, May MJ, Ghosh S, Tak PP: Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation. Arthritis Res Ther 2006, 8:R86
    • (2006) Arthritis Res Ther , vol.8
    • Tas, S.W.1    Vervoordeldonk, M.J.2    Hajji, N.3    May, M.J.4    Ghosh, S.5    Tak, P.P.6
  • 54
    • 2042425906 scopus 로고    scopus 로고
    • The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors
    • DOI 10.1016/S1097-2765(04)00211-4, PII S1097276504002114
    • Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ: The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 2004, 14:395-403 (Pubitemid 38591410)
    • (2004) Molecular Cell , vol.14 , Issue.3 , pp. 395-403
    • Stitt, T.N.1    Drujan, D.2    Clarke, B.A.3    Panaro, F.4    Timofeyva, Y.5    Kline, W.O.6    Gonzalez, M.7    Yancopoulos, G.D.8    Glass, D.J.9
  • 55
    • 4544293878 scopus 로고    scopus 로고
    • IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1
    • DOI 10.1152/ajpendo.00073.2004
    • Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL: IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab 2004, 287:E591-E601 (Pubitemid 39242684)
    • (2004) American Journal of Physiology - Endocrinology and Metabolism , vol.287 , Issue.4
    • Sacheck, J.M.1    Ohtsuka, A.2    McLary, S.C.3    Goldberg, A.L.4
  • 56
    • 77951464177 scopus 로고    scopus 로고
    • MAFbx/Atrogin-1 expression is a poor index of muscle proteolysis
    • Attaix D, Baracos VE: MAFbx/Atrogin-1 expression is a poor index of muscle proteolysis. Curr Opin Clin Nutr Metab Care 2010, 13:223-224
    • (2010) Curr Opin Clin Nutr Metab Care , vol.13 , pp. 223-224
    • Attaix, D.1    Baracos, V.E.2
  • 58
    • 34447131534 scopus 로고    scopus 로고
    • Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha
    • DOI 10.1158/0008-5472.CAN-07-1232
    • Dan HC, Adli M, Baldwin AS: Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. Cancer Res 2007, 67:6263-6269 (Pubitemid 47037508)
    • (2007) Cancer Research , vol.67 , Issue.13 , pp. 6263-6269
    • Dan, H.C.1    Adli, M.2    Baldwin, A.S.3
  • 59
    • 35648958721 scopus 로고    scopus 로고
    • IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway
    • DOI 10.1128/MCB.01101-07
    • Hutti JE, Turk BE, Asara JM, Ma A, Cantley LC, Abbott DW: IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway. Mol Cell Biol 2007, 27:7451-7461 (Pubitemid 350033652)
    • (2007) Molecular and Cellular Biology , vol.27 , Issue.21 , pp. 7451-7461
    • Hutti, J.E.1    Turk, B.E.2    Asara, J.M.3    Ma, A.4    Cantley, L.C.5    Abbott, D.W.6
  • 62
    • 50449101139 scopus 로고    scopus 로고
    • Evidences of apoptosis during the early phases of soleus muscle atrophy in hindlimb suspended mice
    • Ferreira R, Neuparth MJ, Vitorino R, Appell HJ, Amado F, Duarte JA: Evidences of apoptosis during the early phases of soleus muscle atrophy in hindlimb suspended mice. Physiol Res 2008, 57:601-611
    • (2008) Physiol Res , vol.57 , pp. 601-611
    • Ferreira, R.1    Neuparth, M.J.2    Vitorino, R.3    Appell, H.J.4    Amado, F.5    Duarte, J.A.6
  • 63
    • 33645831979 scopus 로고    scopus 로고
    • Hindlimb unloading increases muscle content of cytosolic but not nuclear Id2 and p53 proteins in young adult and aged rats
    • DOI 10.1152/japplphysiol.01012.2005
    • Siu PM, Pistilli EE, Murlasits Z, Alway SE: Hindlimb unloading increases muscle content of cytosolic but not nuclear Id2 and p53 proteins in young adult and aged rats. J Appl Physiol 2006, 100:907-916 (Pubitemid 43671547)
    • (2006) Journal of Applied Physiology , vol.100 , Issue.3 , pp. 907-916
    • Siu, P.M.1    Pistilli, E.E.2    Murlasits, Z.3    Alway, S.E.4
  • 64
    • 77953745513 scopus 로고    scopus 로고
    • Molecular mechanisms in aging and current strategies to counteract sarcopenia
    • Sakuma K, Yamaguchi A: Molecular mechanisms in aging and current strategies to counteract sarcopenia. Curr Aging Sci 2010, 3:90-101
    • (2010) Curr Aging Sci , vol.3 , pp. 90-101
    • Sakuma, K.1    Yamaguchi, A.2
  • 65
    • 77953042829 scopus 로고    scopus 로고
    • Muscle weakness and atrophy are associated with decreased regenerative capacity and changes in mTOR signaling in skeletal muscles of venerable (18-24-month-old) dystrophic mdx mice
    • Mouisel E, Vignaud A, Hourde C, Butler-Browne G, Ferry A: Muscle weakness and atrophy are associated with decreased regenerative capacity and changes in mTOR signaling in skeletal muscles of venerable (18-24-month-old) dystrophic mdx mice. Muscle Nerve 2010, 41:809-818
    • (2010) Muscle Nerve , vol.41 , pp. 809-818
    • Mouisel, E.1    Vignaud, A.2    Hourde, C.3    Butler-Browne, G.4    Ferry, A.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.