메뉴 건너뛰기




Volumn 55, Issue 5, 2000, Pages

Increase of oxidatively modified protein is associated with a decrease of proteasome activity and content in aging epidermal cells

Author keywords

[No Author keywords available]

Indexed keywords

4 HYDROXYNONENAL; BETA GALACTOSIDASE; CHYMOTRYPSIN; PEPTIDE HYDROLASE; PROTEASOME;

EID: 0034122917     PISSN: 10795006     EISSN: None     Source Type: Journal    
DOI: 10.1093/gerona/55.5.B220     Document Type: Article
Times cited : (175)

References (52)
  • 2
    • 0030838767 scopus 로고    scopus 로고
    • The molecular basis of non melanoma skin cancer: New understanding
    • Grossman D, Leffell DJ. The molecular basis of non melanoma skin cancer: new understanding. Arch Dermatol. 1997;133:1263-1270.
    • (1997) Arch Dermatol. , vol.133 , pp. 1263-1270
    • Grossman, D.1    Leffell, D.J.2
  • 3
    • 0028955727 scopus 로고
    • Psoriasis: A T-cell mediated autoimmune disease induced by streptococcal super-antigens?
    • Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L. Psoriasis: a T-cell mediated autoimmune disease induced by streptococcal super-antigens? Immunol Today. 1995;16:145-149.
    • (1995) Immunol Today , vol.16 , pp. 145-149
    • Valdimarsson, H.1    Baker, B.S.2    Jonsdottir, I.3    Powles, A.4    Fry, L.5
  • 5
    • 77049308856 scopus 로고
    • Aging: A theory based on free radical and radiation chemistry
    • Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298-300.
    • (1956) J Gerontol. , vol.11 , pp. 298-300
    • Harman, D.1
  • 6
    • 0030841350 scopus 로고    scopus 로고
    • Protein oxidation in aging, disease, and oxidative stress
    • Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem. 1997;272:20313-20316.
    • (1997) J Biol Chem. , vol.272 , pp. 20313-20316
    • Berlett, B.S.1    Stadtman, E.R.2
  • 7
    • 0031916984 scopus 로고    scopus 로고
    • The free radical theory of aging matures
    • Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78:547-581.
    • (1998) Physiol Rev. , vol.78 , pp. 547-581
    • Beckman, K.B.1    Ames, B.N.2
  • 8
    • 0025790342 scopus 로고
    • Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease
    • Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA. 1991;88:10540-10543.
    • (1991) Proc Natl Acad Sci USA , vol.88 , pp. 10540-10543
    • Smith, C.D.1    Carney, J.M.2    Starke-Reed, P.E.3
  • 9
    • 0025832844 scopus 로고
    • Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone
    • Carney JM, Starke-Reed PE, Oliver CN, et al. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci USA. 1991;88:3633-3636.
    • (1991) Proc Natl Acad Sci USA , vol.88 , pp. 3633-3636
    • Carney, J.M.1    Starke-Reed, P.E.2    Oliver, C.N.3
  • 10
    • 0024788456 scopus 로고
    • Protein oxidation and proteolysis during aging and oxidative stress
    • Starke-Reed PE, Oliver CN. Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys. 1989;275:559-567.
    • (1989) Arch Biochem Biophys. , vol.275 , pp. 559-567
    • Starke-Reed, P.E.1    Oliver, C.N.2
  • 12
    • 0027328852 scopus 로고
    • Protein oxidative damage is associated with life expectancy of houseflies
    • Sohal RS, Agarwal S, Dubey A, Orr WC. Protein oxidative damage is associated with life expectancy of houseflies. Proc Natl Acad Sci USA. 1993;90:7255-7259.
    • (1993) Proc Natl Acad Sci USA , vol.90 , pp. 7255-7259
    • Sohal, R.S.1    Agarwal, S.2    Dubey, A.3    Orr, W.C.4
  • 13
    • 0028272883 scopus 로고
    • Pathogenic effects of advanced glycosylation: Biochemical, biologic, and clinical implications for diabetes and aging
    • Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994;70:138-151.
    • (1994) Lab Invest. , vol.70 , pp. 138-151
    • Vlassara, H.1    Bucala, R.2    Striker, L.3
  • 15
    • 0017640013 scopus 로고
    • Recent developments in the age-related alteration of enzymes: A review
    • Rothstein M. Recent developments in the age-related alteration of enzymes: a review. Mech Aging Dev. 1977;6:241-257.
    • (1977) Mech Aging Dev. , vol.6 , pp. 241-257
    • Rothstein, M.1
  • 16
    • 0002331025 scopus 로고
    • Age-associated changes of oxidative modification and turnover of proteins
    • Cutler RG, Packer L, Bertram J, Mori A, eds. Basel: Birkhaüser Verlag
    • Goto S, Hasegawa A, Nakamoto H, Nakumura A, Takahashi R, Kurochkin IV. Age-associated changes of oxidative modification and turnover of proteins. In: Cutler RG, Packer L, Bertram J, Mori A, eds. Oxidative Stress and Aging. Basel: Birkhaüser Verlag; 1995:151-158.
    • (1995) Oxidative Stress and Aging , pp. 151-158
    • Goto, S.1    Hasegawa, A.2    Nakamoto, H.3    Nakumura, A.4    Takahashi, R.5    Kurochkin, I.V.6
  • 17
    • 0022374263 scopus 로고
    • Purification of a liver alkaline protease which degrades oxidatively modified glutamine synthetase: Characterization as a high molecular weight cysteine proteinase
    • Rivett AJ. Purification of a liver alkaline protease which degrades oxidatively modified glutamine synthetase: characterization as a high molecular weight cysteine proteinase. J Biol Chem. 1985;260:12600-12606.
    • (1985) J Biol Chem. , vol.260 , pp. 12600-12606
    • Rivett, A.J.1
  • 18
    • 0024843661 scopus 로고
    • Macroxyproteinase (M.O.P.) a 670 kDa proteinase that degrades oxidatively denatured proteins in red blood cells
    • Pacifici RE, Salo DC, Davies KJ. Macroxyproteinase (M.O.P.) a 670 kDa proteinase that degrades oxidatively denatured proteins in red blood cells. Free Rad Biol Med. 1989;7:521-536.
    • (1989) Free Rad Biol Med. , vol.7 , pp. 521-536
    • Pacifici, R.E.1    Salo, D.C.2    Davies, K.J.3
  • 19
    • 0030982143 scopus 로고    scopus 로고
    • Degradation of oxidized proteins in mammalian cells
    • Grune T, Reinheckel T, Davies KJ. Degradation of oxidized proteins in mammalian cells. FASEB J. 1997;11:526-534.
    • (1997) FASEB J. , vol.11 , pp. 526-534
    • Grune, T.1    Reinheckel, T.2    Davies, K.J.3
  • 20
    • 0030016595 scopus 로고    scopus 로고
    • Structure and functions of the 20S and 26S proteasomes
    • Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem. 1996;65:801-847.
    • (1996) Annu Rev Biochem. , vol.65 , pp. 801-847
    • Coux, O.1    Tanaka, K.2    Goldberg, A.L.3
  • 21
    • 0029042511 scopus 로고
    • Crystal structure of the 20S proteasome from the archacon T. acidophilum at 3.4 A resolution
    • Lowe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R. Crystal structure of the 20S proteasome from the archacon T. acidophilum at 3.4 A resolution. Science. 1995;268:533-539.
    • (1995) Science , vol.268 , pp. 533-539
    • Lowe, J.1    Stock, D.2    Jap, B.3    Zwickl, P.4    Baumeister, W.5    Huber, R.6
  • 22
    • 0030897031 scopus 로고    scopus 로고
    • Structure of 20S proteasome from yeast at 2.4 A resolution
    • Groll M, Ditzel L, Lowe J, et al. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. 1997;386:463-471.
    • (1997) Nature , vol.386 , pp. 463-471
    • Groll, M.1    Ditzel, L.2    Lowe, J.3
  • 23
    • 0030586350 scopus 로고    scopus 로고
    • Age-related decline of rat liver multicatalytic proteinase activity and protection from oxidative inactivation by heat-shock protein 90
    • Conconi M, Szweda LI, Levine RL, Stadtman ER, Friguet, B. Age-related decline of rat liver multicatalytic proteinase activity and protection from oxidative inactivation by heat-shock protein 90. Arch Biochem Biophys. 1996;331:232-240.
    • (1996) Arch Biochem Biophys. , vol.331 , pp. 232-240
    • Conconi, M.1    Szweda, L.I.2    Levine, R.L.3    Stadtman, E.R.4
  • 24
    • 0029808385 scopus 로고    scopus 로고
    • Allerations of rat liver 20 S proteasome activities by age and food restriction
    • Shibatani T, Nazir M, Ward WF. Allerations of rat liver 20 S proteasome activities by age and food restriction. J Gerontol Biol Sci. 1996; 51A:B316-322.
    • (1996) J Gerontol Biol Sci. , vol.51 A
    • Shibatani, T.1    Nazir, M.2    Ward, W.F.3
  • 25
    • 0031799528 scopus 로고    scopus 로고
    • Dietary self-selection can compensate an age-related decrease of rat liver 20 S proteasome activity observed with standard diet
    • Anselmi B, Conconi M, Veyrat-Durebex, et al. Dietary self-selection can compensate an age-related decrease of rat liver 20 S proteasome activity observed with standard diet. J Gerontol Biol Sci. 1998;53A: B173-179.
    • (1998) J Gerontol Biol Sci. , vol.53 A
    • Anselmi, B.1    Conconi, M.2
  • 26
    • 0032078032 scopus 로고    scopus 로고
    • Age-related changes in the 20 S and 26 S proteasome activities in the liver of male F344 rats
    • Hayashi T, Goto S. Age-related changes in the 20 S and 26 S proteasome activities in the liver of male F344 rats. Mech Aging Dev. 1998; 102:55-66.
    • (1998) Mech Aging Dev. , vol.102 , pp. 55-66
    • Hayashi, T.1    Goto, S.2
  • 27
    • 0030847186 scopus 로고    scopus 로고
    • Accumulation of advanced glycation endproducts in the rat nephron link with circulating AGEs during aging
    • Verbeke P, Perichon M, Borot-Laloi C, Schaeverbeke J, Bakala H. Accumulation of advanced glycation endproducts in the rat nephron link with circulating AGEs during aging. J Histochem Cytochem. 1997;45: 1059-1068.
    • (1997) J Histochem Cytochem. , vol.45 , pp. 1059-1068
    • Verbeke, P.1    Perichon, M.2    Borot-Laloi, C.3    Schaeverbeke, J.4    Bakala, H.5
  • 28
    • 0027326559 scopus 로고
    • Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes
    • Uchida K, Szweda LI, Chae HZ, Stadtman ER. Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes. Proc Natl Acad Sci USA. 1993;90:8742-8746.
    • (1993) Proc Natl Acad Sci USA , vol.90 , pp. 8742-8746
    • Uchida, K.1    Szweda, L.I.2    Chae, H.Z.3    Stadtman, E.R.4
  • 29
    • 0016728261 scopus 로고
    • Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma
    • Rheinwald JG, Green H. Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma. Cell. 1975;6:317-330.
    • (1975) Cell. , vol.6 , pp. 317-330
    • Rheinwald, J.G.1    Green, H.2
  • 30
    • 0032527963 scopus 로고    scopus 로고
    • Protection from oxidative inactivation of the 20 S proteasome by heat-shock protein 90
    • Conconi M, Petropoulos I, Emod I, Turlin E, Biville F, Friguet B. Protection from oxidative inactivation of the 20 S proteasome by heat-shock protein 90. Biochem J. 1998;333:407-415.
    • (1998) Biochem J. , vol.333 , pp. 407-415
    • Conconi, M.1    Petropoulos, I.2    Emod, I.3    Turlin, E.4    Biville, F.5    Friguet, B.6
  • 31
    • 0029010658 scopus 로고
    • The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression
    • Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995; 2:493-506.
    • (1995) Immunity , vol.2 , pp. 493-506
    • Read, M.A.1    Neish, A.S.2    Luscinskas, F.W.3    Palombella, V.J.4    Maniatis, T.5    Collins, T.6
  • 32
    • 0014949207 scopus 로고
    • Cleavage of structural proteins during the assembly of the head of bacteriophage T4
    • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680-685.
    • (1970) Nature , vol.227 , pp. 680-685
    • Laemmli, U.K.1
  • 33
    • 0025375017 scopus 로고
    • Enzyme-linked immunosorbent assay for the epidermal growth factor receptor
    • Stoscheck CM. Enzyme-linked immunosorbent assay for the epidermal growth factor receptor. J Cell Biochem. 1990;43:229-241.
    • (1990) J Cell Biochem. , vol.43 , pp. 229-241
    • Stoscheck, C.M.1
  • 34
    • 0025801937 scopus 로고
    • Double wavelength measurement of 3,3′,5,5′-tetramethylbenzidine (TMB) provides a three-fold enhancement of the ELISA measuring range
    • Madersbacher S, Berger P. Double wavelength measurement of 3,3′,5,5′-tetramethylbenzidine (TMB) provides a three-fold enhancement of the ELISA measuring range. J Immunol Meth. 1991;138:121-124.
    • (1991) J Immunol Meth. , vol.138 , pp. 121-124
    • Madersbacher, S.1    Berger, P.2
  • 35
    • 0028912676 scopus 로고
    • Proteolysis in cultured liver epithelial cells during oxidative stress: Role of the multicatalytic proteinase complex, proteasome
    • Grune T, Reinheckel T, Joshi M, Davies JA. Proteolysis in cultured liver epithelial cells during oxidative stress: role of the multicatalytic proteinase complex, proteasome. J Biol Chem. 1995;270:2344-2351.
    • (1995) J Biol Chem. , vol.270 , pp. 2344-2351
    • Grune, T.1    Reinheckel, T.2    Joshi, M.3    Davies, J.A.4
  • 36
    • 0029984892 scopus 로고    scopus 로고
    • Degradation of oxidized proteins in K562 human hematopoietic cells by proteasome
    • Grune T, Reinheckel T, Davies JA. Degradation of oxidized proteins in K562 human hematopoietic cells by proteasome. J Biol Chem. 1996;271:15504-15509.
    • (1996) J Biol Chem. , vol.271 , pp. 15504-15509
    • Grune, T.1    Reinheckel, T.2    Davies, J.A.3
  • 37
    • 0026776241 scopus 로고
    • Aging, longevity, and immortality in vitro
    • Hayflick L. Aging, longevity, and immortality in vitro. Exp Gerontol. 1992;27:363-368.
    • (1992) Exp Gerontol. , vol.27 , pp. 363-368
    • Hayflick, L.1
  • 38
    • 0011876107 scopus 로고
    • The uses of diploid cell strains in research in aging
    • Griffiths JB, Doyle A, Newell DG, eds. Chichester, UK: Wiley
    • Rattan SIS, Stacey GN. The uses of diploid cell strains in research in aging. In: Griffiths JB, Doyle A, Newell DG, eds. Cell and Tissue Culture: Laboratory Procedure. Chichester, UK: Wiley; 1994;6D:2.1-2.12.
    • (1994) Cell and Tissue Culture: Laboratory Procedure , vol.6 D , pp. 21-212
    • Rattan, S.I.S.1    Stacey, G.N.2
  • 39
    • 0029047362 scopus 로고
    • A biomarker that identifies senescent cells in culture and in aging skin in vivo
    • Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995;92:9363-9367.
    • (1995) Proc Natl Acad Sci USA , vol.92 , pp. 9363-9367
    • Dimri, G.P.1    Lee, X.2    Basile, G.3
  • 40
    • 0030881686 scopus 로고    scopus 로고
    • Oxidative damage during aging targets mitochondrial aconitase
    • Yan LJ, Levine RL, Sohal RS. Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA. 1997;94;11168-11172.
    • (1997) Proc Natl Acad Sci USA , vol.94 , pp. 11168-11172
    • Yan, L.J.1    Levine, R.L.2    Sohal, R.S.3
  • 41
    • 0032573066 scopus 로고    scopus 로고
    • Mitochondrial adenine nucleotide translocase is modified oxidatively during aging
    • Yan LJ, Sohal RS. Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA. 1998;95: 12896-12901.
    • (1998) Proc Natl Acad Sci USA , vol.95 , pp. 12896-12901
    • Yan, L.J.1    Sohal, R.S.2
  • 42
    • 0023655531 scopus 로고
    • Protein damage and degradation by oxygen radicals. III. Modification of secondary and tertiary structure
    • Davies KJ, Delsignore ME. Protein damage and degradation by oxygen radicals. III. Modification of secondary and tertiary structure. J Biol Chem. 1987;262:9908-9913.
    • (1987) J Biol Chem. , vol.262 , pp. 9908-9913
    • Davies, K.J.1    Delsignore, M.E.2
  • 43
    • 0027990369 scopus 로고
    • Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal: Formation of cross-linked protein that inhibits the multicatalytic protease
    • Friguet B, Stadtman ER, Szweda LI. Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal: formation of cross-linked protein that inhibits the multicatalytic protease. J Biol Chem. 1994;269:21639-21643.
    • (1994) J Biol Chem. , vol.269 , pp. 21639-21643
    • Friguet, B.1    Stadtman, E.R.2    Szweda, L.I.3
  • 44
    • 0029986692 scopus 로고    scopus 로고
    • Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: Immunochemical detection in mitochondria exposed to oxidative stress
    • Cohn JA, Tsai L, Friguet B, Szweda LI. Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: immunochemical detection in mitochondria exposed to oxidative stress. Arch Biochem Biophys. 1996;328:158-164.
    • (1996) Arch Biochem Biophys. , vol.328 , pp. 158-164
    • Cohn, J.A.1    Tsai, L.2    Friguet, B.3    Szweda, L.I.4
  • 45
    • 0025948114 scopus 로고
    • Mechanism of formation of the Maillard protein cross-link pentosidine
    • Grandhee SK, Monnier VM. Mechanism of formation of the Maillard protein cross-link pentosidine. J Biol Chem. 1991;18:11649-11653.
    • (1991) J Biol Chem. , vol.18 , pp. 11649-11653
    • Grandhee, S.K.1    Monnier, V.M.2
  • 46
    • 0028889670 scopus 로고
    • Age-dependent association of isolated bovine lens multicatalytic proteinase complex (proteasome) with heat-shock protein 90, an endogenous inhibitor
    • Wagner BJ, Margolis JW. Age-dependent association of isolated bovine lens multicatalytic proteinase complex (proteasome) with heat-shock protein 90, an endogenous inhibitor. Arch Biochem Biophys. 1995;323:455-462.
    • (1995) Arch Biochem Biophys. , vol.323 , pp. 455-462
    • Wagner, B.J.1    Margolis, J.W.2
  • 47
    • 17744405612 scopus 로고    scopus 로고
    • Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27
    • Maksymowych WP, Ikawa T, Yamaguchi A, et al. Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27. Infect Immunol. 1998;66:4624-4632.
    • (1998) Infect Immunol. , vol.66 , pp. 4624-4632
    • Maksymowych, W.P.1    Ikawa, T.2    Yamaguchi, A.3
  • 48
    • 0028326667 scopus 로고
    • Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon gamma for acquirement of the functional diversity responsible for antigen processing
    • Akiyama K, Kagawa S, Tamura T, et al. Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon gamma for acquirement of the functional diversity responsible for antigen processing. FEBS Lett. 1994;343:85-88.
    • (1994) FEBS Lett. , vol.343 , pp. 85-88
    • Akiyama, K.1    Kagawa, S.2    Tamura, T.3
  • 49
    • 0032476030 scopus 로고    scopus 로고
    • Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants
    • Dick TP, Nussbaum AK, Deeg M, et al. Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants. J Biol Chem. 1998;273:25637-25646.
    • (1998) J Biol Chem. , vol.273 , pp. 25637-25646
    • Dick, T.P.1    Nussbaum, A.K.2    Deeg, M.3
  • 50
    • 0030977793 scopus 로고    scopus 로고
    • Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein
    • Friguet B, Szweda LI. Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein. FEBS Lett. 1997;405:21-25.
    • (1997) FEBS Lett. , vol.405 , pp. 21-25
    • Friguet, B.1    Szweda, L.I.2
  • 51
    • 0032526762 scopus 로고    scopus 로고
    • Cytochemical detection of a senescence-associated beta-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels
    • Van der Loo B, Fenton MJ, Erusalimsky JD. Cytochemical detection of a senescence-associated beta-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels. Exp Cell Res. 1998;15:309-315.
    • (1998) Exp Cell Res. , vol.15 , pp. 309-315
    • Van Der Loo, B.1    Fenton, M.J.2    Erusalimsky, J.D.3
  • 52
    • 0017081219 scopus 로고
    • Loss of a critical neutral protease in ageing WI-38 cells
    • Bosmann HB, Gutheil RL, Case KR. Loss of a critical neutral protease in ageing WI-38 cells. Nature. 1976;261:499-501.
    • (1976) Nature , vol.261 , pp. 499-501
    • Bosmann, H.B.1    Gutheil, R.L.2    Case, K.R.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.