메뉴 건너뛰기




Volumn 47, Issue 5, 2004, Pages 926-936

Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element

Author keywords

CREB; Enteroendocrine cells; Fra2; Glucagon like peptides; Peptones; Proglucagon; Transcriptional regulation

Indexed keywords

CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; GLUCAGON; LUCIFERASE; PEPTONE; PROGLUCAGON; PROTEIN HYDROLYSATE; TRANSCRIPTION FACTOR FRA 2;

EID: 2942624436     PISSN: 0012186X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00125-004-1380-0     Document Type: Article
Times cited : (37)

References (46)
  • 1
    • 0031758346 scopus 로고    scopus 로고
    • Glucagon-like peptide 1 (GLP-1): A potent gut hormone with a possible therapeutic perspective
    • Nauck MA (1998) Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective. Acta Diabetol 35:117-129
    • (1998) Acta Diabetol , vol.35 , pp. 117-129
    • Nauck, M.A.1
  • 2
    • 0036158954 scopus 로고    scopus 로고
    • Biological actions and therapeutic potential of the glucagon-like peptides
    • Drucker DJ (2002) Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 122:531-544
    • (2002) Gastroenterology , vol.122 , pp. 531-544
    • Drucker, D.J.1
  • 3
    • 0029921394 scopus 로고    scopus 로고
    • Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum
    • Hoyt EC, Lund PK, Winesett DE et al. (1996) Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum. Diabetes 45: 434-439
    • (1996) Diabetes , vol.45 , pp. 434-439
    • Hoyt, E.C.1    Lund, P.K.2    Winesett, D.E.3
  • 4
    • 0036084248 scopus 로고    scopus 로고
    • Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression
    • Nian M, Gu J, Irwin DM, Drucker DJ (2002) Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression. Am J Physiol 282:R173-R183
    • (2002) Am J Physiol , vol.282
    • Nian, M.1    Gu, J.2    Irwin, D.M.3    Drucker, D.J.4
  • 5
    • 0029838401 scopus 로고    scopus 로고
    • Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats
    • Reimer RA, McBurney MI (1996) Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats. Endocrinology 137:3948-3956
    • (1996) Endocrinology , vol.137 , pp. 3948-3956
    • Reimer, R.A.1    McBurney, M.I.2
  • 6
    • 0030800806 scopus 로고    scopus 로고
    • A physiological level of rhubarb fiber increases proglucagon gene expression and modulates intestinal glucose uptake in rats
    • Reimer RA, Thomson AB, Rajotte RV, Basu TK, Ooraikul B, McBurney MI (1997) A physiological level of rhubarb fiber increases proglucagon gene expression and modulates intestinal glucose uptake in rats. J Nutr 127:1923-1928
    • (1997) J Nutr , vol.127 , pp. 1923-1928
    • Reimer, R.A.1    Thomson, A.B.2    Rajotte, R.V.3    Basu, T.K.4    Ooraikul, B.5    McBurney, M.I.6
  • 7
    • 0031730905 scopus 로고    scopus 로고
    • Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum
    • Dumoulin V, Moro F, Barcelo A, Dakka T, Cuber JC (1998) Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum. Endocrinology 139:3780-3786
    • (1998) Endocrinology , vol.139 , pp. 3780-3786
    • Dumoulin, V.1    Moro, F.2    Barcelo, A.3    Dakka, T.4    Cuber, J.C.5
  • 8
    • 0031750108 scopus 로고    scopus 로고
    • Peptones stimulate both the secretion of the incretin hormone glucagon-like peptide 1 and the transcription of the proglucagon gene
    • Cordier-Bussat M, Bernard C, Levenez F et al. (1998) Peptones stimulate both the secretion of the incretin hormone glucagon-like peptide 1 and the transcription of the proglucagon gene. Diabetes 47:1038-1045
    • (1998) Diabetes , vol.47 , pp. 1038-1045
    • Cordier-Bussat, M.1    Bernard, C.2    Levenez, F.3
  • 9
    • 0026063384 scopus 로고
    • Structure and pancreatic expression of the insulin and glucagon genes
    • Philippe J (1991) Structure and pancreatic expression of the insulin and glucagon genes. Endocr Rev 12:252-271
    • (1991) Endocr Rev , vol.12 , pp. 252-271
    • Philippe, J.1
  • 10
    • 0029655778 scopus 로고    scopus 로고
    • Activation of proglucagon gene transcription through a novel promoter element by the caudal-related homeodomain protein cdx-2/3
    • Jin T, Drucker DJ (1996) Activation of proglucagon gene transcription through a novel promoter element by the caudal-related homeodomain protein cdx-2/3. Mol Cell Biol 16:19-28
    • (1996) Mol Cell Biol , vol.16 , pp. 19-28
    • Jin, T.1    Drucker, D.J.2
  • 11
    • 0033305721 scopus 로고    scopus 로고
    • Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription
    • Hill ME, Asa SL, Drucker DJ (1999) Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. Mol Endocrinol 13:1474-1486
    • (1999) Mol Endocrinol , vol.13 , pp. 1474-1486
    • Hill, M.E.1    Asa, S.L.2    Drucker, D.J.3
  • 12
    • 0026658127 scopus 로고
    • Glucagon gene 5′-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice
    • Lee YC, Asa SL, Drucker DJ (1992) Glucagon gene 5′-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice. J Biol Chem 267:10705-10708
    • (1992) J Biol Chem , vol.267 , pp. 10705-10708
    • Lee, Y.C.1    Asa, S.L.2    Drucker, D.J.3
  • 13
    • 0029095180 scopus 로고
    • The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription
    • Jin T, Drucker DJ (1995) The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription. Mol Endocrinol 9:1306-1320
    • (1995) Mol Endocrinol , vol.9 , pp. 1306-1320
    • Jin, T.1    Drucker, D.J.2
  • 14
    • 0029844024 scopus 로고    scopus 로고
    • Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line
    • Lü F, Jin T, Drucker DJ (1996) Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line. Endocrinology 137:3710-3716
    • (1996) Endocrinology , vol.137 , pp. 3710-3716
    • Lü, F.1    Jin, T.2    Drucker, D.J.3
  • 15
    • 0027411690 scopus 로고
    • Multiple cis-acting domains mediate basal and adenosine 3′5′-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line
    • Gajic D, Drucker DJ (1993) Multiple cis-acting domains mediate basal and adenosine 3′5′-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line. Endocrinology 132:1055-1062
    • (1993) Endocrinology , vol.132 , pp. 1055-1062
    • Gajic, D.1    Drucker, D.J.2
  • 16
    • 0028281001 scopus 로고
    • Stimulation of glucagon-like peptide-1 secretion by muscarinic agonist in a murine intestinal endocrine cell line
    • Abello J, Ye F, Bosshard A, Bernard C, Cuber JC, Chayvialle JA (1994) Stimulation of glucagon-like peptide-1 secretion by muscarinic agonist in a murine intestinal endocrine cell line. Endocrinology 134:2011-2017
    • (1994) Endocrinology , vol.134 , pp. 2011-2017
    • Abello, J.1    Ye, F.2    Bosshard, A.3    Bernard, C.4    Cuber, J.C.5    Chayvialle, J.A.6
  • 17
    • 0029095180 scopus 로고
    • The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription
    • Jin T, Drucker DJ (1995) The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription. Mol Endocrinol 9:1306-1320
    • (1995) Mol Endocrinol , vol.9 , pp. 1306-1320
    • Jin, T.1    Drucker, D.J.2
  • 18
    • 0031883280 scopus 로고    scopus 로고
    • A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos
    • Ahn S, Olive M, Aggarwal S, Krylov D, Ginty DD, Vinson C (1998) A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos. Mol Cell Biol 18:967-977
    • (1998) Mol Cell Biol , vol.18 , pp. 967-977
    • Ahn, S.1    Olive, M.2    Aggarwal, S.3    Krylov, D.4    Ginty, D.D.5    Vinson, C.6
  • 19
  • 20
    • 0023723641 scopus 로고
    • Alpha-cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins
    • Philippe J, Drucker DJ, Knepel W, Jepeal L, Misulovin Z, Habener JF (1988) Alpha-cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins. Mol Cell Biol 8:4877-4888
    • (1988) Mol Cell Biol , vol.8 , pp. 4877-4888
    • Philippe, J.1    Drucker, D.J.2    Knepel, W.3    Jepeal, L.4    Misulovin, Z.5    Habener, J.F.6
  • 21
    • 0025296197 scopus 로고
    • Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression
    • Rindi G, Grant SG, Yiangou Y et al. (1990) Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression. Am J Pathol 136:1349-1363
    • (1990) Am J Pathol , vol.136 , pp. 1349-1363
    • Rindi, G.1    Grant, S.G.2    Yiangou, Y.3
  • 22
    • 0021100690 scopus 로고
    • Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei
    • Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475-1489
    • (1983) Nucleic Acids Res , vol.11 , pp. 1475-1489
    • Dignam, J.D.1    Lebovitz, R.M.2    Roeder, R.G.3
  • 24
    • 0035099751 scopus 로고    scopus 로고
    • Peptones stimulate intestinal cholecystokinin gene transcription via cyclic adenosine monophosphate response element-binding factors
    • Bernard C, Sutter A, Vinson C, Ratineau C, Chayvialle JA, Cordier-Bussat M (2001) Peptones stimulate intestinal cholecystokinin gene transcription via cyclic adenosine monophosphate response element-binding factors. Endocrinology 142:721-729
    • (2001) Endocrinology , vol.142 , pp. 721-729
    • Bernard, C.1    Sutter, A.2    Vinson, C.3    Ratineau, C.4    Chayvialle, J.A.5    Cordier-Bussat, M.6
  • 25
    • 0037151115 scopus 로고    scopus 로고
    • Corequirement of cyclic AMP- and calcium-dependent protein kinases for transcriptional activation of cholecystokinin gene by protein hydrolysates
    • Gevrey JC, Cordier-Bussat M, Nemoz-Gaillard E, Chayvialle JA, Abello J (2002) Corequirement of cyclic AMP- and calcium-dependent protein kinases for transcriptional activation of cholecystokinin gene by protein hydrolysates. J Biol Chem 277:22407-22413
    • (2002) J Biol Chem , vol.277 , pp. 22407-22413
    • Gevrey, J.C.1    Cordier-Bussat, M.2    Nemoz-Gaillard, E.3    Chayvialle, J.A.4    Abello, J.5
  • 26
    • 0025221222 scopus 로고
    • Transcriptional activation of the rat glucagon gene by the cyclic AMP-responsive element in pancreatic islet cells
    • Knepel W, Chafitz J, Habener JF (1990) Transcriptional activation of the rat glucagon gene by the cyclic AMP-responsive element in pancreatic islet cells. Mol Cell Biol 10:6799-6804
    • (1990) Mol Cell Biol , vol.10 , pp. 6799-6804
    • Knepel, W.1    Chafitz, J.2    Habener, J.F.3
  • 27
    • 0026093003 scopus 로고
    • The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells
    • Drucker DJ, Campos R, Reynolds R, Stobie K, Brubaker PL (1991) The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells. Endocrinology 128:394-340
    • (1991) Endocrinology , vol.128 , pp. 394-1340
    • Drucker, D.J.1    Campos, R.2    Reynolds, R.3    Stobie, K.4    Brubaker, P.L.5
  • 28
    • 0027416480 scopus 로고
    • Membrane depolarization and calcium influx induce glucagon gene transcription in pancreatic islet cells through the cyclic AMP-responsive element
    • Schwaninger M, Lux G, Blume R, Oetjen E, Hidaka H, Knepel W (1993) Membrane depolarization and calcium influx induce glucagon gene transcription in pancreatic islet cells through the cyclic AMP-responsive element. J Biol Chem 268:5168-5177
    • (1993) J Biol Chem , vol.268 , pp. 5168-5177
    • Schwaninger, M.1    Lux, G.2    Blume, R.3    Oetjen, E.4    Hidaka, H.5    Knepel, W.6
  • 29
    • 0024332336 scopus 로고
    • Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine
    • Drucker DJ, Brubaker PL (1989) Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. Proc Natl Acad Sci USA 86:3953-3957
    • (1989) Proc Natl Acad Sci USA , vol.86 , pp. 3953-3957
    • Drucker, D.J.1    Brubaker, P.L.2
  • 30
    • 0028575660 scopus 로고
    • Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line
    • Drucker DJ, Jin T, Asa SL, Young TA, Brubaker PL (1994) Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol 8:1646-1655
    • (1994) Mol Endocrinol , vol.8 , pp. 1646-1655
    • Drucker, D.J.1    Jin, T.2    Asa, S.L.3    Young, T.A.4    Brubaker, P.L.5
  • 31
    • 0027999510 scopus 로고
    • A complex array of positive and negative elements regulates the chicken alpha A-crystallin gene: Involvement of Pax-6, USF, CREB and/or CREM, and AP-1 proteins
    • Cvekl A, Sax CM, Bresnick EH, Piatigorsky J (1994) A complex array of positive and negative elements regulates the chicken alpha A-crystallin gene: involvement of Pax-6, USF, CREB and/or CREM, and AP-1 proteins. Mol Cell Biol 14:7363-7376
    • (1994) Mol Cell Biol , vol.14 , pp. 7363-7376
    • Cvekl, A.1    Sax, C.M.2    Bresnick, E.H.3    Piatigorsky, J.4
  • 32
    • 0033043560 scopus 로고    scopus 로고
    • A multiprotein complex consisting of the cellular coactivator p300, AP-1/ATF, as well as NF-kappaB is responsible for the activation of the mouse major histocompatibility class I (H-2K(b)) enhancer A
    • Brockmann D, Putzer BM, Lipinski KS, Schmucker U, Esche H (1999) A multiprotein complex consisting of the cellular coactivator p300, AP-1/ATF, as well as NF-kappaB is responsible for the activation of the mouse major histocompatibility class I (H-2K(b)) enhancer A. Gene Expr 8:1-18
    • (1999) Gene Expr , vol.8 , pp. 1-18
    • Brockmann, D.1    Putzer, B.M.2    Lipinski, K.S.3    Schmucker, U.4    Esche, H.5
  • 33
    • 0036269402 scopus 로고    scopus 로고
    • Promoter specificity and biological activity of tethered AP-1 dimers
    • Bakiri L, Matsuo K, Wisniewska M, Wagner EF, Yaniv M (2002) Promoter specificity and biological activity of tethered AP-1 dimers. Mol Cell Biol 22:4952-4964
    • (2002) Mol Cell Biol , vol.22 , pp. 4952-4964
    • Bakiri, L.1    Matsuo, K.2    Wisniewska, M.3    Wagner, E.F.4    Yaniv, M.5
  • 34
    • 0027373934 scopus 로고
    • Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins
    • Miller CP, Lin JC, Habener JF (1993) Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins. Mol Cell Biol 13:7080-7090
    • (1993) Mol Cell Biol , vol.13 , pp. 7080-7090
    • Miller, C.P.1    Lin, J.C.2    Habener, J.F.3
  • 35
    • 0032852479 scopus 로고    scopus 로고
    • CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals
    • Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821-861
    • (1999) Annu Rev Biochem , vol.68 , pp. 821-861
    • Shaywitz, A.J.1    Greenberg, M.E.2
  • 36
    • 0038532255 scopus 로고    scopus 로고
    • Elements of the glucocorticoid and retinoic acid response units are involved in cAMP-mediated expression of the PEPCK gene
    • Waltner-Law M, Duong DT, Daniels MC et al. (2003) Elements of the glucocorticoid and retinoic acid response units are involved in cAMP-mediated expression of the PEPCK gene. J Biol Chem 278:10427-10435
    • (2003) J Biol Chem , vol.278 , pp. 10427-10435
    • Waltner-Law, M.1    Duong, D.T.2    Daniels, M.C.3
  • 37
    • 0037428472 scopus 로고    scopus 로고
    • Transcriptional activation of the proglucagon gene by lithium and Beta-catenin in intestinal endocrine L cells
    • Ni Z, Anini Y, Fang X, Mills G, Brubaker PL, Jin T (2003) Transcriptional activation of the proglucagon gene by lithium and Beta-catenin in intestinal endocrine L cells. J Biol Chem 278:1380-1387
    • (2003) J Biol Chem , vol.278 , pp. 1380-1387
    • Ni, Z.1    Anini, Y.2    Fang, X.3    Mills, G.4    Brubaker, P.L.5    Jin, T.6
  • 38
    • 0033591344 scopus 로고    scopus 로고
    • Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase
    • Mikkola I, Bruun JA, Bjorkoy G, Holm T, Johansen T (1999) Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. J Biol Chem 274:15115-15126
    • (1999) J Biol Chem , vol.274 , pp. 15115-15126
    • Mikkola, I.1    Bruun, J.A.2    Bjorkoy, G.3    Holm, T.4    Johansen, T.5
  • 39
    • 0037169836 scopus 로고    scopus 로고
    • CCAAT/enhancer binding proteins: Do they possess intrinsic cAMP-inducible activity?
    • Wilson HL, Roesler WJ (2002) CCAAT/enhancer binding proteins: do they possess intrinsic cAMP-inducible activity? Mol Cell Endocrinol 188:15-20
    • (2002) Mol Cell Endocrinol , vol.188 , pp. 15-20
    • Wilson, H.L.1    Roesler, W.J.2
  • 40
    • 0031053897 scopus 로고    scopus 로고
    • Peptones stimulate cholecystokinin secretion and gene transcription in the intestinal cell line STC-1
    • Cordier-Bussat M, Bernard C, Haouche S et al. (1997) Peptones stimulate cholecystokinin secretion and gene transcription in the intestinal cell line STC-1. Endocrinology 138:1137-1144
    • (1997) Endocrinology , vol.138 , pp. 1137-1144
    • Cordier-Bussat, M.1    Bernard, C.2    Haouche, S.3
  • 41
    • 0033825624 scopus 로고    scopus 로고
    • Regulation of glucose-dependent-insulinotropic polypeptide release by protein in the rat
    • Wolfe MM, Zhao KB, Glazier KD, Jarboe LA, Tseng CC (2000) Regulation of glucose-dependent-insulinotropic polypeptide release by protein in the rat. Am J Physiol 279:0561-0566
    • (2000) Am J Physiol , vol.279 , pp. 561-566
    • Wolfe, M.M.1    Zhao, K.B.2    Glazier, K.D.3    Jarboe, L.A.4    Tseng, C.C.5
  • 42
    • 0027459479 scopus 로고
    • Two 3′,5′-cyclic-adenosine monophosphate response elements in the promoter region of the human gastric inhibitory polypeptide gene
    • Someya Y, Inagaki N, Maekawa T, Seino Y, Ishii S (1993) Two 3′,5′-cyclic-adenosine monophosphate response elements in the promoter region of the human gastric inhibitory polypeptide gene. FEBS Lett 317:67-73
    • (1993) FEBS Lett , vol.317 , pp. 67-73
    • Someya, Y.1    Inagaki, N.2    Maekawa, T.3    Seino, Y.4    Ishii, S.5
  • 43
    • 0031132109 scopus 로고    scopus 로고
    • Colonic microflora: Nutrition and health
    • Cummings JH, MacFarlane GT (1997) Colonic microflora: nutrition and health. Nutrition 13:476-478
    • (1997) Nutrition , vol.13 , pp. 476-478
    • Cummings, J.H.1    MacFarlane, G.T.2
  • 45
    • 0028065432 scopus 로고
    • Colonie proteolysis following pancreatic duct ligation in the rat
    • Bustos D, Tiscornia O, Caldarini MI et al. (1994) Colonie proteolysis following pancreatic duct ligation in the rat. Int J Pancreatol 16:45-49
    • (1994) Int J Pancreatol , vol.16 , pp. 45-49
    • Bustos, D.1    Tiscornia, O.2    Caldarini, M.I.3
  • 46
    • 0037312830 scopus 로고    scopus 로고
    • Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium
    • Trinh DK, Zhang K, Hossain M, Brubaker PL, Drucker DJ (2003) Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. Diabetes 52:425-433
    • (2003) Diabetes , vol.52 , pp. 425-433
    • Trinh, D.K.1    Zhang, K.2    Hossain, M.3    Brubaker, P.L.4    Drucker, D.J.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.