메뉴 건너뛰기




Volumn 34, Issue 5, 2014, Pages 832-846

Kinetic, thermodynamic, and structural characterizationsxs of the association between Nrf2-DLGex degron and Keap1

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; AMINO ACID MOTIFS; AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; KINETICS; MICE; MOLECULAR SEQUENCE DATA; MUTATION; NF-E2-RELATED FACTOR 2; PROTEIN BINDING; THERMODYNAMICS;

EID: 84893840509     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/MCB.01191-13     Document Type: Article
Times cited : (195)

References (49)
  • 1
    • 0037055265 scopus 로고    scopus 로고
    • Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors
    • Motohashi H, O'Connor T, Katsuoka F, Engel JD, Yamamoto M. 2002. Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294:1-12. http://dx.doi.org/10.1016/S0378-1119(02)00788-6.
    • (2002) Gene , vol.294 , pp. 1-12
    • Motohashi, H.1    O'Connor, T.2    Katsuoka, F.3    Engel, J.D.4    Yamamoto, M.5
  • 2
    • 33748052967 scopus 로고    scopus 로고
    • Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species
    • Kobayashi M, Yamamoto M. 2006. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv. Enzyme Regul. 46:113-140. http://dx.doi.org/10.1016/j.advenzreg.2006.01.007.
    • (2006) Adv. Enzyme Regul. , vol.46 , pp. 113-140
    • Kobayashi, M.1    Yamamoto, M.2
  • 3
    • 78751703950 scopus 로고    scopus 로고
    • Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
    • Taguchi K, Motohashi H, Yamamoto M. 2011. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123-140. http://dx.doi.org/10.1111/j.1365-2443.2010.01473.x.
    • (2011) Genes Cells , vol.16 , pp. 123-140
    • Taguchi, K.1    Motohashi, H.2    Yamamoto, M.3
  • 4
    • 0032953192 scopus 로고    scopus 로고
    • Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
    • Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. 1999. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13:76-86.
    • (1999) Genes Dev. , vol.13 , pp. 76-86
    • Itoh, K.1    Wakabayashi, N.2    Katoh, Y.3    Ishii, T.4    Igarashi, K.5    Engel, J.D.6    Yamamoto, M.7
  • 5
    • 33750613056 scopus 로고    scopus 로고
    • Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism
    • Tong KI, Kobayashi A, Katsuoka F, Yamamoto M. 2006. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol. Chem. 387:1311-1320.
    • (2006) Biol. Chem. , vol.387 , pp. 1311-1320
    • Tong, K.I.1    Kobayashi, A.2    Katsuoka, F.3    Yamamoto, M.4
  • 6
    • 3543008924 scopus 로고    scopus 로고
    • Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2
    • Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M. 2004. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24:7130-7139. http://dx.doi.org/10.1128/MCB.24.16.7130-7139.2004.
    • (2004) Mol. Cell. Biol. , vol.24 , pp. 7130-7139
    • Kobayashi, A.1    Kang, M.I.2    Okawa, H.3    Ohtsuji, M.4    Zenke, Y.5    Chiba, T.6    Igarashi, K.7    Yamamoto, M.8
  • 8
    • 3843104763 scopus 로고    scopus 로고
    • Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redoxinsensitive Neh6 degron
    • McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. 2004. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redoxinsensitive Neh6 degron. J. Biol. Chem. 279:31556-31567. http://dx.doi.org/10.1074/jbc.M403061200.
    • (2004) J. Biol. Chem. , vol.279 , pp. 31556-31567
    • McMahon, M.1    Thomas, N.2    Itoh, K.3    Yamamoto, M.4    Hayes, J.D.5
  • 9
    • 35648970026 scopus 로고    scopus 로고
    • Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response
    • Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M. 2007. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol. Cell. Biol. 27:7511-7521. http://dx.doi.org/10.1128/MCB.00753-07.
    • (2007) Mol. Cell. Biol. , vol.27 , pp. 7511-7521
    • Tong, K.I.1    Padmanabhan, B.2    Kobayashi, A.3    Shang, C.4    Hirotsu, Y.5    Yokoyama, S.6    Yamamoto, M.7
  • 10
    • 33344463325 scopus 로고    scopus 로고
    • Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model
    • Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. 2006. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26:2887-2900. http://dx.doi.org/10.1128/MCB.26.8.2887-2900.2006.
    • (2006) Mol. Cell. Biol. , vol.26 , pp. 2887-2900
    • Tong, K.I.1    Katoh, Y.2    Kusunoki, H.3    Itoh, K.4    Tanaka, T.5    Yamamoto, M.6
  • 11
    • 77649261371 scopus 로고    scopus 로고
    • Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains
    • Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M. 2010. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc. Natl. Acad. Sci. U. S. A. 107:2842-2847. http://dx.doi.org/10.1073/pnas.0914036107.
    • (2010) Proc. Natl. Acad. Sci. U. S. A. , vol.107 , pp. 2842-2847
    • Ogura, T.1    Tong, K.I.2    Mio, K.3    Maruyama, Y.4    Kurokawa, H.5    Sato, C.6    Yamamoto, M.7
  • 14
    • 84867777145 scopus 로고    scopus 로고
    • The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases
    • Joshi G, Johnson JA. 2012. The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat. CNS Drug Discov. 7:218-229. http://dx.doi.org/10.2174/157488912803252023.
    • (2012) Recent Pat. CNS Drug Discov. , vol.7 , pp. 218-229
    • Joshi, G.1    Johnson, J.A.2
  • 15
    • 0037356451 scopus 로고    scopus 로고
    • Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice
    • Ramos-Gomez M, Dolan PM, Itoh K, Yamamoto M, Kensler TW. 2003. Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24:461-467. http://dx.doi.org/10.1093/carcin/24.3.461.
    • (2003) Carcinogenesis , vol.24 , pp. 461-467
    • Ramos-Gomez, M.1    Dolan, P.M.2    Itoh, K.3    Yamamoto, M.4    Kensler, T.W.5
  • 16
    • 4644328941 scopus 로고    scopus 로고
    • Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis
    • Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M. 2004. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 64:6424-6431. http://dx.doi.org/10.1158/0008-5472.CAN-04-1906.
    • (2004) Cancer Res. , vol.64 , pp. 6424-6431
    • Iida, K.1    Itoh, K.2    Kumagai, Y.3    Oyasu, R.4    Hattori, K.5    Kawai, K.6    Shimazui, T.7    Akaza, H.8    Yamamoto, M.9
  • 17
    • 84880048347 scopus 로고    scopus 로고
    • Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis
    • Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. 2013. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 73:4158-4168. http://dx.doi.org/10.1158/0008-5472.CAN-12-4499.
    • (2013) Cancer Res. , vol.73 , pp. 4158-4168
    • Satoh, H.1    Moriguchi, T.2    Takai, J.3    Ebina, M.4    Yamamoto, M.5
  • 18
    • 84874468267 scopus 로고    scopus 로고
    • Role of Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis
    • Ohkoshi A, Suzuki T, Ono M, Kobayashi T, Yamamoto M. 2013. Role of Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis. Cancer Prev. Res. 6:149 -159. http://dx.doi.org/10.1158/1940-6207.CAPR-12-0401-T.
    • (2013) Cancer Prev. Res. , vol.6
    • Ohkoshi, A.1    Suzuki, T.2    Ono, M.3    Kobayashi, T.4    Yamamoto, M.5
  • 20
    • 77958129306 scopus 로고    scopus 로고
    • Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance
    • Singh A, Bodas M, Wakabayashi N, Bunz F, Biswal S. 2010. Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid. Redox Signal. 13:1627-1637. http://dx.doi.org/10.1089/ars.2010.3219.
    • (2010) Antioxid. Redox Signal. , vol.13 , pp. 1627-1637
    • Singh, A.1    Bodas, M.2    Wakabayashi, N.3    Bunz, F.4    Biswal, S.5
  • 21
    • 76649089973 scopus 로고    scopus 로고
    • Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth
    • Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, Wu H, Bova SG, Biswal S. 2010. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol. Cancer Ther. 9:336- 346. http://dx.doi.org/10.1158/1535-7163.MCT-09-0589.
    • (2010) Mol. Cancer Ther. , vol.9
    • Zhang, P.1    Singh, A.2    Yegnasubramanian, S.3    Esopi, D.4    Kombairaju, P.5    Bodas, M.6    Wu, H.7    Bova, S.G.8    Biswal, S.9
  • 23
    • 77953139490 scopus 로고    scopus 로고
    • NFE2L2 gene mutation in male Japanese squamous cell carcinoma of the lung
    • Sasaki H, Hikosaka Y, Okuda K, Kawano O, Moriyama S, Yano M, Fujii Y. 2010. NFE2L2 gene mutation in male Japanese squamous cell carcinoma of the lung. J. Thorac. Oncol. 5:786-789. http://dx.doi.org/10.1097/JTO.0b013e3181db3dd3.
    • (2010) J. Thorac. Oncol. , vol.5 , pp. 786-789
    • Sasaki, H.1    Hikosaka, Y.2    Okuda, K.3    Kawano, O.4    Moriyama, S.5    Yano, M.6    Fujii, Y.7
  • 27
    • 0031059866 scopus 로고    scopus 로고
    • Processing of X-ray diffraction data collected in oscillation mode
    • Otwinowski Z, Minor W. 1997. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276:307-326. http://dx.doi.org/10.1016/S0076-6879(97)76066-X.
    • (1997) Methods Enzymol. , vol.276 , pp. 307-326
    • Otwinowski, Z.1    Minor, W.2
  • 29
    • 13244281317 scopus 로고    scopus 로고
    • Coot: model-building tools for molecular graphics
    • Emsley P, Cowtan K. 2004. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60:2126-2132. http://dx.doi.org/10.1107/S0907444904019158.
    • (2004) Acta Crystallogr. D Biol. Crystallogr. , vol.60 , pp. 2126-2132
    • Emsley, P.1    Cowtan, K.2
  • 30
    • 0030924992 scopus 로고    scopus 로고
    • Refinement of macromolecular structures by the maximum-likelihood method
    • Murshudov GN, Vagin AA, Dodson EJ. 1997. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr.DBiol. Crystallogr. 53:240-255. http://dx.doi.org/10.1107/S0907444996012255.
    • (1997) Acta Crystallogr.DBiol. Crystallogr. , vol.53 , pp. 240-255
    • Murshudov, G.N.1    Vagin, A.A.2    Dodson, E.J.3
  • 32
    • 84863091925 scopus 로고    scopus 로고
    • Mutation of the Nrf2 gene in non-small cell lung cancer
    • Hu Y, Ju Y, Lin D, Wang Z, Huang Y, Zhang S, Wu C, Jiao S. 2012. Mutation of the Nrf2 gene in non-small cell lung cancer. Mol. Biol. Rep. 39:4743-4747. http://dx.doi.org/10.1007/s11033-011-1266-4.
    • (2012) Mol. Biol. Rep. , vol.39 , pp. 4743-4747
    • Hu, Y.1    Ju, Y.2    Lin, D.3    Wang, Z.4    Huang, Y.5    Zhang, S.6    Wu, C.7    Jiao, S.8
  • 33
    • 84880858384 scopus 로고    scopus 로고
    • Genomic structure and variation of nuclear factor (erythroid- derived 2)-like 2
    • Cho HY. 2013. Genomic structure and variation of nuclear factor (erythroid- derived 2)-like 2. Oxid. Med. Cell. Longev. 2013:286524. http://dx.doi.org/10.1155/2013/286524.
    • (2013) Oxid. Med. Cell. Longev. , vol.2013 , pp. 286524
    • Cho, H.Y.1
  • 35
    • 37249005205 scopus 로고    scopus 로고
    • The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
    • Niesen FH, Berglund H, Vedadi M. 2007. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2:2212-2221. http://dx.doi.org/10.1038/nprot.2007.321.
    • (2007) Nat. Protoc. , vol.2 , pp. 2212-2221
    • Niesen, F.H.1    Berglund, H.2    Vedadi, M.3
  • 36
    • 0035442411 scopus 로고    scopus 로고
    • Direct measurement of protein binding energetics by isothermal titration calorimetry
    • Leavitt S, Freire E. 2001. Direct measurement of protein binding energetics by isothermal titration calorimetry. Curr. Opin. Struct. Biol. 11: 560-566. http://dx.doi.org/10.1016/S0959-440X(00)00248-7.
    • (2001) Curr. Opin. Struct. Biol. , vol.11 , pp. 560-566
    • Leavitt, S.1    Freire, E.2
  • 37
    • 0037044791 scopus 로고    scopus 로고
    • Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response elementmediated transcription
    • Huang HC, Nguyen T, Pickett CB. 2002. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response elementmediated transcription. J. Biol. Chem. 277:42769-42774. http://dx.doi.org/10.1074/jbc.M206911200.
    • (2002) J. Biol. Chem. , vol.277 , pp. 42769-42774
    • Huang, H.C.1    Nguyen, T.2    Pickett, C.B.3
  • 38
    • 0033731182 scopus 로고    scopus 로고
    • Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NFE2- related factor 2
    • Huang HC, Nguyen T, Pickett CB. 2000. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NFE2- related factor 2. Proc. Natl. Acad. Sci. U. S. A. 97:12475-12480. http://dx.doi.org/10.1073/pnas.220418997.
    • (2000) Proc. Natl. Acad. Sci. U. S. A. , vol.97 , pp. 12475-12480
    • Huang, H.C.1    Nguyen, T.2    Pickett, C.B.3
  • 39
    • 0242666198 scopus 로고    scopus 로고
    • Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response elementmediated NAD(P)H:quinone oxidoreductase-1 gene expression
    • Bloom DA, Jaiswal AK. 2003. Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response elementmediated NAD(P)H:quinone oxidoreductase-1 gene expression. J. Biol. Chem. 278:44675-44682. http://dx.doi.org/10.1074/jbc.M307633200.
    • (2003) J. Biol. Chem. , vol.278 , pp. 44675-44682
    • Bloom, D.A.1    Jaiswal, A.K.2
  • 40
    • 71449099635 scopus 로고    scopus 로고
    • Antioxidant-induced modification of INrf2 cysteine 151 and PKC-σ-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance
    • Niture SK, Jain AK, Jaiswal AK. 2009. Antioxidant-induced modification of INrf2 cysteine 151 and PKC-σ-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance. J. Cell Sci. 122:4452-4464. http://dx.doi.org/10.1242/jcs.058537.
    • (2009) J. Cell Sci. , vol.122 , pp. 4452-4464
    • Niture, S.K.1    Jain, A.K.2    Jaiswal, A.K.3
  • 41
    • 42449150854 scopus 로고    scopus 로고
    • Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1
    • Padmanabhan B, Tong KI, Kobayashi A, Yamamoto M, Yokoyama S. 2008. Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1. J. Synchrotron Radiat. 15:273-276. http://dx.doi.org/10.1107/S090904950705114X.
    • (2008) J. Synchrotron Radiat. , vol.15 , pp. 273-276
    • Padmanabhan, B.1    Tong, K.I.2    Kobayashi, A.3    Yamamoto, M.4    Yokoyama, S.5
  • 44
    • 0342813129 scopus 로고    scopus 로고
    • Experimental design for kinetic analysis of protein-protein interactions with surface plasmon resonance biosensors
    • Karlsson R, Fält A. 1997. Experimental design for kinetic analysis of protein-protein interactions with surface plasmon resonance biosensors. J. Immunol. Methods 200:121-133. http://dx.doi.org/10.1016/S0022-1759(96)00195-0.
    • (1997) J. Immunol. Methods , vol.200 , pp. 121-133
    • Karlsson, R.1    Fält, A.2
  • 45
    • 0034426852 scopus 로고    scopus 로고
    • Experimental design for analysis of complex kinetics using surface plasmon resonance
    • Lipschultz CA, Li Y, Smith-Gill S. 2000. Experimental design for analysis of complex kinetics using surface plasmon resonance. Methods 20:310- 318. http://dx.doi.org/10.1006/meth.1999.0924.
    • (2000) Methods , vol.20
    • Lipschultz, C.A.1    Li, Y.2    Smith-Gill, S.3
  • 46
    • 81355124042 scopus 로고    scopus 로고
    • Kinetic analyses of Keap1-Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance
    • Chen Y, Inoyama D, Kong AN, Beamer LJ, Hu L. 2011. Kinetic analyses of Keap1-Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance. Chem. Biol. Drug Des. 78:1014-1021. http://dx.doi.org/10.1111/j.1747-0285.2011.01240.x.
    • (2011) Chem. Biol. Drug Des. , vol.78 , pp. 1014-1021
    • Chen, Y.1    Inoyama, D.2    Kong, A.N.3    Beamer, L.J.4    Hu, L.5
  • 47
    • 33747728194 scopus 로고    scopus 로고
    • Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex
    • McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. 2006. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J. Biol. Chem. 281:24756-24768. http://dx.doi.org/10.1074/jbc.M601119200.
    • (2006) J. Biol. Chem. , vol.281 , pp. 24756-24768
    • McMahon, M.1    Thomas, N.2    Itoh, K.3    Yamamoto, M.4    Hayes, J.D.5
  • 49
    • 84884338770 scopus 로고    scopus 로고
    • Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex
    • Baird L, Llères D, Swift S, Dinkova-Kostova AT. 2013. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc. Natl. Acad. Sci. U. S. A. 110:15259-15264. http://dx.doi.org/10.1073/pnas.1305687110.
    • (2013) Proc. Natl. Acad. Sci. U. S. A. , vol.110 , pp. 15259-15264
    • Baird, L.1    Llères, D.2    Swift, S.3    Dinkova-Kostova, A.T.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.