{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1363670319113362432.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1158/0008-5472.can-07-5003"}},{"identifier":{"@type":"URI","@value":"https://aacrjournals.org/cancerres/article-pdf/68/5/1303/2600621/1303.pdf"}},{"identifier":{"@type":"PMID","@value":"18316592"}}],"dc:title":[{"@value":"Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n                  <jats:p>Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase II detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer–derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2. [Cancer Res 2008;68(5):1303–9]</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1383670319113362437","@type":"Researcher","foaf:name":[{"@value":"Tsutomu Ohta"}],"jpcoar:affiliationName":[{"@value":"1Center for Medical Genomics,"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362432","@type":"Researcher","foaf:name":[{"@value":"Kumiko Iijima"}],"jpcoar:affiliationName":[{"@value":"1Center for Medical Genomics,"},{"@value":"5Department of Computational Biology, Tokyo Medical and Dental University, Tokyo, Japan;"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362435","@type":"Researcher","foaf:name":[{"@value":"Mamiko Miyamoto"}],"jpcoar:affiliationName":[{"@value":"1Center for Medical Genomics,"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362433","@type":"Researcher","foaf:name":[{"@value":"Izumi Nakahara"}],"jpcoar:affiliationName":[{"@value":"1Center for Medical Genomics,"},{"@value":"5Department of Computational Biology, Tokyo Medical and Dental University, Tokyo, Japan;"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362439","@type":"Researcher","foaf:name":[{"@value":"Hiroshi Tanaka"}],"jpcoar:affiliationName":[{"@value":"5Department of Computational Biology, Tokyo Medical and Dental University, Tokyo, Japan;"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362434","@type":"Researcher","foaf:name":[{"@value":"Makiko Ohtsuji"}],"jpcoar:affiliationName":[{"@value":"6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and"},{"@value":"7Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362438","@type":"Researcher","foaf:name":[{"@value":"Takafumi Suzuki"}],"jpcoar:affiliationName":[{"@value":"6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and"},{"@value":"7Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362304","@type":"Researcher","foaf:name":[{"@value":"Akira Kobayashi"}],"jpcoar:affiliationName":[{"@value":"6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and"},{"@value":"7Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362440","@type":"Researcher","foaf:name":[{"@value":"Jun Yokota"}],"jpcoar:affiliationName":[{"@value":"2Biology Division,"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362441","@type":"Researcher","foaf:name":[{"@value":"Tokuki Sakiyama"}],"jpcoar:affiliationName":[{"@value":"1Center for Medical Genomics,"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362436","@type":"Researcher","foaf:name":[{"@value":"Tatsuhiro Shibata"}],"jpcoar:affiliationName":[{"@value":"3Pathology Division, and"},{"@value":"4Cancer Genomics Project, National Cancer Center Research Institute;"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362305","@type":"Researcher","foaf:name":[{"@value":"Masayuki Yamamoto"}],"jpcoar:affiliationName":[{"@value":"6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and"},{"@value":"7Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670319113362442","@type":"Researcher","foaf:name":[{"@value":"Setsuo Hirohashi"}],"jpcoar:affiliationName":[{"@value":"3Pathology Division, and"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00085472"},{"@type":"EISSN","@value":"15387445"}],"prism:publicationName":[{"@value":"Cancer Research"}],"dc:publisher":[{"@value":"American Association for Cancer Research (AACR)"}],"prism:publicationDate":"2008-03-01","prism:volume":"68","prism:number":"5","prism:startingPage":"1303","prism:endingPage":"1309"},"reviewed":"false","dcterms:accessRights":"http://purl.org/coar/access_right/c_abf2","url":[{"@id":"https://aacrjournals.org/cancerres/article-pdf/68/5/1303/2600621/1303.pdf"}],"createdAt":"2008-03-03","modifiedAt":"2022-06-17","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Nucleus","dc:title":"Cell Nucleus"},{"@id":"https://cir.nii.ac.jp/all?q=Kelch-Like%20ECH-Associated%20Protein%201","dc:title":"Kelch-Like ECH-Associated Protein 1"},{"@id":"https://cir.nii.ac.jp/all?q=Lung%20Neoplasms","dc:title":"Lung Neoplasms"},{"@id":"https://cir.nii.ac.jp/all?q=NF-E2-Related%20Factor%202","dc:title":"NF-E2-Related Factor 2"},{"@id":"https://cir.nii.ac.jp/all?q=Molecular%20Sequence%20Data","dc:title":"Molecular Sequence Data"},{"@id":"https://cir.nii.ac.jp/all?q=Intracellular%20Signaling%20Peptides%20and%20Proteins","dc:title":"Intracellular Signaling Peptides and Proteins"},{"@id":"https://cir.nii.ac.jp/all?q=Mice,%20Transgenic","dc:title":"Mice, Transgenic"},{"@id":"https://cir.nii.ac.jp/all?q=Fibroblasts","dc:title":"Fibroblasts"},{"@id":"https://cir.nii.ac.jp/all?q=Gene%20Expression%20Regulation,%20Neoplastic","dc:title":"Gene Expression Regulation, Neoplastic"},{"@id":"https://cir.nii.ac.jp/all?q=Mice","dc:title":"Mice"},{"@id":"https://cir.nii.ac.jp/all?q=Oxidative%20Stress","dc:title":"Oxidative Stress"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Line,%20Tumor","dc:title":"Cell Line, Tumor"},{"@id":"https://cir.nii.ac.jp/all?q=Animals","dc:title":"Animals"},{"@id":"https://cir.nii.ac.jp/all?q=Humans","dc:title":"Humans"},{"@id":"https://cir.nii.ac.jp/all?q=Amino%20Acid%20Sequence","dc:title":"Amino Acid Sequence"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Proliferation","dc:title":"Cell Proliferation"}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1050566774865104768","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1"}]},{"@id":"https://cir.nii.ac.jp/crid/1360002215932630272","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Molecular basis of the Keap1–Nrf2 system"}]},{"@id":"https://cir.nii.ac.jp/crid/1360002216015604992","@type":"Article","resourceType":"学術雑誌論文(journal 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Squamous Cell Carcinoma"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004232066886912","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Mitochondrial SKN-1/Nrf Mediates a Conserved Starvation Response"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004232280989440","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004232402902784","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The Keap1–Nrf2 system as an in vivo sensor for electrophiles"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004233956391168","@type":"Article","resourceType":"学術雑誌論文(journal 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article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene"}]},{"@id":"https://cir.nii.ac.jp/crid/1360009142695069824","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283692125959040","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283693155958912","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Accumulation of p62/<scp>SQSTM</scp>1 is associated with poor prognosis in patients with lung adenocarcinoma"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283693331688064","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis‐resistance to non‐thermal plasma therapy"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283694774568320","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"NRF2 Mutation Confers Malignant Potential and Resistance to Chemoradiation Therapy in Advanced Esophageal Squamous Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285707013856640","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Pathophysiological roles of aldo–keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285708404004992","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285708506685568","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285709527990528","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285710970409216","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response"}]},{"@id":"https://cir.nii.ac.jp/crid/1360290617598749568","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360294643730729088","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling"}]},{"@id":"https://cir.nii.ac.jp/crid/1360306905168119680","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Splicing junction-based classifier for the detection of abnormal constitutive activation of the KEAP1-NRF2 system"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565165802997248","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565165886053120","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Roles of Nrf2 in cell proliferation and differentiation"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565166771932032","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565166772364416","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565168423564416","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Dual Regulation of the Transcriptional Activity of Nrf1 by β-TrCP- and Hrd1-Dependent Degradation Mechanisms"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565168636782464","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Select Heterozygous\n                    <i>Keap1</i>\n                    Mutations Have a Dominant-Negative Effect on Wild-Type Keap1\n                    <i>In Vivo</i>"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567184718604032","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Generation of a 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article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Effects of Nrf2 knockdown on the properties of irradiated cell conditioned medium from A549 human lung cancer cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567189645034240","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Increased NRF2 gene (NFE2L2) copy number correlates with mutations in lung squamous cell carcinomas"}]},{"@id":"https://cir.nii.ac.jp/crid/1360572092648499200","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"NRF2-Dependent Bioactivation of Mitomycin C as a Novel Strategy To Target KEAP1-NRF2 Pathway Activation in Human Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360588380135481216","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Specific cancer types and prognosis in patients with variations in the <scp>KEAP1</scp>‐<scp>NRF2</scp> system: A retrospective cohort study"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846643120091136","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846643598921728","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Roles Nrf2 Plays in Myeloid Cells and Related Disorders"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846643613457536","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846643614863360","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846645588663296","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The KEAP1–NRF2 System in Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360853567838933248","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone"}]},{"@id":"https://cir.nii.ac.jp/crid/1360857593659617664","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines"}]},{"@id":"https://cir.nii.ac.jp/crid/1360865815671142528","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function"}]},{"@id":"https://cir.nii.ac.jp/crid/1360869854342404480","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases"}]},{"@id":"https://cir.nii.ac.jp/crid/1360869855112142720","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The Complex Roles of Redox and Antioxidant Biology in 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