{"created":"2023-07-27T06:55:15.666764+00:00","id":51027,"links":{},"metadata":{"_buckets":{"deposit":"8ceb71d8-18ed-4789-bce9-09044af5e435"},"_deposit":{"created_by":18,"id":"51027","owners":[18],"pid":{"revision_id":0,"type":"depid","value":"51027"},"status":"published"},"_oai":{"id":"oai:kanazawa-u.repo.nii.ac.jp:00051027","sets":["2812:2813:2828"]},"author_link":["72412","65"],"item_9_biblio_info_8":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2007-12-12","bibliographicIssueDateType":"Issued"},"bibliographicPageStart":"3p.","bibliographicVolumeNumber":"2003-2005","bibliographic_titles":[{"bibliographic_title":"平成17(2005)年度 科学研究費補助金 基盤研究(B) 研究成果報告書概要"},{"bibliographic_title":"2005 Fiscal Year Final Research Report Summary","bibliographic_titleLang":"en"}]}]},"item_9_creator_33":{"attribute_name":"著者別表示","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{}],"nameIdentifiers":[{},{}]}]},"item_9_description_21":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"A promising area in current cancer research explores the wide range of molecular events including aberrant/alternative gene splicing, epigenetic changes, cellular signal transduction, transcriptional regulation and post-translational modifications, which determine the fate of cells (growth, differentiation, and programmed cell death). One of such events takes place in the Wnt signaling pathway, and its aberrant activation is involved in malignant transformation of cells, β-catenin has two distinct functions, namely, maintaining cell-to-cell adhesion and mediating the Wnt/β-catenin pathway, which plays pivotal roles in embryogenesis and in certain tumors, particularly development and progression of colorectal cancer (CRC)^<16>. On the basis of our previous studies showing association of distinct patterns of β-catenin activation with malignant potential of the tumors and clinical outcome of CRC patients^6, in the present study we addressed the molecular and cellular mechanisms underlying activation and deregulation of Wnt/β-catenin signaling in colorectal cancer.\nThe oncogenic properties of Wnt/β-catenin signaling stem from alteration in ubiquitin-mediated degradation and subcellular localization of β-catenin from cell membrane to the nucleus, where it binds to T cell factor (Tcf) ; the complex facilitates transcription of genes encoding factors for cell proliferation and inhibition of apoptosis. We previously found that β-transducin repeat-containing protein (β-TrCP) is a component of the ubiquitin ligase complex targeting β-catenin and IκBα for proteasomal degradation and thus a negative regulator of Wnt/β-catenin signaling and a positive regulator of NF-κB pathway. Increased induction of β-TrCP via the β-catenin/Tcf pathway results in degradation of β-catenin, indicating that a negative feedback loop controls the β-catenin/Tcf pathway under physiologic conditions (Mol Cell 2000;5:877-82). Here we demonstrated that, in CRC, increased expression of β-TrCP by an impairment in the negative feedback loop regulation between β-TrCP and β-catenin is associated with activation of both β-catenin and NF-κB, suggesting that the integration of these signaling pathways by β-TrCP overexpresion contributes to an inhibition of apoptosis and tumor metastasis^9.\nAs mentioned above, in non-neoplastic cells harboring wild-type CTNNB1 and APC genes, β-catenin/Tcf signaling increases levels of β-TrCP mRNA and protein in a Tcf-dependent manner (Mol Cell 2000;5:877-82). In this study, we identified a novel β-catenin/Tcf target gene X ; protein product of which binds to the coding region of β-TrCP1 mRNA and stabilizes it. It was also demonstrated that X protein is essential for induction of mRNA of β-TrCP1 as well as c-myc by β-catenin/Tcf signaling in colon cancer cells. In human CRC, increased expression of X protein and β-TrCP coincides with activation of β-catenin and NF-κB in the same tumor, which is associated, with inhibition of apoptosis and tumor metastasis (unpublished data).\nWith regards to the canonical view that GSK3β is a negative regulator of Wnt signaling, one may consider that it functions like a tumor suppressor in CRC. Reportedly GSK3β has opposing roles ; removing a neoplastic trigger by phosphorylation-dependent degradation of β-catenin in the ubiquitin system, and maintaining cell survival and proliferation through the NF-κB pathway. Here we demonstrated an unrecognized role (tumor supportive properties) of GSK3β in CRC by transcriptionally and pharmacologically modulating its expression and activity, and warrant proposing this kinase as a potential therapeutic target in CRC^<14>.","subitem_description_type":"Abstract"},{"subitem_description":"近年のがん研究は様々な分子細胞現象を包含し,細胞内シグナル伝達など広範な生命現象の解明へと多様化している.Wntシグナルは個体発生と細胞・組織分化を司る基幹的情報伝達系であり,その制御機構の破綻は大腸発がん進展過程を促進する.このシグナル指令の実行分子が細胞接着因子として発見されたβ-cateninである.本研究において我々はまず,大腸癌の浸潤先進部におけるβ-cateninの活性化が発がんから浸潤・転移に至る経路をリンクし,がん病態,治療感受性や術後生存率に影響する重要ながん化シグナルであることを約300症例の解析から見出した.細胞内局在に依存するβ-cateninの細胞接着と情報伝達機能はユビキチンシステムにより制御されている.そこで我々は,β-cateninとIκBαを認識するE3ユビキチン連結酵素β-TrCPを同定し,その発現誘導はWnt/β-cateninシグナルに依存することを示した.このユビキチン経路の異常に起因して,大腸癌におけるβ-cateninとβ-TrCP発現のnegative feedback制御の破綻がWntシグナルとNF-κB経路をリンクして癌細胞のアポトーシスを抑制し,がんの浸潤や転移を促進することを明らかにした.つぎに,Wntシグナルによるβ-TrCPの発現誘導はそのmRNA安定化によることと,これに作用するβ-catenin/Tcf転写複合体の標的分子Xを同定した(投稿中).Xはc-mycやIGF-IIのmRNAを安定化する既知のRNAトランス因子であることから,大腸癌においてXが過剰発現する結果として複数の細胞生存・増殖シグナル(Wnt/β-catenin, NF-κB, c-Myc, IGF-II)を統御し,発がん・進展を加速するがん標的であることを想定し,今後の主要な研究対象として位置づけた.このように本研究を通じて,大腸癌の発生進展に関わるシグナル伝達系の新しい分子細胞メカニズムの解明に立脚するがん制御のための基盤成果を得た.","subitem_description_type":"Abstract"}]},"item_9_description_22":{"attribute_name":"内容記述","attribute_value_mlt":[{"subitem_description":"研究課題/領域番号:15390391, 研究期間(年度):2003-2005","subitem_description_type":"Other"},{"subitem_description":"出典：研究課題「大腸癌におけるがん化シグナルの特異的活性化・制御機構の個別的ならびに網羅的解析」課題番号15390391\n（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） \n（https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-15390391/153903912005kenkyu_seika_hokoku_gaiyo/）を加工して作成","subitem_description_type":"Other"}]},"item_9_description_5":{"attribute_name":"提供者所属","attribute_value_mlt":[{"subitem_description":"金沢大学がん進展制御研究所","subitem_description_type":"Other"}]},"item_9_identifier_registration":{"attribute_name":"ID登録","attribute_value_mlt":[{"subitem_identifier_reg_text":"10.24517/00057330","subitem_identifier_reg_type":"JaLC"}]},"item_9_relation_28":{"attribute_name":"関連URI","attribute_value_mlt":[{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/search/?qm=50239323"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/search/?qm=50239323","subitem_relation_type_select":"URI"}},{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390391/"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390391/","subitem_relation_type_select":"URI"}},{"subitem_relation_name":[{"subitem_relation_name_text":"https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-15390391/153903912005kenkyu_seika_hokoku_gaiyo/"}],"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-15390391/153903912005kenkyu_seika_hokoku_gaiyo/","subitem_relation_type_select":"URI"}}]},"item_9_version_type_25":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_ab4af688f83e57aa","subitem_version_type":"AM"}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2022-05-19"}],"displaytype":"detail","filename":"CA-PR-MINAMOTO-T-kaken 2007-3p.pdf","filesize":[{"value":"139.5 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"CA-PR-MINAMOTO-T-kaken 2007-3p.pdf","url":"https://kanazawa-u.repo.nii.ac.jp/record/51027/files/CA-PR-MINAMOTO-T-kaken 2007-3p.pdf"},"version_id":"d7d049a8-add2-4ddd-b623-15720ad09f17"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_title":"大腸癌におけるがん化シグナルの特異的活性化・制御機構の個別的ならびに網羅的解析","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"大腸癌におけるがん化シグナルの特異的活性化・制御機構の個別的ならびに網羅的解析"},{"subitem_title":"Activation and regulation of oncogenic signaling networks in colorectal cancer","subitem_title_language":"en"}]},"item_type_id":"9","owner":"18","path":["2828"],"pubdate":{"attribute_name":"公開日","attribute_value":"2022-05-19"},"publish_date":"2022-05-19","publish_status":"0","recid":"51027","relation_version_is_last":true,"title":["大腸癌におけるがん化シグナルの特異的活性化・制御機構の個別的ならびに網羅的解析"],"weko_creator_id":"18","weko_shared_id":-1},"updated":"2023-07-27T13:06:04.511263+00:00"}