DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation

• Material Type: 博士論文
• Title: DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation
• Author/Editor: 冨野, 高広
• Author Heading: 冨野, 高広
• Publication Date: 2018-09-25
• Publication Date (W3CDTF): 2018-09-25
• Alternative Title: 恒常活性型Rac1P29S変異により誘導される癌細胞の浸潤応答およびマクロピノサイトーシスはDOCK1阻害により抑制される
• Contributor: 小田, 義直; 古江, 増隆; 伊藤, 隆司
• Degree grantor/type: 九州大学
• Date Granted: 2018-09-25
• Date Granted (W3CDTF): 2018-09-25
• Dissertation Number: 甲第14184号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第14184号
• Text Language Code: eng
• Target Audience: 一般
• Note (General): Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1P29S, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1P29S. Enforced expression of Rac1P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.; PubMed番号 : 29432733
• DOI: info:doi/10.1016/j.bbrc.2018.02.073; https://doi.org/info:doi/10.1016/j.bbrc.2018.02.073
• Persistent ID (NDL): info:ndljp/pid/11194624; https://dl.ndl.go.jp/pid/11194624
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2018-12-03T16:15:19+09:00
• Date Created (W3CDTF): 2018-11-05
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): http://hdl.handle.net/2324/1959087
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp

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