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KAKEN_24590091seika.pdf
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Title |
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JAK/STATシグナル伝達における残された課題への挑戦と創薬への試み
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Kana |
JAK/STAT シグナル デンタツ ニ オケル ノコサレタ カダイ エノ チョウセン ト ソウヤク エノ ココロミ
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JAK/STAT shigunaru dentatsu ni okeru nokosareta kadai eno chosen to soyaku eno kokoromi
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Investigation of JAK/STAT signalling and development of new reagents regulating JAK/STAT pathways
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笠原, 忠
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カサハラ, タダシ
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Kasahara, Tadashi
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慶應義塾大学・薬学部・名誉教授
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Research team head
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科研費研究者番号 : 60049096
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多胡, めぐみ
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タゴ, メグミ
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Tago, Megumi
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慶應義塾大学・薬学部・准教授
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Research team member
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科研費研究者番号 : 30445192
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2015
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科学研究費補助金研究成果報告書
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2014
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Abstract |
骨髄増殖性腫瘍(MPN)患者ではJAK2のJH2領域V617F変異がみられるが, その異常増殖や腫瘍形成に至る機序を解析した。(1) JAK2V617変異体発現細胞において, c-Mycを介したODCの活性化やAurkaの活性化, ならびにFANCCの活性化を見いだした。ODCの阻害剤はin vivoでの腫瘍形成を抑制した。(2) 変異体細胞はCDDPのような抗がん剤抵抗性がみられたが, ファンコニ因子FANCCの活性化がその理由と考えられた。(3) フラーレン誘導体変異体細胞の増殖と造腫瘍性が抑制されることを明らかにし, MPN治療薬となる可能性を示した。
JAK2/STAT pathway is involved in many cytokine signaling of which mechanism still requires precise investigation. JAK2 V617F mutation is observed in majority of patients with myeloproliferative neoplasms (MPNs). We investigated how JAK2V617F mutation induces dysregulated proliferation and tumorigenesis. JAK2 V617F mutation induced significant c-Myc mRNA expression mediated by STAT5 activation, which induced subsequent ornithine decarboxylase (ODC). An ODC inhibitor prevented proliferation of JAK2V617F cells. Further, JAK2V617F exhibited resistance to anti-cancer drugs such as CDDP. We found that FANCC, a member of the Fanconi anemia (FA) proteins, is responsible to the resistance against the drug-induced DNA damage. In addition, pyrrolidinium fullerene markedly induced apoptosis of JAK2 V617F cells. These observations indicated that fullerene derivatives are suitable candidates inhibiting the JAK2 V617F-mediated proliferation and tumorigenesis.
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研究種目 : 基盤研究(C)
研究期間 : 2012~2014
課題番号 : 24590091
研究分野 : 免疫学, 生化学
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