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細胞老化誘導のマスター制御遺伝子Pointedの同定とそれによるがん制御機構の解明

井藤, 喬夫 京都大学 DOI:10.14989/doctor.r13431

2021.07.26

概要

細胞老化は細胞周期の不可逆的な停止を引き起こす現象であり、多細胞生物がもつがん抑制機構の1つと考えられている。例えば、細胞内でがん遺伝子Rasが活性化すると、細胞増殖シグナルが活性化する一方で、細胞老化が誘導されて細胞周期停止が誘導され、一見、相反するシグナルが活性化する。したがって、Rasを活性化した腫瘍が進展し悪性化するには、細胞老化を回避する必要があると考えられる。

しかし、Ras活性化細胞がどのようなメカニズムで細胞老化を克服するかについては、依然として不明な点が多い。本研究で申請者は、ショウジョウバエをモデル生物として用い、がん進展の要因の1つとして知られる上皮細胞極性の崩壊によってRas誘導性の細胞老化が阻害され、これによりRas活性化腫瘍の悪性化が引き起こされることを見いだした。まず申請者は、ショウジョウバエ上皮組織に誘導した活性化Ras(RasV12)発現細胞クローン(Ras活性化腫瘍)の増殖を促進する遺伝子変異の遺伝学的スクリーニングを行った。その結果、ETS転写因子Pointed(ETS1/2ホモログ分子)の機能欠失変異によりRas活性化腫瘍の増殖が強く促進されることを見いだした。

さらに、活性化Rasによって発現誘導されるPointedの発現を抑制すると、Ras活性化腫瘍の細胞老化誘導が阻害されることで腫瘍増殖が顕著に亢進することがわかった。一方、活性化Rasがない状態でPointedを単独で強制発現させた細胞クローンでは細胞老化が誘導された。つまり、PointedはRasシグナルの活性化によって起こる細胞老化誘導に必要十分な下流因子であることがわかった。ショウジョウバエ上皮において、Rasを活性化した細胞クローンにapico-basal極性遺伝子の機能欠失変異を同時に導入すると大過剰に増殖し、浸潤・転移能をもつ悪性腫瘍へと進展することが知られていたが、申請者は、このような極性が崩壊したRas活性化腫瘍内においてもPointedの発現が阻害されていることを見いだした。さらなる遺伝学的解析により、極性が崩壊したRas活性化腫瘍内では転写共役因子Yorkie(がん抑制経路Hippo経路の下流標的因子YAPのホモログ分子)の働きによってPointedの発現が抑制され、これにより細胞老化が阻害されることを見いだした。さらにそのメカニズムとして、活性化したYorkieにより発現誘導されるmicroRNA bantamがE3 ligase会合タンパク質TribblesのmRNAを標的にしてその発現を抑制し、その結果Tribblesにより発現抑制されている転写因子FoxOの発現が上昇することを見いだした。このFoxOがpointed mRNAを標的とするmicroRNA であるmiR-9cおよびmiR-79の発現を誘導し、その結果Pointedの発現が抑制されることがわかった。

本研究成果は、Ras活性化腫瘍がいかにして細胞老化を克服し、悪性腫瘍へと進展していくのかを説明する新たなメカニズムを提示するものである。本メカニズムに関わる因子群の進化的保存性の高さから、本研究成果が新たながん治療戦略の基盤構築につながることが期待されると考察している。

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