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SMYD3は,MAP3K2のライシンメチル化とRas誘発がんを関連付けている

Pawel K Mazur¹, Nicolas Reynoird², Purvesh Khatri³

¹1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3].

|May 23, 2014

まとめ

SMYD3 (タンパク質3を含むSETおよびMYNDドメイン) によるライシンメチル化は,MAPキナーゼシグナル伝達を活性化することによって,Ras駆動がんを促進します. SMYD3の触媒活性を阻害すると,腫瘍の発達が止まり,潜在的な治療戦略が提供されます.

科学分野:

バイオケミストリーバイオケミストリー
分子生物学は分子生物学である.
がん研究がん研究

背景:

リジンメチル化の緩和は,がんの重要な要因です.
ヒストンリジンメチルトランスファーゼ (KMT) 阻害剤は,化学療法薬として開発されています.
細胞質KMT SMYD3は,多くのヒト腫瘍で過剰発現しているが,がんにおける役割は不明である.

研究の目的:

癌経路におけるSMYD3の分子メカニズムを解明する.
腫瘍形成におけるSMYD3の役割を研究する. in vivo.
SMYD3の標的を特定し,がんシグナル伝達の規制を理解する.

主な方法:

臓および肺腺癌のマウスモデルを使用した.
SMYD3の標的を特定するために,タンパク質配列技術を使用した.
MAP3K2のSMYD3媒介メチル化とその信号伝達経路への影響について調査した.

主要な成果:

SMYD3はMAP3K2をメチレートし,MAPキナーゼシグナル伝達を強化し,Ras誘発性がんを促進する.
SMYD3の触媒活性を取り除くと,マウスモデルでの腫瘍発育が抑制されました.
SMYD3の枯渇は,MEK阻害剤と連携して,Ras主導の腫瘍形成を阻害する.
SMYD3によるMAP3K2のメチル化は,PP2Aフォスファタゼ複合体との相互作用を阻害する.

結論:

SMYD3は,ライシンメチル化による腫瘍性Rasシグナリングの調節に中心的な役割を果たしています.
この研究では,サイトプラズマキナーゼシグナルカスケードを統合する際にライシンメチル化の新たな役割が明らかになりました.
SMYD3は,Ras駆動がんの潜在的な治療標的である.

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