活性化ドメインが欠けているJun転写因子の変換抑制活性

A Lloyd¹, N Yancheva, B Wasylyk

¹LGME-CNRS, U184-INSERM, Institut de Chimie Biologique, Faculté de Medecine, Strasbourg, France.

Nature

|August 15, 1991

まとめ

オンコタンパク質c-Junは,Ras媒介の細胞変容に不可欠である. 支配的な陰性Jun変異体はRas変換を阻害し,正常な細胞成長を回復させ,抗腫瘍遺伝子として作用する.

科学分野:

腫瘍学腫瘍学
分子生物学は分子生物学である.
細胞の変容細胞の変容

背景:

オンコタンパク質c-Junは,Ras媒介の細胞変換に関与しています.
c-Jun合成と転写因子の活性の両方が Ras.によって上調されます.
c-JunとRasは変換アッセイで協力し,異なるが相互作用する経路を示唆しています.

研究の目的:

Ras媒介細胞変異のために,潜在的に相互作用する因子を持つc-Junの必要性を調査する.
主要負のジュン変異体が転写と細胞変異に及ぼす影響を特徴付けるため.
抗腫瘍遺伝子としてのジュン変異体の可能性を調査する.

主な方法:

活性化ドメインを欠いた支配的陰性変異転写因子 (Jun変異) を利用した.
様々なオンコタンパク質と腫瘍プロモーター (TPA) による転写刺激の抑制を評価した.
Jun結合モチーフに対する抑制の特異性を検討し,NF-kappa B/Relモチーフの活性化と対比した.
ラス型変異細胞におけるジュン変異体の抗腫瘍性活性を評価し,成長特性と腫瘍発生性を評価した.

主要な成果:

主要負のジュン変異体は,特にRasや他のオンコタンパク質によって媒介される転写刺激をブロックする.
抑制はJun結合モチーフに特異的であり,NF-kappa B/Relの活性化は影響を受けません.
Jun変異体は,Ras変異細胞における抗腫瘍遺伝子として機能し,非変異型フェノタイプへの逆転を誘発する.
リバータント細胞は,回復した固定と密度依存の成長を示し,in vivo腫瘍発生性が低下しています.

結論:

c-Junは,潜在的に相互作用するパートナーと,Ras媒介の細胞変換に必要である.
支配的陰性Jun変異体は,抗腫瘍遺伝子として機能し,腫瘍性現象型を逆転させることができます.
このアプローチは,信号伝導と変換における転写因子の役割を研究するための方法を提供します.

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