BCR-ABLによる血液形成変異のためのRASの代替信号

A Goga¹, J McLaughlin, D E Afar

¹Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.

Cell

|September 22, 1995

まとめ

BCR-ABLはオンコゲン系である.

科学分野:

腫瘍性シグナル伝達経路について
癌の発症の分子メカニズムについて

背景:

BCR-ABL腫瘍遺伝子は,活性化されたチロシンキナーゼ活性によって癌を誘発する.
SRCホモロジー2 (SH2) ドメインのような特定のドメインは,BCR-ABL機能にとって極めて重要です.

研究の目的:

細胞変換におけるBCR-ABLドメインとシグナル伝達経路の異なる役割を調査する.
BCR-ABLがRASを活性化して血液形成の変異を起こす仕組みを理解する.

主な方法:

サイト指向型変異により,主要なBCR-ABLドメイン (SH2,GRB2結合,自己リン酸化部位) を無効化する.
ティロシンキナーゼ活性,線維芽細胞変異,および血液形成細胞系成長因子の独立性を測定する.
骨髄細胞のインビトロ変異と悪性病の可能性のインビボ評価.
RASシグナル伝達を研究するために,SHCアダプタータンパク質レベルを操作する.

主要な成果:

SH2ドメイン,GRB2結合部位,またはキナーゼ自己リン酸化部位の突然変異は下流シグナル伝達を損なうが,キナーゼ活性には影響を及ぼさない.
線維芽細胞の変換が失われても,変異体は血液形成の変換能力を保持していた.
SH2ドメインは,in vivo悪性潜在性において重要なことが証明されました.
SHCアダプタータンパク質の投与量は,BCR-ABL変換効率に大きな影響を及ぼし,代替RAS経路を強調しました.

結論:

BCR-ABLは,RASへの複数の並列経路を利用して,血液形成の変換を行う.
SH2ドメインは,BCR-ABL.の in vivo 腫瘍性活性において重要な役割を果たします.
特定のBCR-ABLシグナリングノードをターゲットにすることは,潜在的な治療戦略を提供します.

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