ニュー腫瘍遺伝子の点変異は,受容体集約のリガンド誘導を模倣する

D B Weiner¹, J Liu, J A Cohen

¹Department of Pathology, University of Pennsylvania, Philadelphia 19104-6082.

Nature

|May 18, 1989

まとめ

発がん性ニュー遺伝子産物であるp185neuは,その非発がん性同位体であるp185c-neu.とは異なり,細胞膜で集積を形成する. この結合はチロシンキナーゼの活性を増大させ,細胞の変容を促します.

科学分野:

分子生物学は分子生物学である.
腫瘍学腫瘍学
細胞シグナリング細胞シグナリング

背景:

ネズミのノイ遺伝子は,表皮成長因子受容体に似たタンパク質をコードし,プロトオンコゲンとして機能します.
ポイント突然変異は,neu遺伝子を腫瘍遺伝子に変換し,腫瘍性タンパク質 (p185neu) の生成につながり,その正常な同位体 (p185c-neu) は腫瘍性ではない.
両方のタンパク質は,細胞外システインに富んだドメイン,トランスメブラン領域,細胞内チロシンキナーゼ領域を含むチロシンキナーゼ成長因子受容体と構造的特徴を共有しています.

研究の目的:

腫瘍誘発性p185neuと腫瘍誘発性でないp185c-neuタンパク質の構造と機能の違いを調査する.
変異したニュー遺伝子産物 (p185neu) が腫瘍発生性であり,正常産物 (p185c-neu) は腫瘍発生性ではない理由を理解する.
p185neu.の腫瘍性活性におけるタンパク質集積の役割を調査する.

主な方法:

ニュー遺伝子製品,p185neuとp185c-neuの比較分析.
p185neuのトランスメブラン領域におけるアミノ酸置換 (位置664のバリンからグルタミン酸) の調査.
プラズマ膜におけるp185neuとp185c-neuの結合状態 (集積) の評価.

主要な成果:

腫瘍性タンパク質であるp185neuは,p185c-neuと異なっており,p185c-neuは,トランスメブラン領域における単一のアミノ酸置換 (バリンからグルタミン酸) によって異なっている.
この置換は,p185neuの固有のチロシンキナーゼ活性を増強し,細胞変換と相関しています.
p185neuは,主にプラズマ膜で集積された形で組織されているが,p185c-neuはそうではない.

結論:

プラズマ膜でのp185neuの集積は,その腫瘍発生の可能性の重要な要因である.
この集約は,リガンド誘発の受容体集約を模倣し,持続的な酵素活性化と細胞変換につながる可能性があります.
p185neuの集積状態をターゲットにすることは,neu腫瘍遺伝子が誘導する癌の治療戦略である可能性があります.

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