p63とp73は,DNA損傷への反応としてp53-依存アポトーシスに必須です
Elsa R Flores1, Kenneth Y Tsai, Denise Crowley
1Massachusetts Institute of Technology, Department of Biology and Center for Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Nature
|April 5, 2002
まとめ
腫瘍抑制遺伝子p53は,DNA損傷反応に不可欠である. p63とp73の喪失は,機能的なp53であっても,DNA損傷によるアポトーシスを防ぐ.
科学分野:
- 分子生物学は分子生物学である.
- がん研究 がん研究
- 細胞生物学 細胞生物学
背景:
- 腫瘍抑制遺伝子p53は,DNA損傷に対する細胞の反応において重要な役割を果たし,ヒトのがんでは頻繁に変異を起こします.
- p53ファミリーメンバーであるp63およびp73は,構造的にはp53に類似しており,アポトーシスに関与しているが,腫瘍抑制との直接的な関連は不明である.
研究 の 目的:
- DNA損傷によるアポトーシスにおけるp63およびp73の役割を調べ,p53との構造的類似性とp53標的遺伝子をトランザクティベーションする能力を考えると.
- p63とp73がDNA損傷への反応としてアポトーシスに不可欠であるかどうかを判断する,特に機能的なp53.3の文脈で.
主な方法:
- p53ファミリーメンバーの1つまたは2つの組み合わせで欠けているマウス胚線維芽細胞を使用した.
- アデノウイルスE1Aの腫瘍遺伝子を用いて,アポトーシス誘導のための細胞を感知させ,生化学的分析を促進しました.
- アポトーシスがp53-依存であるインビトロ (E1Aシステム) およびインビボモデルの両方を用いてp63およびp73機能を試験した.
主要な成果:
- p63とp73の結合欠乏は,DNA損傷によるアポトーシスの失敗につながった.
- この失敗は,機能的なp53を有する細胞でも発生し,p53の直接的な機能を超えてp63とp73の重要な役割を果たしていることを示しています.
- DNA損傷後のアポトーシスの開始に p63 と p73 が不可欠であることを示した.
結論:
- p63とp73は,DNA損傷によるアポトーシスに不可欠である.
- p63とp73の両方の喪失は,p53の機能的状態に関係なく,DNA損傷に対する細胞防衛機構を損なう.
- これらの発見は,p53ファミリーがゲノムの完全性を維持し,がんの発症を予防する上で重要な協力的役割を果たしていることを明らかにしています.
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