DNA損傷によって誘発されたp53のリン酸化は,MDM2による抑制を緩和する
1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Cell
|November 18, 1997
まとめ
DNA損傷は,セリン15でのリン酸化経由でp53の活性化を誘発し,MDM2.2との相互作用を減少させます. このリン酸化,特にDNA依存タンパク質キナーゼ (DNA-PK) によって,p53を強化する.
科学分野:
- 分子生物学は分子生物学である.
- セルラー・シグナリング
- がん研究 がん研究
背景:
- DNAを損傷する物質は,転写後のメカニズムを通して腫瘍抑制物質p53を活性化させます.
- p53とその負の調節体であるMDM2 (マウリン・ダブル・ミニート2) との相互作用は,p53の調節に極めて重要です.
- DNAの損傷とp53の活性化を結びつける正確な分子現象は,まだ完全に理解されていません.
研究 の 目的:
- DNA損傷がp53.3に信号を送るポストトランスクリプションメカニズムを解明する.
- MDM2.2との相互作用を調節するp53リン酸化の役割を調査する.
- p53依存トランザクティベーションに対するp53リン酸化の機能的影響を決定する.
主な方法:
- ウェスタン・ブロッティングは,p53リン酸化をセリン15で検出する.
- 同免疫プレシピテーションアッセイは,p53-MDM2の相互作用を in vitro および in vivo で評価するものです.
- 精製されたDNA依存タンパク質キナーゼ (DNA-PK) とp53.3を用いたインビトロキナーゼアッセイ.
- Reporterは,p53依存のトランザクションアクティビティを測定するためのアッセイである.
主要な成果:
- ヒトのp53のセルリン15でのリン酸化は,DNAの損傷後に起こります.
- セリン15でのリン酸化は,p53とMDM2.2の間のインビボおよびインビトロ相互作用を減少させます.
- DNA-PKによるp53のセルリン15と37でのリン酸化は,MDM2のp53トランザクティベーションを阻害する能力を損なう.
- これらの効果は,p53.3におけるフォスフォリレーション誘発による形状の変化に起因する.
結論:
- セリン15でのp53のリン酸化は,DNA損傷とp53の活性化を結びつける重要な転写後のイベントです.
- このリン酸化イベントは,p53-MDM2の相互作用を妨害し,p53.3のMDM2媒介抑制を緩和します.
- DNA-PKと潜在的に他のキナーゼはp53のリン酸化を媒介し,DNA損傷への反応としてp53誘導のためのメカニズムを提供します.
関連する概念動画
Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Nucleotide Excision Repair
Overview
DNA Damage can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Nucleotide Excision Repair
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
DNA Damage Can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...


