Bcl-xL脱アミデーションは,DNA損傷に対する応答の調節における重要なスイッチです
Benjamin E Deverman1, Brian L Cook, Scott R Manson
1Division of Urology, Department of Cell Biology and Physiology, School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63110, USA.
Cell
|October 10, 2002
まとめ
DNAを損傷するがん薬は,正常な細胞ではなく,腫瘍細胞のBcl-xLをデアミダートすることによってアポトーシスを引き起こす. このデアミデーションにより,腫瘍細胞はアポトーシスに敏感になり,がん治療における重要なメカニズムを強調しています.
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:
- DNAにダメージを与える抗腫瘍剤の治療効果は,選択的腫瘍細胞アポトーシスに依存しています.
- 異なるアポトーシス誘導のメカニズムを理解することは,がん治療において極めて重要です.
研究 の 目的:
- DNAを損傷する物質に対する差異的なアポプトシス反応におけるBcl-xLデアミデーションの役割を調査する.
- Bcl-xLデアミデーションがアポトーシスの感受性に影響するメカニズムを解明する.
主な方法:
- 様々な腫瘍細胞系および線維芽細胞におけるBcl-xLデアミデーションの分析.
- DNA損傷後のアポトーシス誘導の評価.
- Bcl-xLとBH3ドメインのみのタンパク質の相互作用の調査.
主要な成果:
- Bcl-xLの非構造的なループにおける2つのアスパラジンのデアミデーションは,腫瘍細胞における主要なアポプトシス反応として特定されました.
- Bcl-xLデアミデーションは,その機能を破壊し,プロアポプトティックBH3タンパク質の抑制を損なうことでアポトーシスの感受性を高めます.
- 繊維芽細胞はBcl-xLのデアミデーションを積極的に抑制し,DNA損傷によるアポトーシスに対する耐性を高めます.
結論:
- Bcl-xLデアミデーションの調節は,DNAを損傷する抗ネオプラスティック剤の腫瘍特異的な効果にとって非常に重要です.
- Bcl-xLデアミデーション経路をターゲットにすることで,がん治療の改善のための新しい戦略を提供することができます.
関連する概念動画
02:25Overview of DNA Repair
In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Chemically...
01:54Base Excision Repair
One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
The first step of...
02:04Fixing Double-strand Breaks
The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
02:36DNA 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...
01:31The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
02:36DNA 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...