通过SIRT6/Nrf2依赖的抗氧化反应,PKCδ调节DNA损伤和细胞死亡
Trisiani Affandi1, Angela M Ohm2, Jordan T Speidel1
1University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
Molecular cancer research : MCR
|May 13, 2025
概括
削弱蛋白激酶C三角酶 (PKCδ) 增强了身体的天然抗氧化防御,减少了DNA损伤和细胞死亡. 这表明了在放射治疗期间保护健康组织的新方法.
科学领域:
- 细胞生物学 细胞生物学
- 辐射瘤学 辐射瘤学
- 生物化学 生化学
背景情况:
- 蛋白激酶C三角酶 (PKCδ) 在DNA修复和亡中起作用.
- 抑制PKCδ在提供辐射保护方面表现有前途.
- 了解PKCδ介导辐射保护背后的机制对于临床应用至关重要.
研究的目的:
- 研究PKCδ枯竭在线粒体活性氧物种 (ROS) 生产和随后的抗氧化反应中的作用.
- 阐明参与PKCδ调节的细胞对辐射反应的信号通路,包括Nrf2和Sirtuin 6 (SIRT6).
- 探索针对PKCδ/SIRT6通路进行辐射保护的潜力.
主要方法:
- 使用淘汰技术减少PKCδ.
- 测量线粒体ROS的产生,DNA损伤和细胞死亡.
- 评估抗氧化剂反应途径,包括Nrf2激活.
- 分析电子运输链 (ETC) 复杂活动和线粒体功能.
- 使用PKCδ/SIRT6双击细胞和N-乙-L-氨酸治疗进行实验验验证.
主要成果:
- 减少PKCδ会增加线粒体ROS的产生,并通过Nrf2激活内源抗氧化反应.
- 这导致基底和辐射诱导的DNA损伤和细胞死亡的减少.
- 辐射保护依赖于抗氧化剂反应,可以通过自由基清除剂逆转.
- 特定于复杂I和复杂III的ETC功能障碍被确定为线粒体ROS增加的来源.
- 通过SIRT6调节PKCδ调节的抗氧化反应,双重倒退扭转了观察到的效应.
结论:
- PKCδ的枯竭会触发内源性抗氧化反应,提供显著的辐射保护.
- PKCδ/SIRT6信号通路是调节DNA修复和细胞死亡的核心.
- 准这种途径为在放射治疗期间保护健康组织提供了一种新的策略.
相关概念视频
DNA Damage can Stall the Cell Cycle
9.0K
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...
9.0K
Nucleotide Excision Repair
3.4K
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...
3.4K
Regulation of the Unfolded Protein Response
2.3K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.3K
Inhibition of Cdk Activity
4.6K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K
Overview of DNA Repair
29.4K
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...
29.4K
Negative Regulator Molecules
35.0K
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.
35.0K


