在对DNA损伤的反应中,PIDD调解NF-kappaB的激活
Sophie Janssens1, Antoine Tinel, Saskia Lippens
1Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Cell
|December 20, 2005
概括
蛋白质PIDD对于激活DNA损伤后NF-kappaB信号至关重要,促进细胞存活和化学抵抗. 这一发现揭示了可以针对改善癌症治疗的途径.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
背景情况:
- 核因子kappa B (NF-kappaB) 激活后遗传毒性压力有助于DNA修复和细胞存活,有助于癌症中的化学抵抗.
- 了解基因毒性压力诱导NF-kappaB激活的机制对于开发有效的癌症疗法至关重要.
- 此前,p53-inducible蛋白PIDD与DNA损伤后的caspase-2激活和亡有关.
研究的目的:
- 调查PIDD在DNA损伤诱导的NF-kappaB激活中的作用.
- 阐明PIDD影响NF-kappaB信号的分子机制,以应对基因毒性压力.
主要方法:
- 细胞模型中的基因毒性应激诱导.
- 同免疫沉测试用于识别蛋白质复合体.
- 西方斑点测试用于评估蛋白质的修饰 (sumoylation,ubiquitination).
- 通过RNA干扰 (siRNA) 来消耗特定的蛋白质 (PIDD,RIP1,caspase-2).
主要成果:
- 基因毒性压力诱导了PIDD-RIP1-NEMO复合物的形成.
- 通过增加NEMO合和无处不在,PIDD增强了NF-kappaB的激活.
- 缺少PIDD或RIP1,但不是caspase-2,可以防止DNA损伤引起的NEMO修饰和随后的NF-kappaB激活.
结论:
- 在DNA损伤诱导的NF-kappaB激活中,PIDD起到关键的调解作用.
- PIDD作为分子开关,在DNA损伤后平衡细胞生存和死亡途径.
- 准PIDD-RIP1-NEMO轴可能为克服癌症治疗中的化学抵抗提供新的策略.
相关概念视频
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.
Long-patch Base Excision Repair
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These 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...
NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
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...
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...


