DYRK2 和 USP28 之间的新反循环调节癌症平衡和DNA损伤信号
Lucía Suanes-Cobos1,2,3, Irene Aguilera-Ventura1,2,3, Miguel Torres-Ramos1,2,3
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
Cell death and differentiation
|August 26, 2025
概括
双特异性氨酸酸化调节激酶2 (DYRK2) 和泛特异性酶28 (USP28) 具有新的反循环. 这种相互作用调节了蛋白质的稳定性,DNA损伤反应和癌细胞死亡.
科学领域:
- 细胞生物学
- 分子瘤学
- 生物化学
背景情况:
- 在细胞应激过程中,随处可见和化等转化后修饰是蛋白质稳定的关键.
- DYRK2和USP28对于细胞周期,DNA损伤反应和瘤信号传递至关重要.
- DYRK2和USP28之间的功能关系尚不清楚.
研究的目的:
- 阐明DYRK2和USP28之间的新双向监管机制.
- 调查这种相互作用如何整合DNA损伤反应和泛胺介导的蛋白质降解.
- 探索癌细胞死亡和基因组稳定性的影响.
主要方法:
- 研究了DYRK2对USP28的酸化及其对USP28无处不在和降解的影响.
- 研究了USP28对DYRK2的二基因酶活性及其对DYRK2稳定性和激酶活性的影响.
- 使用了共同定位和相互作用研究,重点是DYRK2 521-541区域和T525残留物.
- 评估了对p53信号和对DNA损伤的亡反应的影响.
主要成果:
- DYRK2 化USP28, 促进其无处不在和降解, 独立于激酶活性, 保持致癌蛋白质平衡.
- 稳定DYRK2并增强其激酶活性.
- DYRK2和USP28相互作用和同定位,而DYRK2 521-541区域 (T525) 对于USP28介导的稳定至关重要.
- 这种相互调节会影响p53的信号传递;USP28的耗尽会减少DYRK2介导的p53酸化,从而损害apoptosis.
结论:
- 一个新的反循环存在,DYRK2和USP28相互调节.
- 这种相互作用控制了原蛋白平衡和DNA损伤信号.
- 这些发现表明向异常无处不在和基因组不稳定的癌症的治疗潜力.
相关概念视频
DNA Damage can Stall the Cell Cycle
9.3K
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...
9.3K
Regulation of the Unfolded Protein Response
2.6K
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...
2.6K
Abnormal Proliferation
4.6K
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...
4.6K
Negative Regulator Molecules
35.9K
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.
35.9K
mTOR Signaling and Cancer Progression
3.9K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.9K
Nucleotide Excision Repair
3.8K
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...
3.8K


