瘤抑制剂TPD52-受控制的内质网膜应激受APCCdc20调节
Weichao Dan1,2,3, Yizeng Fan1,2,3, Yuzhao Wang1,2,3
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|October 14, 2024
概括
瘤蛋白D52 (TPD52) 通过整合内质网膜 (ER) 应激和展开蛋白质响应 (UPR) 信号,作为一种新的瘤抑制剂. 它被Cdc20 E3酶降解会促进癌症,这表明TPD52是治疗标.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 细胞应激反应的应激反应
背景情况:
- 异常的内等质网膜 (ER) 应激和展开的蛋白质响应 (UPR) 信号与癌症进展有关.
- UPR传感器ATF6是一种潜在的癌症生物标志物,但其在致癌过程中的直接作用尚不清楚.
- 瘤蛋白D52 (TPD52) 被视为瘤基因,但其在ER压力路径中的确切功能尚不清楚.
研究的目的:
- 研究TPD52在整合ER压力和UPR信号中的作用.
- 为了确定TPD52,ATF6和致癌之间的关系.
- 确定TPD52的上游调节者及其对癌细胞对ER压力诱导因子敏感性的影响.
主要方法:
- 研究了TPD52与ER压力和UPR组件的相互作用,包括ATF6裂变.
- 在膀癌模型中评估TPD52作为瘤抑制剂的功能.
- 确定了APCCdc20 E3酶作为TPD52蛋白解的上游调节器.
- 评估了Cdc20失活对癌细胞对ER压力诱导物的反应的影响.
主要成果:
- TPD52促进了ATF6的S2P介导裂变,整合了ER压力和UPR信号.
- 在膀癌中,TPD52作为一种新型瘤抑制剂,其减少可促进某些癌症的瘤发生.
- 在APCCdc20的目标是TPD52的多基化和蛋白质分解.
- 失活Cdc20以TPD52依赖的方式增强癌细胞对ER压力诱导物的敏感性.
结论:
- 通过调节ER压力和UPR信号,TPD52作为一种新型瘤抑制剂.
- TPD52是APCCdc20E3结合酶的基质,将蛋白质分解与ER压力调节联系起来.
- 针对TPD52-Cdc20轴可能为表现出ER压力失调的癌症提供治疗策略.
相关概念视频
00:50Anaphase Promoting Complex
2.8K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.8K
02:23Abnormal Proliferation
4.5K
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...
4.5K
03:03mTOR Signaling and Cancer Progression
3.8K
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...
3.8K
01:37The Unfolded Protein Response
4.4K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.4K
01:17Role of ER in the Secretory Pathway
5.3K
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
5.3K
01:31Regulation of the Unfolded Protein Response
2.4K
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...
2.4K