USP8-EIF2S1信号增强了在TKI诱导的压力下CML细胞的存活率
Chethampadi Gopi Mohan1, Keechilat Pavithran2
1Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.
The FEBS journal
|December 26, 2025
概括
USP8二维基丁酶稳定了eIF2α,维持了未折叠的蛋白质反应 (UPR),并在慢性髓性白血病 (CML) 中调解了氨酸激酶抑制剂 (TKI) 耐药性. 针对这个USP8-eIF2α轴可以克服CML患者的TKI耐药性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 慢性髓性白血病 (CML) 是由BCR-ABL融合激酶驱动的.
- 对氨酸激酶抑制剂 (TKI) 的耐药性是CML治疗的主要临床障碍.
研究的目的:
- 确定CML中TKI耐药性背后的新机制.
- 研究USP8在TKI治疗下调解CML细胞存活中的作用.
主要方法:
- 这项研究使用了分子生物学技术来分析USP8在CML细胞中的功能.
- 研究了USP8,EIF2S1和未折叠蛋白质响应 (UPR) 途径之间的相互作用.
主要成果:
- USP8被确定为TKI抗性的关键调解者.
- USP8通过去除与K48结合的ubiquitin链,使EIF2S1 (eIF2α) 脱并稳定.
- 稳定EIF2S1维持PERK-EIF2S1介导的UPR信号,促进CML细胞的存活.
结论:
- 在TKI治疗期间,USP8-EIF2S1轴对CML细胞适应和生存至关重要.
- 准USP8-EIF2S1通路是一种潜在的治疗策略,可以克服CML中的TKI耐药性.
相关概念视频
mTOR Signaling and Cancer Progression
4.6K
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...
4.6K
Inhibition of Cdk Activity
5.5K
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...
5.5K
Mitogens and the Cell Cycle
7.7K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.7K
Abnormal Proliferation
5.0K
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...
5.0K
Targeted Cancer Therapies
8.6K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
8.6K
The Intrinsic Apoptotic Pathway
8.2K
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...
8.2K


