SMAD4通过PI3K/Akt信号通路调节影响化学抗原受体-T细胞增殖的LCK表达
Rongxue Wan1,2,3, Bowen Fu3,4, Xiaokang Fu3
1Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Journal of cellular physiology
|January 7, 2025
概括
转录因子SMAD4调节LCK表达,通过PI3K/Akt通路影响CAR-T细胞的增殖. 了解这种机制是改善固体瘤中CAR-T细胞治疗的关键.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 癌症治疗 癌症治疗
背景情况:
- 在固体瘤中,CAR-T细胞的增殖是有限的.
- 管理CAR-T细胞增殖的监管机制仍然不完全理解.
研究的目的:
- 阐明调节CAR-T细胞增殖的分子机制.
- 确定参与CAR-T细胞扩张和功能的关键因素.
主要方法:
- 在T细胞中的重组CD19CAR表达.
- 过度表达和LCK和SMAD4的淘汰.
- 细胞周期分析和细胞亡试验.
- 对于PI3K/Akt路径激活的西部涂抹.
- 染色体免疫沉以评估SMAD4与LCK促进体的结合.
主要成果:
- 在CAR-T细胞中,CD19CAR表达增加了基底和LCK激活.
- LCK和SMAD4对于CAR-T细胞增殖至关重要,过度表达促进并抑制它.
- 抑制LCK或SMAD4导致细胞亡和细胞循环停止的增加.
- 过度表达LCK或SMAD4增强PI3K/Akt酸化,而抑制剂则阻断了这种效应.
- SMAD4直接与LCK促进体结合,调节其表达.
结论:
- SMAD4调节LCK表达,这反过来又通过PI3K/Akt信号通路影响CAR-T细胞的增殖.
- 这项研究揭示了CAR-T细胞扩张的新型调控轴,为提高CAR-T细胞在固体瘤中的疗效提供了潜在的治疗点.
更多相关视频
09:12Author Spotlight: Advancements in Hypoxia-Sensitive CAR-T Therapy for Enhanced Cancer Immunotherapy
Published on: June 14, 2024
797
11:32Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
6.7K
相关概念视频
PI3K/mTOR/AKT Signaling Pathway
3.4K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.4K
mTOR Signaling and Cancer Progression
3.7K
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...
3.7K
The JAK-STAT Signaling Pathway
8.7K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.7K
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
TGF - β Signaling Pathway
7.2K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K
Abnormal Proliferation
4.4K
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...
4.4K
