在白血病中,依赖架构的CASP1抑制了细胞内在过度的炎症信号传递
Emma E Uible1, Issac Choi1, Courtnee A Clough2
1Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
Cell chemical biology
|January 7, 2026
概括
卡斯巴酶-1 (CASP1) 损失会损害白血病的生长,并通过支架mTORC1-NF-κB信号传递而不是蛋白酶活动来减少瘤负担. 这显示出CASP1.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 免疫学 免疫学 免疫学
背景情况:
- 卡斯帕-1 (CASP1) 主要用于介质蛋白-1β (IL-1β) 处理和热.
- 在本研究之前,CASP1在白血病病原发生中的特定作用在很大程度上仍未被定义.
研究的目的:
- 为了阐明Caspase-1 (CASP1) 在白血病中的功能.
- 研究CASP1在白血病细胞中的作用背后的分子机制.
- 探索CASP1作为白血病中潜在的治疗点.
主要方法:
- 在白血病模型中利用了CASP1的遗传删除和其CARD域的破坏.
- 研究了对白血病细胞生长,分化和体内瘤负担的影响.
- 开发并测试了针对Pro-CASP1.1的蛋白质分解向化马体 (PROTAC) 降解剂.
主要成果:
- 失去CASP1会影响白血病细胞生长,促进分化,并减少白血病负担.
- 独立于蛋白酶活动的CASP1的支架功能对其影响至关重要.
- CASP1与RPTOR (mTORC1组件) 相互作用,调节激活B细胞 (NF-κB) 信号的核因子卡帕-光链增强器.
结论:
- 酶-1 (CASP1) 作为一个关键的支架枢纽,调节白血病中的mTORC1-NF-κB信号传递.
- CASP1的支架活动,而不是它的酶功能,是它在白血病中的关键作用.
- 准CASP1,特别是其支架功能,代表了白血病治疗中的新型治疗脆弱性.
相关概念视频
01:31The Intrinsic Apoptotic Pathway
8.3K
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...
8.3K
01:24Caspases
13.7K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
13.7K
01:07MAPK Signaling Cascades
7.9K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.9K
01:19Interactions Between Signaling Pathways
7.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.2K
01:20The JAK-STAT Signaling Pathway
11.9K
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...
11.9K
01:17The Extrinsic Apoptotic Pathway
8.0K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
8.0K