雅努斯酶1对胰腺癌的发病和进展至关重要
Hridaya Shrestha1, Patrick D Rädler2, Rayane Dennaoui1
1Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
Cell reports
|May 11, 2024
概括
简氏氨酸激酶1 (JAK1) 缺乏通过阻断STAT3激活来防止KRAS驱动的胰腺瘤. 针对JAK1或其下游效应器C/EBPδ,可能提供新的胰腺癌治疗方法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 介素-6 (IL-6) 类细胞因子激活了Janus氨酸激酶 (JAK) /信号转换器和转录激活器 (STAT) 途径,促进胰腺管道腺癌 (PDAC) 的发展.
- 细胞内信号传导媒介在PDAC病变发生中的特定作用仍然不完全理解.
研究的目的:
- 研究JAK1在KRAS驱动的胰腺瘤形成中的作用.
- 在PDAC中识别JAK1信号的下游目标.
- 评估JAK1作为PDAC的潜在治疗点.
主要方法:
- 采用了一种结合体控制的,胰腺特异性淘汰小鼠模型.
- 评估了JAK1缺乏对KRASG12D诱导的瘤发育的影响.
- 研究了STAT3的激活状态,并确定了CCAAT/增强剂结合蛋白δ (C/EBPδ) 作为下游目标.
- 评估了C/EBPδ恢复在JAK1缺乏癌细胞和异种移植模型中的功能后果.
主要成果:
- 在小鼠中,JAK1缺乏完全阻止了KRASG12D诱导的胰腺瘤的形成.
- JAK1对于STAT3的构成性激活至关重要,这是PDAC的一个关键特征.
- 鉴定出CCAAT/增强剂结合蛋白δ (C/EBPδ) 是JAK1信号传导的关键下游媒介,在人类PDAC中被上调.
- 在JAK1缺陷模型中,恢复C/EBPδ表达拯救了瘤细胞在体外 (瘤球) 和体内 (异种移植) 的生长.
结论:
- 在PDAC发育中,JAK1在调解IL-6类细胞因子的瘤功能方面发挥着至关重要的作用,主要通过STAT3和C/EBPδ.
- C/EBPδ是PDAC中JAK1信号的关键下游效应因子.
- JAK1及其下游目标C/EBPδ代表了预防和治疗PDAC的有希望的分子标.
相关概念视频
The JAK-STAT Signaling Pathway
8.8K
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...
8.8K
PI3K/mTOR/AKT Signaling Pathway
3.5K
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...
3.5K
mTOR 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
MAPK Signaling Cascades
5.4K
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...
5.4K
Interactions Between Signaling Pathways
6.3K
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...
6.3K
cAMP-dependent Protein Kinase Pathways
6.3K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.3K


