BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
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IF 3.5
Lu Liu,Zhendong Song,Guangjin Fan,Linlin Lou,Yuanxiang Wang,Xiaolei Zhang,Xiao-Feng Xiong
KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC 50 = 1.53 μM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.
研究领域:
肿瘤学
·
分子生物学
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药物化学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2024
·
IF 3.8
Ying Zhang,Jing Xie,Huimin Zhang,Jiacheng Li,Xing Mi,Xuyi Zhou,Zhenhua Ding
Introduction Local exposure to ionizing radiation (IR) can induce changes in biological processes in distant tissues and organs. Exosomes are nanoscale vesicles that transport biomolecules, mediate communication between cells and tissues, and can affect the abscopal effects of radiotherapy. Methods Mice were treated with 8.0 Gy doses of chest and abdomen IR, after which serum samples were taken 24 h after exposure. Their serum exosomes were then isolated via ultracentrifugation and the small RNA portions were extracted for sequencing and bioinformatic analysis. Exosomes were injected intravenously into the mice to assess their ability to cross the blood-brain barrier (BBB). Glioma cells and gliomal stem cells (GSCs) were examined for malignant biological behaviors, stemness, and tumorigenic capacity after co-culturing with different types of exosomes. Results We found that serum exosomes crossed the BBB in mice after local IR exposure—which induced decreases in the expression of BBB tight-junction proteins and increased brain endothelial cell apoptosis. Exosomes from the exposed groups promoted malignant biological behaviors, stemness, and tumorigenic capacity in glioma cells and GSCs by upregulating the expression of SOS1. Phospho-MEK1/2 and Phospho-ERK1/2, of the MAPK signaling pathway, were found to be up-regulated in cells that were co-cultured with the exposing groups of the exosomes. Further analyses demonstrated that differentially expressed levels of miR-93-5p in mouse serum exosomes regulated the cellular expression of SOS1. Conclusion Following local IR exposure, serum exosomes cross the BBB to promote the progression of distant gliomas. Exosomal microRNAs play an important role in this process.
研究领域:
肿瘤学
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分子生物学
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放射生物学
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产品关联
DOI
PubMed
高影响因子
PLANT PHYSIOLOGY
·
2024
·Vol. 197
·期 1
·
IF 6.5
Song Ru-Feng,Liao Cai-Yi,Wang Lin-Feng,Lu Kai-Kai,Zhang Chi,Wu Run-Xin,Wu Ji-Xiao,Ma Yu-Qing,Kuang Lei,Guo Ning,Yuan Hong-Mei,Liu Wen-Cheng
The plasma membrane (PM)-localized Na+/H+ antiporter Salt Overly Sensitive1 (SOS1) is essential for plant salt tolerance through facilitating Na+ efflux; however, how SOS1 localization and protein accumulation is regulated in plants remains elusive. Here, we report that Sorting Nexin 1 (SNX1) is required for plant salt-stress tolerance through affecting endosomal trafficking of SOS1 in Arabidopsis (Arabidopsis thaliana). Disruption of SNX1 caused salt hypersensitivity with increased Na+ accumulation and decreased Na+ efflux in Arabidopsis when challenged with high salinity stress. SNX1 co-localized and interacted with SOS1 in endosomes, promoting its PM localization and protein stability in plants under saline conditions. SOS1 overexpression promoted salt tolerance in the wild-type, whereas such effect was greatly compromised in the snx1-2 mutant. Pharmaceutical results showed that SOS1 recycling from the cytosol to the PM was largely blocked while its vacuolar degradation was accelerated in the snx1-2 mutant. Furthermore, salt-induced SOS1 phosphorylation enhanced its interaction and co-localization with SNX1, which is required for SOS1 PM localization in plants. Our study elucidates that SNX1 facilitates SOS1 PM localization and protein accumulation through endosomal trafficking, thereby enhancing salt tolerance in plants.
研究领域:
植物学
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分子生物学
✓ 已验证
DOI
高影响因子
DEVELOPMENTAL CELL
·
2025
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IF 8.7
Kai-Kai Lu,Hong Yang,Cai-Yi Liao,Ru-Feng Song,Xiao-Yu Hu,Feng Ren,Wen-Cheng Liu
Salt stress impacts plant growth and development, threatening agricultural production. The Na + /H + antiporter SALT OVERLY SENSITIVE 1 (SOS1) functions in cellular ion homeostasis through facilitating Na + excretion and is therefore essential for plant salt tolerance. Here, we report that the transcription factors AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 are required for salt-induced SOS1 expression and salt tolerance in Arabidopsis thaliana . ARF7 and ARF19 activate SOS1 transcription by binding to SOS1 coding region rather than its promoter. Additionally, an E3 ubiquitin ligase, CHY ZINC-FINGER AND RING PROTEIN 1 (CHYR1), interacts with and degrades ARF7 and ARF19, dampening SOS1 expression. Upon high salinity, CHYR1 expression is inhibited in plants, stabilizing ARF7 and ARF19 proteins and increasing SOS1 expression. Collectively, our study identifies a transcriptional cis -element within SOS1 coding region recognized by ARF7 and ARF19 and elucidates a molecular mechanism governing ARF7 and ARF19 protein stability and SOS1 expression during plant salt stress response.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Rice Science
·
2026
·
IF 7.4
Liu Yan,Zhang Yuhan,Bai Yijie,Li Shan,Wang Songyuan,Yao Yuanyuan,Yang Yuechao
Fulvic acid (FA) has been widely used as a plant growth regulator to alleviate salt stress. However, the mechanism by which it enhances salt tolerance in rice remains unclear. This study systematically investigated the chemical structure of FA and its role in enhancing rice salt tolerance through the regulation of plasma membrane (PM) H + -ATPase. The results demonstrated that the increased molecular weight (MW) of FA companied by progressive aromaticity enhancement and functional group depletion. Principal component analysis revealed that low-MW FA fractions (< 3 kDa), enriched in carboxylic-C, phenolic-C, and lignin-like substances, exhibited a strong positive correlation with root growth, membrane potential (MP) hyperpolarization, and Na + efflux under 100 mmol/L NaCl stress. Mechanistically, FA directly activated PM H + -ATPase (activity increased by 30.3%‒86.2%), generating a proton gradient that energized SOS1 to mediate Na + efflux, leading to salt tolerance in rice. Genetic validation using osa1 knockout mutants confirmed the indispensable role of PM H + -ATPase in FA-induced responses, as both MP and Na + efflux remained unaltered upon FA1‒FA5 treatment. This research found that FA fractions with high functional group density and low aromaticity can serve as optimal plant biostimulants for salt stress mitigation, providing a new strategy for sustainable lignite valorization in precision agriculture.
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DOI
高影响因子
危险品化学品经营许可证（带存储）