LABORATORY INVESTIGATION
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2023
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IF 5
Wei Zhao,Jing Zhao,Kun Li,Yanjiao Hu,Dongxia Yang,Bin Tan,Jian Shi
Nuclear factor of activated T cells 2 (NFATC2) is reported to contribute to the initiation and progression of various cancers; however, its expression and function in cholangiocarcinoma (CCA) remain elusive. Herein, we investigated the expression pattern, clinicopathological characteristics, cell biological functions, and potential mechanisms of NFATC2 in CCA. Real-time PCR and immunohistochemistry were performed to analyze the expression of NFATC2 in human CCA tissues. CCK-8, colony formation, flow cytometry, Western blotting and transwell assays, and in vivo xenograft and pulmonary metastasis models were used to explore the effect of NFATC2 on the proliferation and metastasis of CCA. A dual-luciferase reporter system, oligonucleotide pull down, chromatin immunoprecipitation, immunofluorescence, and coimmunoprecipitation were performed to reveal the potential mechanisms. We found that NFATC2 was upregulated in CCA tissues and cells, and its aberrantly high levels were associated with poorer differentiation pattern. Functionally, NFATC2 overexpression promoted CCA cell proliferation and metastasis, whereas knockdown of NFATC2 led to the opposite results. Mechanistically, NFATC2 could be enriched in the promoter region of neural precursor cell expressed developmentally downregulated 4 (NEDD4) to facilitate its expression. Furthermore, NEDD4 targeted fructose-1, 6-bisphosphatase 1 (FBP1), and inhibited FBP1 expression via ubiquitination. In addition, silencing NEDD4 rescued the effects of NFATC2 overexpression on CCA cells. NEDD4 was upregulated in human CCA tissues, and its expression levels were positively correlated with those of NFATC2. We thus conclude that NFATC2 promotes the progression of CCA via the NEDD4/FBP1 axis, emphasizing the oncogenic role of NFATC2 in CCA progression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
Cell Metabolism
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2021
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IF 27.287
Guang-Nian Zhao,Zheng-Wei Tian,Tian Tian,Zhi-Peng Zhu,Wen-Jie Zhao,Han Tian,Xu Cheng,Feng-Jiao Hu,Man-Li Hu,Song Tian,Ting Ding,Siping Chen,Yan-Xiao Ji,Peng Zhang,Xiao-Jing Zhang,Zhi-Gang She,Yufeng Yuan,Wenping Chen,Lan Bai,Hongliang Li
Summary Obesity is characterized by the excessive accumulation of the white adipose tissue (WAT), but healthy expansion of WAT via adipocyte hyperplasia can offset the negative metabolic effects of obesity. Thus, identification of novel adipogenesis regulators that promote hyperplasia may lead to effective therapies for obesity-induced metabolic disorders. Using transcriptomic approaches, we identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as an inhibitor of adipogenesis. Gain or loss of function of TMBIM1 in preadipocytes inhibited or promoted adipogenesis, respectively. In vivo , in response to caloric excess, adipocyte precursor (AP)-specific Tmbim1 knockout (KO) mice displayed WAT hyperplasia and improved systemic metabolic health, while overexpression of Tmbim1 in transgenic mice showed the opposite effects. Moreover, mature adipocyte-specific Tmbim1 KO did not affect WAT cellularity or nutrient homeostasis. Mechanistically, TMBIM1 binds to and promotes the autoubiquitination and degradation of NEDD4, which is an E3 ligase that stabilizes PPARγ. Our data show that TMBIM1 is a potent repressor of adipogenesis and a potential therapeutic target for obesity-related metabolic disease.
研究领域:
分子生物学
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代谢学
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肥胖研究
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细胞生物学
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DOI
PubMed
高影响因子
Cell Reports
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2022
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IF 9.995
Ruipeng Zhuge,Chao Wang,Jie Wang,Shuyu Yu,Liming Liao,Xiaofeng Zheng
Summary YAP1 functions in lineage differentiation of pluripotent embryonic stem cells (ESCs); however, the detailed mechanisms underlying the regulation of YAP1 activity during ESC differentiation remain elusive. Here, we report that hCINAP serves as a negative regulator of YAP1 during ESC fate decisions. The expression of mCINAP, the murine homolog of hCINAP, is downregulated during the differentiation process of murine ESC (mESC) ectoderm lineage, leading to liquid-liquid phase separation (LLPS) of NEDD4 and activation of YAP1. Mechanistically, hCINAP interacts with and prevents NEDD4 from forming cytoplasmic condensates that compartmentalize YAP1 and its kinase NLK, facilitating YAP1 phosphorylation at Ser128 and promoting YAP1 activation. mCINAP depletion leads to the formation of NEDD4 condensates and YAP1 activation, which impedes endoderm differentiation of mESCs. Our study shows that hCINAP is a vital regulator of YAP1 activity and is essential for stem cell fate decisions, which provides mechanistic insight into early embryogenesis.
研究领域:
干细胞生物学
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细胞信号传导
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发育生物学
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DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
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IF 10.6
Nan Su,Wenhua Lian,Baoding Zhang,Yuan Tian,Linying Li,Yiyu Chen,Xiang Zhi,Taoling Zeng,Qiao Wu,Lanfen Chen,Dawang Zhou,Hong-Rui Wang,Shih-Chin Cheng,Li Li,Xianming Deng
Tumor immune microenvironment greatly influences triple-negative breast cancer (TNBC) progression. Identifying targets to convert “cold” tumors into “hot” tumors holds promise for improving treatment outcomes. Here, we show that high expression of NEDD4, an HECT-type E3 ubiquitin ligase, correlates with poor prognosis and reduced CD8 + T cell infiltration in TNBC patients. NEDD4 depletion in TNBC cells significantly inhibits tumor growth through enhancing CD8 + T cell-mediated cytotoxicity in immunocompetent hosts. Mechanistically, NEDD4 depletion stabilizes β-TrCP, leading to YAP ubiquitination and degradation. Downregulated YAP reprograms the immunosuppressive tumor extracellular matrix (ECM) to increase CD8 + T cell infiltration. Furthermore, a small-molecule inhibitor of NEDD4, XMU-MP-10, exhibits significant in vivo efficacy in inhibiting TNBC tumor growth by enhancing CD8 + T cell infiltration in mouse models. Collectively, our findings suggest that the genetic depletion or pharmacological inhibition of NEDD4 enhances antitumor immune responses via the β-TrCP/YAP/ECM cascades, offering a promising therapeutic strategy for TNBC treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Ping Lv,Dandan Li,Wei Song,Jizhe Wang
Allergic rhinitis (AR) is a chronic inflammatory disorder characterized by type 2 T helper (Th2) cell-dominant immune responses. NEDD4 like E3 ubiquitin protein ligase (NEDD4L) plays a role in regulating T cell activation and Th cell differentiation. Dipeptidyl peptidase 4 (DPP4) is involved in Th2 inflammatory responses in AR. In this study, NEDD4L was found to be downregulated in peripheral blood CD4 + –enriched T cells from AR patients. In a BALB/c mouse model of AR, established by intraperitoneal sensitization with 25 μg ovalbumin (OVA) followed by intranasal challenge with 500 μg OVA, NEDD4L expression was also reduced in splenic T cells enriched in CD4 + populations. T cell-specific overexpression of NEDD4L, achieved via tail vein injection of lentivirus carrying the CD3δ promoter, significantly alleviated AR symptoms, as shown by reduced sneezing and nose-wiping frequency, and decreased serum levels of OVA-specific immunoglobulin E (IgE) and histamine. Moreover, NEDD4L overexpression attenuated nasal mucosal thickening, inflammatory cell infiltration, and goblet cell hyperplasia. In vitro , lentiviral-mediated NEDD4L overexpression in T cells, enriched in CD4 + populations, is associated with suppression of Th2-linked inflammation, as indicated by decreased GATA-binding protein 3 (GATA-3) and JunB proto-oncogene (JunB) protein levels, reduced secretion of Th2 cytokines, and a lower proportion of CD4 + IL-4 + cells. Mechanistically, NEDD4L ubiquitinates DPP4 at the K583 site to promote its degradation, and DPP4 overexpression reversed the anti-inflammatory effects of NEDD4L. Collectively, NEDD4L is consistent with acting as a negative regulator of Th2-linked inflammation, potentially via ubiquitination-mediated degradation of DPP4.
✓ 已验证
DOI
PubMed
高影响因子
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