YES proto-oncogene 1(YES1)is an SRC family kinase(SFK)that plays a key role in cancer cell proliferation,adhesion,invasion,survival,and angiogenesis during tumorigenesis and tumor development.Reports suggest that YES1...YES proto-oncogene 1(YES1)is an SRC family kinase(SFK)that plays a key role in cancer cell proliferation,adhesion,invasion,survival,and angiogenesis during tumorigenesis and tumor development.Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors(TKIs)in human malignancies.However,the mechanisms of drug resistance have not been fully elucidated.In this article,we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies.Moreover,recent advances in targeted therapy for YES1-amplified malignancies are summarized.Finally,we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.展开更多
Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac functio...Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.展开更多
BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein couple...BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.展开更多
目的O-GlcNAc糖基化(O-linked beta-N-acetylglucosamine,O-GlcNAc)和Yes相关蛋白1(yes-associated protein 1,YAP1)是否会发生糖基化、在结直肠癌中的表达情况及发挥作用的机制都尚未得到充分阐明。本研究旨在借助癌症基因组图谱(the c...目的O-GlcNAc糖基化(O-linked beta-N-acetylglucosamine,O-GlcNAc)和Yes相关蛋白1(yes-associated protein 1,YAP1)是否会发生糖基化、在结直肠癌中的表达情况及发挥作用的机制都尚未得到充分阐明。本研究旨在借助癌症基因组图谱(the cancer genome atlas,TCGA)数据库、组织标本和细胞系探究O-GlcNAc糖基化和YAP1糖基化在结直肠中所发挥的作用。方法采用免疫组化法检测O-GlcNAc和OGT蛋白(O-linked-N-acetylglucosamine transferase,OGT)在结直肠组织和癌旁组织中的表达情况;运用qPCR检测结直肠组织和癌旁组织中OGT mRNA表达水平;借助在线分析TCGA数据库,了解OGT的表达情况及其对预后产生的影响;通过Western Blot检测OSMI-1对O-GlcNAc糖基化的抑制作用;采用CCK-8和Transwell检测,在抑制O-GlcNAc糖基化后,观察肠癌细胞增殖、侵袭及迁移能力的变化;借助数据库分析YAP1的表达情况及其O-GlcNAc糖基化位点,并经质谱分析确定YAP1是否发生O-GlcNAc糖基化修饰;运用Co-IP和免疫荧光实验验证YAP1和OGT之间的结合关系;采用qPCR和免疫荧光明确抑制O-GlcNAc糖基化后YAP1表达位置的改变以及下游效应基因表达的改变情况。结果研究发现,OGT蛋白和mRNA在结直肠组织中的表达水平明显升高,但对患者的预后并无明显影响;OSMI-1能够抑制肠癌细胞的O-GlcNAc糖基化,并且抑制细胞增殖、侵袭与迁移能力;YAP1可与OGT结合并发生O-GlcNAc糖基化,当抑制O-GlcNAc糖基化后,YAP1入核数量减少,转录活性降低。结论在结直肠癌中,O-GlcNAc糖基化水平呈现升高趋势,OGT和YAP1结合,使YAP1发生O-GlcNAc糖基化修饰,促进其转录活性。展开更多
基金Special Funding for Qilu Sanitation and Health Leading Talents Cultivation ProjectKey Research and Development Project of Shandong Province,Grant/Award Number:2017GSF18147。
文摘YES proto-oncogene 1(YES1)is an SRC family kinase(SFK)that plays a key role in cancer cell proliferation,adhesion,invasion,survival,and angiogenesis during tumorigenesis and tumor development.Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors(TKIs)in human malignancies.However,the mechanisms of drug resistance have not been fully elucidated.In this article,we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies.Moreover,recent advances in targeted therapy for YES1-amplified malignancies are summarized.Finally,we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.
基金supported by the National Natural Science Founda-tion of China(82370417,82330011,and U21A20339)the Science Fund for Distinguished Young Scholars of Heilongjiang Province(JQ2024H001)the Heilongjiang Provincial Postdoctoral Science Foundation(LBH-Z23212).
文摘Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.
文摘BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.
文摘目的O-GlcNAc糖基化(O-linked beta-N-acetylglucosamine,O-GlcNAc)和Yes相关蛋白1(yes-associated protein 1,YAP1)是否会发生糖基化、在结直肠癌中的表达情况及发挥作用的机制都尚未得到充分阐明。本研究旨在借助癌症基因组图谱(the cancer genome atlas,TCGA)数据库、组织标本和细胞系探究O-GlcNAc糖基化和YAP1糖基化在结直肠中所发挥的作用。方法采用免疫组化法检测O-GlcNAc和OGT蛋白(O-linked-N-acetylglucosamine transferase,OGT)在结直肠组织和癌旁组织中的表达情况;运用qPCR检测结直肠组织和癌旁组织中OGT mRNA表达水平;借助在线分析TCGA数据库,了解OGT的表达情况及其对预后产生的影响;通过Western Blot检测OSMI-1对O-GlcNAc糖基化的抑制作用;采用CCK-8和Transwell检测,在抑制O-GlcNAc糖基化后,观察肠癌细胞增殖、侵袭及迁移能力的变化;借助数据库分析YAP1的表达情况及其O-GlcNAc糖基化位点,并经质谱分析确定YAP1是否发生O-GlcNAc糖基化修饰;运用Co-IP和免疫荧光实验验证YAP1和OGT之间的结合关系;采用qPCR和免疫荧光明确抑制O-GlcNAc糖基化后YAP1表达位置的改变以及下游效应基因表达的改变情况。结果研究发现,OGT蛋白和mRNA在结直肠组织中的表达水平明显升高,但对患者的预后并无明显影响;OSMI-1能够抑制肠癌细胞的O-GlcNAc糖基化,并且抑制细胞增殖、侵袭与迁移能力;YAP1可与OGT结合并发生O-GlcNAc糖基化,当抑制O-GlcNAc糖基化后,YAP1入核数量减少,转录活性降低。结论在结直肠癌中,O-GlcNAc糖基化水平呈现升高趋势,OGT和YAP1结合,使YAP1发生O-GlcNAc糖基化修饰,促进其转录活性。
