ACTN4

更新于：2025-05-07

基本信息

别名

actinin alpha 4、ACTN4、Alpha-actinin-4

+ [2]

简介

F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein (Probable). Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation (PubMed:15772161). Involved in tight junction assembly in epithelial cells probably through interaction with MICALL2. Links MICALL2 to the actin cytoskeleton and recruits it to the tight junctions (By similarity). May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA (PubMed:22351778). Association with IGSF8 regulates the immune synapse formation and is required for efficient T-cell activation (PubMed:22689882).

关联

100 项与 ACTN4 相关的临床结果

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100 项与 ACTN4 相关的转化医学

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0 项与 ACTN4 相关的专利（医药）

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587

项与 ACTN4 相关的文献（医药）

2025-12-31·Annals of Medicine

Identification of multicohort-based predictive signature for NMIBC recurrence reveals SDCBP as a novel oncogene in bladder cancer

Article

作者: Liu, Xudong ; Yin, Hubin ; Chen, Junrui ; Li, Tinghao ; Zhang, Chen ; He, Weiyang ; Ren, Ke ; Li, Bo

BACKGROUNDDespite surgical and intravesical chemotherapy interventions, non-muscle invasive bladder cancer (NMIBC) poses a high risk of recurrence, which significantly impacts patient survival. Traditional clinical characteristics alone are inadequate for accurately assessing the risk of NMIBC recurrence, necessitating the development of novel predictive tools.METHODSWe analyzed microarray data of NMIBC samples obtained from the ArrayExpress and GEO databases. LASSO regression was utilized to develop the predictive signature. We combined gene signature and clinicopathological factors to construct a clinical nomogram for estimating NMIBC recurrence in a local cohort. Finally. the biological functions and potential mechanisms of SDCBP in bladder cancer were investigated experimentally in vitro and in vivo.RESULTSAn 8-gene signature was developed, and its efficiency for predicting NMIBC recurrence was evaluated using Kaplan-Meier and time-dependent ROC curves in both training and validation datasets. Immunohistochemical testing revealed elevated levels of ACTN4 and SDCBP in recurrent NMIBC tissues. We integrated the two proteins with clinical factors to develop a nomogram model, which showed superior accuracy compared to individual parameters. Gene Set Variation Analysis and Gene Set Enrichment Analysis unveiled SDCBP exerted cancer-promoting biological processes, such as angiogenesis, EMT, metastasis and proliferation. Experimental procedures demonstrated that silencing SDCBP attenuated cell growth, glucose metabolism and extracellular acidification rate, accompanied by decreased expression of p-AKT, p-ERK1/2, LDHA and Vimentin.CONCLUSIONSThe established 8-gene signature holds promise as a tool for predicting NMIBC recurrence, while targeting SDCBP may represent a potential strategy for delaying disease relapse.

2025-07-01·Journal of Hazardous Materials

Triclosan-mediated metabolic oxidative stress-triggered cytoskeletal alterations in zebrafish gills and intestine: An integrated biomolecular and NMR-based metabolomics study

Article

作者: Dar, Owias Iqbal ; Gao, Yanan ; Jia, Ai-Qun ; Wang, Peng ; Vinothkanna, Annadurai ; Chen, Ligang ; Ke, Xiaosu

Triclosan (TCS) is a common disinfectant in consumer products, raising concerns about its effects on aquatic life. This study assessed the accumulation and impact of TCS on zebrafish (Danio rerio) by examining histological, biochemical, and NMR-based metabolomic changes in gill and intestinal tissue after 30 d of exposure to environmental concentrations (30, 50, and 70 µg/L). Both tissues showed TCS accumulation, which resulted in histopathological damage. The activity of catalase, lactate dehydrogenase, and acetylcholinesterase increased, while superoxide dismutase and glutathione S-transferase declined. Conversely, the content of malondialdehyde rose, but soluble protein decreased. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis displayed a varied spectrum of protein profiles, demonstrating alterations in the cytoskeletal proteins. Fourier-transform infrared spectroscopy indicated concentration-dependent alterations in the cytoskeletal protein secondary structures. Gene expression studies revealed alterations in the mRNA expression of genes associated with oxidative stress (sod-Cu/Zn, cat and mgst3b), metabolism (ldha), neural activity (ache), and cytoskeletal dynamics (actn4, myl9a, tpma, tuba1b and desmb). Nuclear magnetic resonance spectroscopy revealed significant changes in metabolic pathway profiles, validated by amino acid analysis. These results suggest that TCS can disrupt aquatic ecosystems by inducing oxidative stress, affecting cytoskeletal dynamics, and modifying metabolic processes.

2025-03-03·Journal of General Physiology

Structural and functional insights into α-actinin isoforms and their implications in cardiovascular disease

Review

作者: Noureddine, Maya ; Denning, Chris ; Morgan, Neil V. ; Loughna, Siobhan ; Mohammed, Fiyaz ; Gehmlich, Katja ; Mikolajek, Halina

α-actinin (ACTN) is a pivotal member of the actin-binding protein family, crucial for the anchoring and organization of actin filaments within the cytoskeleton. Four isoforms of α-actinin exist: two non-muscle isoforms (ACTN1 and ACTN4) primarily associated with actin stress fibers and focal adhesions, and two muscle-specific isoforms (ACTN2 and ACTN3) localized to the Z-disk of the striated muscle. Although these isoforms share structural similarities, they exhibit distinct functional characteristics that reflect their specialized roles in various tissues. Genetic variants in α-actinin isoforms have been implicated in a range of pathologies, including cardiomyopathies, thrombocytopenia, and non-cardiovascular diseases, such as nephropathy. However, the precise impact of these genetic variants on the α-actinin structure and their contribution to disease pathogenesis remains poorly understood. This review provides a comprehensive overview of the structural and functional attributes of the four α-actinin isoforms, emphasizing their roles in actin crosslinking and sarcomere stabilization. Furthermore, we present detailed structural modeling of select ACTN1 and ACTN2 variants to elucidate mechanisms underlying disease pathogenesis, with a particular focus on macrothrombocytopenia and hypertrophic cardiomyopathy. By advancing our understanding of α-actinin’s role in both normal cellular function and disease states, this review lays the groundwork for future research and the development of targeted therapeutic interventions.

项与 ACTN4 相关的新闻（医药）

2024-08-30

·今日头条

铁死亡新发现！浙江大学合作发文：克服肝癌耐药的新途径

【导读】索拉非尼被广泛用于治疗晚期肝细胞癌(HCC)。然而，其延长患者生存期的有效性受到耐药性发展的限制。 8月29日，浙江大学与杭州医学院研究人员合作在期刊《Journal of Experimental & Clinical Cancer Research》上发表了研究论文，题为“CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis”，本研究分析发现，含有热休克蛋白伴侣TCP1亚基3（CCT3）的蛋白发生赖氨酸21（K21）的泛素化与索拉非尼耐药相关。对接受索拉非尼治疗的HCC患者的转录组数据分析显示，与非响应者相比，响应者CCT3表达较低。实验上，抑制CCT3表达可增强HCC细胞对索拉非尼的敏感性，并增强索拉非尼诱导的铁死亡。此外，研究人员发现CCT3与ACTN4相互作用，阻碍转铁蛋白受体蛋白1（TFRC）的循环，从而阻碍铁的内吞作用。机制上，CCT3抑制铁死亡依赖于K6连接的非降解性泛素化在K21上的去泛素化，该过程在索拉非尼治疗时发生。此外，CCT3敲低可增强索拉非尼在裸鼠体内的抗肿瘤效果。总之，研究人员发现了一种新型的热休克蛋白伴侣蛋白的功能。靶向CCT3/ACTN4/TFRC轴提供了一种有前途的策略，可增强铁死亡并克服索拉非尼耐药性在HCC中的作用。 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03169-7#Sec1 背景知识 01 肝癌在全球所有癌症类型中排名第六，是第三大癌症相关死亡原因。在原发性肝癌中，肝细胞癌（HCC）是最常见的。在HCC的早期阶段，手术干预仍然是主要的治疗模式。然而，大约50%的晚期HCC病例需要索拉非尼和局部消融作为主要的治疗策略。索拉非尼是一种口服多靶点酪氨酸激酶抑制剂，通过靶向血管内皮生长因子受体（VEGFR）、血小板衍生生长因子受体（PDGFR）、Raf家族激酶等，有效抑制肿瘤细胞的增殖和血管生成。因此，HCC患者的生存率有所改善。尽管索拉非尼对治疗HCC有效，但它对患者总生存期的影响有限，仅将其延长了三个月。耐药的出现给索拉非尼治疗HCC患者的有效性带来了重大挑战。深入了解肝癌中索拉非尼耐药的分子机制，有助于改善疾病预后，并有助于识别能够绕过化疗耐药的治疗靶点。表观遗传学、转运过程、肿瘤微环境和调控性细胞死亡已被确定为索拉非尼耐药的潜在触发因素和贡献者。在治疗耐药机制领域，越来越多的关注集中在铁死亡上，其在形态学、生化和遗传学方面的特征与凋亡、自噬、坏死和其他形式的细胞死亡不同。在铁死亡过程中，铁和脂质过氧化显著积累。主要调节机制包括Xc系统、谷胱甘肽过氧化物酶4(GPX4)活性和活性氧(ROS)产生。与其他酪氨酸激酶抑制剂不同，索拉非尼能够在多种癌细胞系中诱导铁死亡。研究表明，铁死亡与索拉非尼在HCC中的耐药性有关。然而，需要进一步的研究来阐明索拉非尼耐药性中铁死亡的分子机制。 CCT3通过抑制铁死亡来促进索拉非尼耐药性 02 为了探究CCT3如何促进HCC对索拉非尼的耐药，研究人员对97 L和LM3细胞在索拉非尼治疗和CCT3表达抑制后的蛋白质表达进行了全面分析。研究结果显示，97 L和LM3细胞在索拉非尼治疗和CCT3抑制后出现了显著的蛋白质表达变化。KEGG途径分析表明，在抑制CCT3后出现差异表达的蛋白质涉及多种细胞过程，包括谷胱甘肽代谢、自噬和内吞作用，这些过程与细胞内铁运输和铁死亡有关。研究人员通过GO分析也证实了CCT3敲低的有效性，研究人员使用KEGG进行的分析还揭示了索拉非尼响应中涉及铁死亡、活性氧和氧化磷酸化的情况。蛋白质组学研究的综合结果表明，抑制CCT3可增强索拉非尼的敏感性，这可能是通过诱导铁死亡实现的。为了验证这一假设，研究人员使用了3-甲基腺嘌呤（3-MA）、Necrostatin-1（Nec-1）、Z-VAD-FMK、去铁胺（DFO）和Ferrostatin-1（Fer-1）分别抑制自噬、坏死、凋亡和铁死亡。研究结果表明，只有铁死亡抑制剂DFO和Fer-1减弱了CCT3对索拉非尼敏感性的影响，而其他细胞死亡途径的抑制剂则没有。为了研究铁死亡的中心事件，即铁积累和脂质过氧化，研究人员进行了进一步的分析。通过使用FerroOrange，一种检测铁离子的探针，研究人员观察到，CCT3表达下调导致索拉非尼处理的97 L和LM3细胞中二价铁离子的积累增加。此外，CCT3的敲低促进了这些细胞中的脂质过氧化。与预期相符，研究结果表明，CCT3水平的降低导致细胞内谷胱甘肽水平降低。透射电子显微镜的实验结果表明，CCT3表达量的减少导致97 L和LM3细胞线粒体体积减小、膜密度增加。值得注意的是，拯救实验揭示，CCT3过表达减轻了索拉非尼处理后97 L和LM3细胞中铁离子积累的干扰影响。总之，CCT3在HCC细胞中起着索拉非尼诱导的铁死亡抑制剂的作用。抑制CCT3可促进索拉非尼治疗的HCC细胞发生铁死亡抑制CCT3增强了索拉非尼在体内的抗癌效果 03 研究人员进行了进一步的研究，以确定CCT3在体内环境中对索拉非尼疗效的影响。研究人员将对照组和CCT3敲低的LM3细胞通过皮下注射注入裸鼠体内，一周后进行腹腔注射，注射物为DMSO或索拉非尼，并于三周后收集皮下肿瘤。与体外研究结果一致，CCT3的持续敲低与索拉非尼联合使用导致肿瘤体积和质量显著下降。令人惊讶的是，对照组在接受索拉非尼治疗后，肿瘤大小和重量仅出现轻微且统计学上不显著的下降，这可能与在实验设计中使用的低剂量和不频繁的索拉非尼给药有关。此外，CCT3敲低组肿瘤组织中的4-HNE染色强度在索拉非尼治疗后超过对照组，这表明肿瘤内氧化应激加剧。基于这些结果，CCT3敲低后，索拉非尼的铁死亡诱导和肿瘤抑制作用得到增强。研究小结 04 总之，本研究采用蛋白质翻译后修饰组学和CRISPR/Cas9敲除文库筛选的方法系统地鉴定出CCT3为与索拉非尼耐药相关的重要基因。值得注意的是，本研究发现CCT3通过与ACTN4的相互作用阻碍TFRC的循环，这一调节机制受K6-连接的K21位点泛素化调控。这项研究通过揭示分子伴侣的新功能和铁死亡的先前未知的负反馈机制具有理论意义。此外，这项研究在指导HCC治疗和解决索拉非尼耐药问题方面具有重要的临床意义。【参考资料】 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-03169-7#Sec1 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜09月11日 ▶ 微驭万物-单细胞空间组学技术前沿与临床应用研讨会 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

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