更新于：2024-09-19

SEPTIN2

更新于：2024-09-19

基本信息

别名

DIFF6、hNedd5、KIAA0158

+ [8]

简介

Filament-forming cytoskeletal GTPase. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830). Required for normal organization of the actin cytoskeleton. Plays a role in the biogenesis of polarized columnar-shaped epithelium by maintaining polyglutamylated microtubules, thus facilitating efficient vesicle transport, and by impeding MAP4 binding to tubulin. Required for the progression through mitosis. Forms a scaffold at the midplane of the mitotic splindle required to maintain CENPE localization at kinetochores and consequently chromosome congression. During anaphase, may be required for chromosome segregation and spindle elongation. Plays a role in ciliogenesis and collective cell movements. In cilia, required for the integrity of the diffusion barrier at the base of the primary cilium that prevents diffusion of transmembrane proteins between the cilia and plasma membranes: probably acts by regulating the assembly of the tectonic-like complex (also named B9 complex) by localizing TMEM231 protein. May play a role in the internalization of 2 intracellular microbial pathogens, Listeria monocytogenes and Shigella flexneri.

关联

100 项与 SEPTIN2 相关的临床结果

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100 项与 SEPTIN2 相关的转化医学

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0 项与 SEPTIN2 相关的专利（医药）

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133

项与 SEPTIN2 相关的文献（医药）

2024-10-01·Pharmacological Research

BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer

Article

作者: Wang, Deyu ; Zhang, Rui ; Zhao, Luoyi ; Zhao, Nan ; Yu, Mingxin ; Liu, Quan ; Li, Munan ; Wang, Shuai ; Zhang, Siwei ; Zhao, Ying ; Han, Fangbin ; Liu, Nan

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.

2024-06-30·Drug Discoveries & Therapeutics

The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection

Letter

作者: Li, Lanfang ; He, Lu ; Li, Chuanhua ; Qu, Hongtao ; Zhang, Ying

Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.

2024-06-26·Molecular Human Reproduction

SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction

Article

作者: Su, Yuyan ; Nie, Xinmin ; Liu, Gang ; Mao, Zenghui ; Xing, Xiaowei ; He, Xiyi ; Zhang, Yunfei ; Huang, Lihua

AbstractAcephalic spermatozoa syndrome (ASS) is a severe teratospermia with decaudated, decapitated, and malformed sperm, resulting in male infertility. Nuclear envelope protein SUN5 localizes to the junction between the sperm head and tail. Mutations in the SUN5 gene have been identified most frequently (33–47%) in ASS cases, and its molecular mechanism of action is yet to be explored. In the present study, we generated Sun5 knockout mice, which presented the phenotype of ASS. Nuclear membrane protein LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation–mass spectrometry in mouse testis. Further studies demonstrated that SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12. The binding between SUN5 and Septin12 promoted their aggregation together in the sperm neck. The disruption of the LaminB1/SUN5/Septin12 complex by Sun5 deficiency caused separation of the Septin12-proximal centriole from the nucleus, leading to the breakage of the head-to-tail junction. Collectively, these data provide new insights into the pathogenesis of ASS caused by SUN5 deficiency.

项与 SEPTIN2 相关的新闻（医药）

2024-02-23

·生物探索

Circulation | 南京医科大学季勇/谢利平/王东进发现加重主动脉瘤和夹层的新机理

引言S-亚硝基化(SNO)是一种典型的基于氧化还原的翻译后修饰，与心血管疾病有关。主动脉瘤和夹层是目前尚无有效治疗方法的高危心血管疾病。2024年2月15日，南京医科大学季勇、谢利平及王东进共同通讯在Circulation (IF 38)在线发表题为“S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages”的研究论文，该研究表明巨噬细胞中Septin2的S-亚硝基化通过偶联TIAM1-RAC1轴加重主动脉瘤和夹层。在接受主动脉夹层手术的患者和注射血管紧张素II的Apoe-/-小鼠的主动脉组织中，Septin2被鉴定为S-亚硝基化的半胱氨酸111 (Cys111)。SNO-Septin2被证实可促进主动脉瘤和夹层的发展。通过RNA测序，证实巨噬细胞中的SNO-Septin2可加剧主动脉瘤血管炎症和细胞外基质降解。接下来，TIAM1 (T淋巴瘤侵袭和转移诱导蛋白1)被确定为SNO-Septin2的靶蛋白。机制上，与未修饰的Septin2相比，SNO-Septin2减少了与TIAM1的相互作用，激活了TIAM1- RAC1轴及其相关的核因子-κB信号通路，导致巨噬细胞介导的炎症和细胞外基质降解更强。一致地，R-Ketorolac和NSC23766治疗通过抑制TIAM1-RAC1轴来保护主动脉瘤和夹层。总之，SNO-Septin2通过偶联巨噬细胞中的TIAM1-RAC1轴，激活核因子-κB信号通路依赖性炎症和细胞外基质降解，驱动主动脉瘤和夹层。因此，R-Ketorolac或NSC23766对RAC1的药理学阻断可能是治疗主动脉瘤和夹层的潜在方法。主动脉瘤和主动脉夹层是高死亡率的心血管疾病。主动脉瘤的特征是主动脉局部或弥漫性扩张，这逐渐增加了急性主动脉夹层的风险。主动脉夹层被定义为内膜破裂，导致主动脉壁层分离，随后形成真腔和假腔。尽管在影像学和血管开放修复和血管内修复方面取得了重大进展，但有效的药物治疗仍然不可用。巨噬细胞积聚在动脉瘤主壁上，通过影响细胞外基质(ECM)降解和炎症，促进了动脉瘤和夹层的发生研究发现，浸润于主动脉瘤血管壁及夹层的大量巨噬细胞高度表达诱导型一氧化氮(NO)合成酶(iNOS)，可催化产生大量NO，并通过蛋白S-亚硝基化(SNO)发挥多种病理生理作用。SNO是将NO部分可逆的共价加成到半胱氨酸硫醇上，形成S-亚硝基蛋白，参与心脏肥厚、心脏纤维化、动脉粥样硬化等多种心血管疾病的发病。因此，SNO可能发生在主动脉瘤及夹层血管组织中iNOS高表达并参与主动脉瘤及夹层的巨噬细胞中。Cys111突变的Septin2减轻主动脉瘤（Credit: Circulation）Septin2属于Septin家族。Septin是一个高度保守的蛋白家族，在细胞分裂、细胞内物质运输、细胞周期调节和细胞凋亡中被越来越多地认为是细胞骨架的一个新组成部分。已被证明在阿尔茨海默病、癌症、感染和系统性红斑狼疮中发挥重要作用Septin2参与维持内皮细胞连接和内皮完整性。Septin2还可以通过增强内皮细胞的迁移来促进血管生成。然而，Septin2在主动脉瘤和夹层中的作用尚不清楚。该研究证实了在半胱氨酸111 (Cys111)位点Septin2的SNO加重血管紧张素II (Ang II)诱导的主动脉瘤和β-氨基丙腈(BAPN)诱导的主动脉瘤和夹层。机制上，SNO-Septin2减少其与巨噬细胞中TIAM1 (T淋巴瘤侵袭和转移诱导蛋白1)的相互作用，激活TIAM1RAC1 (Ras相关的C3肉毒毒素底物1)轴及其相关的核因子-κB (NF-κB)信号通路，促进更强的炎症反应和ECM降解。总之，这些发现表明SNO-Septin2可能是动脉瘤和夹层的治疗靶点。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1161/CIRCULATIONAHA.123.066404责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

2023-03-13

·生物谷

Mol Cancer：我国科学家揭示赖氨酸羟化酶1促进肝癌细胞和胰腺癌细胞迁移和转移

癌症转移是导致癌症相关死亡的一个主要原因。在一项新的研究中，来自中国香港城市大学和重庆医科大学第二附属医院的研究人员发现了一种引发肝癌细胞和胰腺癌细胞迁移和转移并且与患者的生存时间缩短有关的蛋白。癌症转移是导致癌症相关死亡的一个主要原因。在一项新的研究中，来自中国香港城市大学和重庆医科大学第二附属医院的研究人员发现了一种引发肝癌细胞和胰腺癌细胞迁移和转移并且与患者的生存时间缩短有关的蛋白。这些研究结果经体外和体内模型验证，并有临床数据支持，有望为癌症治疗提供一种新的潜在靶标。相关研究结果近期发表在Molecular Cancer期刊上，论文标题为“Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network”。论文共同通讯作者、香港城市大学生物医学讲座教授Michael Yang Mengsu博士说，“癌症转移是一个复杂的过程。众所周知，肿瘤和周围组织的硬化程度随着肿瘤的生长而增加，这在多种癌症类型中为肿瘤细胞的迁移和转移创造了有限空间（confined space），即通道状的孔隙轨道。但这种在有限空间中迁移（下称受限迁移）的机制仍不清楚。我们的目标是深入研究癌症转移机制，并确定与之相关的新基因和蛋白。” 作为最常见的肝癌类型，肝细胞癌（HCC）是世界上第二大癌症死因。胰腺导管腺癌（PDAC）是另一种高度侵袭性的癌症，五年生存率不到10%。这两种癌症都具有实体瘤的典型特征，即胞外基质（ECM）沉积过多，含有使癌细胞迁移的有限孔隙或通道状轨道。因此，这些作者选择了这两种不同的癌症类型作为研究对象。开发研究迁移机制的方法这些作者首先收集了分别来自153名和63名患者的HCC和PDAC样本进行分析。这些作者在手术前没有接受化疗或放疗。他们还从美国国家卫生研究院获得了人类肝癌和胰腺癌细胞系。 Yang教授解释说，“主要的挑战是模拟复杂的癌症微环境。但目前缺乏关于细胞在有限环境中迁移的研究模型。因此，我们开发了一系列多维平台以及二维和三维体外和体内模型，以全面研究细胞迁移过程。” 这些平台和模型包括用于研究单个细胞和集体细胞迁移的微流控芯片，以及用于模拟体内环境的三维侵袭试验的不同硬度的水凝胶。他们还利用下一代测序（NGS）和液相色谱-质谱（LC-MS）来确定癌症组织中差异表达的基因和蛋白。 LH1是促进HCC和PDAC细胞受限迁移的一种关键因子基于下一代测序的转录组分析和基于LC-MS的蛋白质组分析，这些作者确定了一种名为赖氨酸羟化酶1（lysyl hydroxylase 1, LH1）的蛋白是HCC组织中最明显过表达的蛋白之一。他们开发的微流控芯片和三维侵袭模型展示了LH1在多维度上促进受限迁移的能力，包括HCC和PDAC细胞的迁移速度和侵袭能力。这些作用可以通过敲除LH1的表达而被抑制。 LH1高表达与HCC和PDAC患者预后不良相关。图片来自Molecular Cancer, 2023, doi:10.1186/s12943-023-01727-9。他们还证实LH1可以结合并稳定Septin2（SEPT2）以增强肌动蛋白网络的形成；作为一种蛋白，SEPT2在为细胞的高机械迁移需求做准备时起着至关重要的作用。肌动蛋白网络是细胞骨架中最有活力的元素，分布在整个细胞质中，并控制着细胞的力学和运动。因此，增强肌动蛋白网络的形成可以促进HCC和PDAC细胞的受限迁移和转移。 LH1高表达水平导致癌症患者预后不良这些作者还分析了LH1与HCC和PDAC患者的预后（即疾病的发展和复发的机会）之间的相关性。临床样本显示LH1表达较高伴随着预后不佳的患者的生存率只有LH1低表达的患者的一半。此外，LH1高表达的HCC和PDAC患者从确诊到死亡的总生存时间较短，分别为39和17个月，而LH1水平较低的患者则为86和22个月。另外，LH1高表达的HCC和PDAC患者从初次治疗到疾病复发的无病生存时间分别为11.5和14个月，而LH1水平较低的患者为41和19个月。 Yang教授说，“我们开发的平台和方法为研究癌细胞的受限迁移提供了一种独特的方法。我们证实了LH1通过稳定SEPT2促进癌细胞的受限迁移和转移，并且高水平的LH1与HCC和PDAC患者的不良预后有关。这些发现有望为癌症诊断和药物开发提供一种潜在的新靶标。”（生物谷 Bioon.com）参考资料： Zihan Yang et al. Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network. Molecular Cancer, 2023, doi:10.1186/s12943-023-01727-9.