更新于：2024-05-01

TOM

pre-mRNA processing factor 6

更新于：2024-05-01

基本信息

别名

Androgen receptor N-terminal domain-transactivating protein 1、ANT-1、bB152O15.1

+ [13]

简介

Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome (PubMed:28781166, PubMed:21549338). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation.

关联

100 项与 TOM 相关的临床结果

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100 项与 TOM 相关的转化医学

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0 项与 TOM 相关的专利（医药）

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499

项与 TOM 相关的文献（医药）

2024-01-01·Journal of otology

Co-infection with Neisseria mucosa in a patient with tuberculous otitis media.

Article

作者: Tatsuya Hioki ; Kazuaki Soejima ; Yuki Goto ; Makoto Sugiura ; Takumi Umemura ; Yoshimi Ishihara ; Yoshikazu Mutoh ; Daisuke Sakanashi ; Hiroshige Mikamo

Tuberculous otitis media (TOM) is a rare manifestation caused by Mycobacterium tuberculosis with low incidence rates among extrapulmonary tuberculosis cases. Diagnosis is often delayed because of the presence of several clinical manifestations and the high prevalence of secondary bacterial infections. Few reports have attributed secondary bacterial infections in patients with TOM to commensal Neisseria. Thus, understanding the pathogenic mechanisms and clinical features of commensal Neisseria is important, considering its recent presentation as an infection-causing pathogen. Neisseria mucosa is a commensal inhabitant in humans and is generally considered non-pathogenic but can cause infection in rare cases. Here, we report an atypical secondary infection caused by Neisseria mucosa in an 81-year-old woman with TOM being treated for pulmonary tuberculosis. Direct purulent otorrhea smear microscopy revealed no acid-fast bacilli using Ziehl-Neelsen staining, whereas the phagocytosis of gram-negative cocci by white blood cells was confirmed using Gram staining. Otorrhea culture revealed the growth of N. mucosa. Subsequently, M. tuberculosis infection in the otorrhea was identified using a culture-based method. Vigilance is critical for the early detection of TOM to prevent further complications. This report raises awareness regarding TOM and provides insight into the pathogenicity of N. mucosa in otitis media.

2023-12-18·International journal of molecular sciences

Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome.

Article

作者: Jacques S Fritze ; Felizitas F Stiehler ; Uwe Wolfrum

Pre-mRNA splicing is an essential process orchestrated by the spliceosome, a dynamic complex assembled stepwise on pre-mRNA. We have previously identified that USH1G protein SANS regulates pre-mRNA splicing by mediating the intranuclear transfer of the spliceosomal U4/U6.U5 tri-snRNP complex. During this process, SANS interacts with the U4/U6 and U5 snRNP-specific proteins PRPF31 and PRPF6 and regulates splicing, which is disturbed by variants of USH1G/SANS causative for human Usher syndrome (USH), the most common form of hereditary deaf-blindness. Here, we aim to gain further insights into the molecular interaction of the splicing molecules PRPF31 and PRPF6 to the CENTn domain of SANS using fluorescence resonance energy transfer assays in cells and in silico deep learning-based protein structure predictions. This demonstrates that SANS directly binds via two distinct conserved regions of its CENTn to the two PRPFs. In addition, we provide evidence that these interactions occur sequentially and a conformational change of an intrinsically disordered region to a short α-helix of SANS CENTn2 is triggered by the binding of PRPF6. Furthermore, we find that pathogenic variants of USH1G/SANS perturb the binding of SANS to both PRPFs, implying a significance for the USH1G pathophysiology.

2023-12-13·Respiratory research

Tom70-regulated mitochondrial biogenesis via TFAM improves hypoxia-induced dysfunction of pulmonary vascular endothelial cells and alleviates hypoxic pulmonary hypertension.

Article

作者: Lei Ma ; Yanxia Wang ; Xiaoqian Li ; Zefang Wang ; Bo Zhang ; Ying Luo ; Yousheng Wu ; Zhichao Li ; Wen Niu

BACKGROUND:

Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. A large number of studies have shown that pulmonary vascular endothelial cells (PVECs) dysfunction plays an important role in the initiation and development stages of HPH, but the mechanism of PVECs dysfunction after hypoxia remains unclear. In this study, we explored the exact mechanism of PVECs dysfunction after hypoxia.

METHODS:

In vitro, we used primary cultured PVECs hypoxia model to mimic HPH injury. We detected the expressions of mitochondrial biogenesis markers, mitochondrial transcription factor A (TFAM) level inside mitochondria, mitochondrial quantity and function, and the components expressions of translocase of outer mitochondrial membrane (TOM) at 24 h after hypoxia. To explore the effects of Tom70 on mitochondrial biogenesis and functions of PVECs after hypoxia, Tom70 overexpression adenovirus was constructed, and the expressions of mitochondrial biogenesis markers, TFAM level inside mitochondria, mitochondrial quantity and function, and the functions of PVECs were detected. And in vivo, we used cre-dependent overexpression adenovirus of Tom70 in the Cdh5-CreERT2 mouse model of HPH to verify the role of upregulating PVECs Tom70 in improving HPH.

RESULTS:

Hypoxia obviously increased the expressions of mitochondrial biogenesis markers for PGC-1α, NRF-1 and TFAM, but reduced the content of TFAM in mitochondria and the quantity and functions of mitochondria. In addition, only Tom70 expression among the TOM components was significantly decreased after hypoxia, and up-regulation of Tom70 significantly increased the content of TFAM in mitochondria of PVECs by transporting TFAM into mitochondria after hypoxia, enhanced the quantity and functions of mitochondria, improved the functions of PVECs, and ultimately alleviated HPH.

CONCLUSION:

The findings of present study demonstrated that hypoxia induced the decreased expression of Tom70 in PVECs, reduced the mitochondrial biogenesis-associated TFAM protein transporting into mitochondria, inhibited mitochondrial biogenesis, caused PVECs injury, and prompted the formation of HPH. However, up-regulation of Tom70 abolished the hypoxia-induced injurious effects on PVECs and alleviated HPH.

项与 TOM 相关的新闻（医药）

2022-09-30

·药明康德

帕金森病、胃溃疡... 一图看懂近期大脑、胃肠道疾病临床转化潜力靶点

▎药明康德内容团队编辑每一个成功开发的临床药物背后最早都是来自科学家在实验室中的努力，而这其中的第一步便是识别合适的靶点以开发相对应的治疗药物。在今天的文章中，药明康德内容团队为大家盘点近期在各个顶尖科学期刊上所发表，具有潜力成为治疗神经肌肉、肠胃道等疾病靶点的文章，以提供为产业界研究发展的参考！靶点：TMEM175疾病：帕金森病（Parkinson’s disease）期刊/PMID: 《细胞》/ 35750034发现：溶酶体（lysosome）依赖其V-腺苷三磷酸酶（V-ATPase）功能引起质子流入，以及一种尚未发现的质子流失途径来维持溶酶体腔pH值于4.5-5.0之间，以有效地消化腔内的大分子。研究人员发现TMEM175可以作为溶酶体膜上质子活化兼质子选择性通道（LyPAP）以介导溶酶体质子流失。TMEM175以往被认为是帕金森病遗传风险因子。溶酶体过度的酸化会活化LyPAP，而一种内源的多不饱和脂肪酸与合成的激动剂亦可以活化TMEM175以释放溶酶体内质子。而TMEM175的缺失则会造成溶酶体过度酸化并影响蛋白水解，进而促进帕金森病神经病理特征α突触核蛋白（α-synuclein）在体内的聚集。因此借由调控TMEM175或溶酶体腔内pH值，有潜力调节溶酶体降解以及帕金森病理进展。靶点：PRPF6疾病：脑室旁异位（periventricular heterotopia，PH）期刊/PMID:《科学》/ 35709258发现：中心体（centrosome）是细胞内细胞骨架的联结，调节细胞分裂、迁移与纤毛形成。研究人员通过空间蛋白质组学分析来自人类诱导多能干细胞的神经干细胞（NSC）与神经细胞在中心体上蛋白质的互动网络。在分析神经发育疾病队列时，研究人员发现脑室旁异位患者的NSC中心体上蛋白有许多变异。当研究人员表达PRPF6变异蛋白时，可以在发育中的小鼠大脑复制脑室异位情形。因PRPF6参与mRNA前体的剪接，这显示中心体上微管相关激酶转录物的错误剪接对于产生脑部疾病表现是必须的，而变异的PRPF6则可能为潜力靶点。靶点：GAT3疾病：脑部受损（brain injury）期刊/PMID: Science Translational Medicine / 35857628发现：脑部受伤后所产生的不可控炎症反应与患者癫痫风险和认知损伤增加有关，而脑部的视丘（thalamus）则是在脑部损伤后特别容易受到这类损害的部位。研究人员发现在小鼠模型中，视丘炎症本身便足以引发细胞与回路的高刺激性、增加癫痫风险等脑部损伤所引起的负面作用。而此现象是由视丘星形胶质细胞（astrocyte）中的GABA运输蛋白GAT3下调所引起。而增加视丘星形胶质细胞GAT3蛋白的表达则可在小鼠脑损伤模型当中，降低癫痫风险、修复皮质状态并且保护因严重化学惊厥（chemoconvulsant）所引发的癫痫与死亡。因此GAT3表达可能有助于减少脑部损害所带来负面作用。靶点：ZBP1疾病：艾卡迪-古特雷斯综合征（Aicardi–Goutières syndrome，AGS）期刊/PMID:《自然》/ 35859175、35859176发现：RNA1腺苷脱氨酶（ADAR1）是一种RNA编辑酶，可以限制具内源免疫刺激性双链RNA（dsRNA）的积累。在人类体内ADAR1活性的减少会造成严重的早发罕见遗传性炎症疾病——艾卡迪-古特雷斯综合征（AGS），此疾病主要影响患者大脑与皮肤。AGS患者带有的ADAR1突变在小鼠身上会造成自身炎症反应。发在同一期《自然》的两篇论文发现ADAR1可以抑制左旋Z-核酸感应蛋白ZBP1。ZBP1可以促进1型干扰素（IFN）活化。在缺乏ADAR1的细胞当中，ZBP1会引起胱天蛋白酶-8（caspase-8）依赖性细胞凋亡以及MLKL介导的坏死性凋亡。研究人员发现ADAR1的Zα结构域可促进A转变成I碱基编辑，避免双链RNA（dsRNA）形成以及后续ZBP1蛋白活化。因此靶向ZBP1具潜力治疗因ADAR1突变在AGS患者所引起ZBP1介导的干扰素病（interferonopathies）。靶点：HRH4疾病：肠易激综合征（IBS）期刊/PMID: Science Translational Medicine / 35895832发现：肠道中的微生物是造成包含IBS在内的慢性、疼痛肠道不适原因之一，但详细机制却仍不清楚。研究人员发现由肠道细菌所生产的组胺（histamine），一种神经免疫调节物，会引起IBS小鼠模型的腹部疼痛。机制上，细菌组胺可以通过活化组胺4受体（HRH4）吸引肥大细胞至结肠，使得其变得高度敏感。IBS患者粪便中被发现大量含有这种释放组胺的Klebsiella aerogenes细菌，而以药物抑制HRH4则可以减缓小鼠结肠内的肥大细胞累积与肠道敏感情形。因此降低细菌组胺或靶向肠道组胺4受体可能有助于改善IBS症状。靶点：RASAL1疾病：消化性溃疡（peptic ulcer）期刊/PMID：Science Translational Medicine / 35857828发现：消化性溃疡是一项常见的临床问题，可能会引发像是出血或穿孔的严重并发症。胃酸的分泌是造成消化性溃疡的决定性因素之一，而其分泌则由胃部G细胞制造的胃泌素（gastrin）所控制。研究人员发现轴突导向蛋白（semaphorin）和神经丛蛋白（plexin）信号通路可以抑制G细胞分泌胃泌素，进而限制由食物引起的胃酸分泌，而Ras GTP酶活化蛋白RASAL1是此信号通路的中央介导物。此外RASAL1也被发现与由非甾体抗炎药（NSAID）这种造成人类消化性溃疡主要风险因子所引起的病程相关。因此靶向RASAL1药物具潜力抑制胃酸分泌并缓解消化性溃疡。希望这些优秀的研究成果可以早日进入临床转化，为各类疾病的患者带来不同的治疗选择与可能的生活品质改善！药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息参考资料：[1] Hu, Meiqin et al. (2022) Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 185,13: 2292-2308.e20. DOI:10.1016/j.cell.2022.05.021[2] O'Neill, Adam C et al. (2002) Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity. Science 376,6599: eabf9088. DOI:10.1126/science.abf9088[3] Cho, Frances S et al. (2022) Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents. Science translational medicine 14,652: eabj4310. DOI:10.1126/scitranslmed.abj4310[4] De Palma, Giada et al. (2022) Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Science translational medicine14,655: eabj1895. DOI:10.1126/scitranslmed.abj1895[5] Xu, Rui et al. (2022) A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers. Science translational medicine 14,654: eabf1922. DOI:10.1126/scitranslmed.abf1922[6] de Reuver, Richard et al. (2022) ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature 607,7920: 784-789. DOI:10.1038/s41586-022-04974-w[7] Jiao, Huipeng et al. (2022) ADAR1 averts fatal type I interferon induction by ZBP1. Nature 607,7920: 776-783. DOI:10.1038/s41586-022-04878-9免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

信使RNA疫苗

2022-06-20

·Science Daily

Diversity of centrosomes delivers new clues for neurological diseases

A neurobiologist is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders. Internationally renowned neurobiologist Magdalena Götz is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team at Helmholtz Munich and Ludwig-Maximilians-Universität München, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders. The centrosome is the organelle responsible for the organization of the cytoskeleton during cell division, an essential function in organisms from yeast to humans. Until now, scientists assumed that the centrosome was very similar in all cells due to its general tasks. However, Magdalena Götz and her team evaluated this notion in neurons and their developmental precursors, so-called neuronal stem cells. "There is so much we don't yet know about these cells, including how the centrosomes of neurons compare to those of neural stem cells and other cell types," Götz says. Their subsequent discoveries now fundamentally challenge the assumption that all centrosomes are created equal. Centrosomes are in fact not "one type fits all" In close collaboration with the Helmholtz Munich Proteomic Core Facility led by Stefanie Hauck, the researchers found that the composition of proteins in centrosomes differs profoundly depending on the cell type. "We were surprised not only by the unexpected high degree of heterogeneity of the centrosomes, but also by the discovery of many unexpected proteins associated with them -- for example, RNA-binding proteins and even proteins responsible for splicing (the processing of RNA), which normally takes place in the nucleus," Götz explains: The location of centrosome-associated proteins is crucial for disease The scientists discovered that a specific protein (the ubiquitously expressed splicing protein PRPF6) is enriched at the centrosome in neural stem cells, but not in neurons. A mutation of the protein found in patients with brain malformation periventricular heterotopia also leads to a similar phenotype in animal models. Magdalena Götz concludes, "This means that the location of a protein is crucial for a disease. With our centrosome analysis, we now have an important resource to test further associations with neuronal diseases. In particular, our research can explain for the first time why a protein that is present in all cells, after mutation, causes a phenotype only in the brain, but not in other organs. This will allow further insights into disease mechanisms -- and thus get one step closer to their treatment." About the people Professor Magdalena Götz is a director at Helmholtz Munich since 2004, where she heads the Institute of Stem Cell Research. She also holds the Chair of Physiological Genomics at Ludwig-Maximilians-Universität München. In 2019, she received the Mendel Medal of the National Academy of Sciences Leopoldina for her scientific achievements. She conducted the current study together with first authors Adam C. O'Neill, Fatma Uzbas, Giulia Antognolli and Florencia Merino, among others.