更新于：2024-05-01

TEAD1

TEA domain transcription factor 1

更新于：2024-05-01

基本信息

别名

AA、NTEF-1、Protein GT-IIC

+ [10]

简介

Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and cooperatively to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription in vivo in a cell-specific manner. The activation function appears to be mediated by a limiting cell-specific transcriptional intermediary factor (TIF). Involved in cardiac development. Binds to the M-CAT motif.

关联

项与 TEAD1 相关的药物

TT-10

靶点

TEAD1 x YAP1

作用机制

A2aR拮抗剂 [+2]

在研机构

Portage Biotech, Inc.

原研机构

Tarus Therapeutics, Inc.初创企业

在研适应症

去势抵抗性前列腺癌 [+3]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

SW-682

靶点

TEAD1

作用机制

TEAD1抑制剂

在研机构

SpringWorks Therapeutics LLC [+1]

原研机构

SpringWorks Therapeutics LLC

在研适应症

晚期恶性实体瘤 [+3]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

IK-930

靶点

TEAD1

作用机制

TEAD1抑制剂

在研机构

Ikena Oncology, Inc.

原研机构

Ikena Oncology, Inc.

在研适应症

晚期恶性实体瘤 [+4]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 TEAD1 相关的临床试验

NCT06251310 / Not yet recruiting临床1期

A Phase 1a/1b Dose Escalation, Dose Expansion Study of SW-682 in Participants With Advanced Solid Tumors Enriched for Those With Hippo Pathway Mutations

This is a first-in-human (FIH), Phase 1a/1b open-label, multicenter, dose escalation and dose expansion study of SW-682 in adult participants with metastatic or unresectable advanced solid tumors with or without Hippo pathway alterations that are refractory to, or have progressed, during or after appropriate prior systemic anticancer therapy, including chemotherapy, immunotherapy, radiation therapy or targeted therapy, or for which no treatment is available, or prior standard of care (SOC) therapy was not tolerated and for which there is no further SOC treatment available. The study includes a Part 1 (Phase 1a) dose escalation phase and a Part 2 (Phase 1b) dose expansion to optimize the dose to be used for further development. All participants will self-administer SW-682 by mouth in 28-day cycles.

开始日期2024-07-01

申办/合作机构

Springworks Therapeutics, Inc.

IRCT20220424054643N2 / Recruiting临床2/3期IIT

Safety and Effect of Celastrol Supplementation on Rate of Union in Femur and Tibia Fracture Patients

开始日期2023-12-22

申办/合作机构

Shahid Beheshti University of Medical Sciences

NCT04969315 / Recruiting临床1/2期

Phase I/II First-in-Human Study of TT-10 as a Single Agent in Subjects With Advanced Selected Solid Tumors

The purpose of this study is to evaluate the safety and tolerability of orally administered TT-10 in subjects with advanced selected solid tumors. The dose escalation portion of the study will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of TT-10.

开始日期2023-06-23

申办/合作机构

Portage Biotech, Inc.

[+1]

100 项与 TEAD1 相关的临床结果

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100 项与 TEAD1 相关的转化医学

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0 项与 TEAD1 相关的专利（医药）

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3,093

项与 TEAD1 相关的文献（医药）

2024-03-01·Food research international (Ottawa, Ont.)

Effect of composition, casein genetic variants and glycosylation degree on bovine milk whipping properties.

Article

作者: Barana Hewa Nadugala ; Graham Hepworth ; Michael Mazzonetto ; Tom Nebl ; Charles N Pagel ; Jared K Raynes ; C S Ranadheera ; Amy Logan

This study investigated the individual and combined effects of ĸ-Casein (ĸ-CN; AA, AB, BB), β-Casein (β-CN; A1A1, A1A2, A2A2) and high and low ratios of glycosylated ĸ-CN to total ĸ-CN, referred to as the glycosylation degree (GD), on bovine cream whipping properties. The genetic variants of individual cows were identified using reversed-phase high-performance liquid chromatography (RP-HPLC) and verified through liquid chromatography-mass spectrometry (LC-MS). A previously discovered relationship between days-in-milk and GD was validated and used to obtain high and low GD milk. Whipped creams were created through the mechanical agitation of fat standardised cream from milk of different ĸ-CN, β-CN, and GD combinations, and whipping properties (the ability to whip, overrun, whipping time and firmness) were evaluated. No significant correlation was measured in whipping properties for cream samples from milks with different ĸ-CN and β-CN genetic variants. However, 80 % of samples exhibiting good whipping properties (i.e., the production of a stiffened peak) were from milk with low GD suggesting a correlation between whipping properties and levels of glycosylation. Moreover, cream separated from skim milk of larger casein micelle size showed superior whipping properties with shorter whipping times (<5 min), and higher firmness and overrun. Milk fat globule (MFG) size, on the other hand, did not affect whipping properties. Results indicate that the GD of κ-CN and casein micelle size may play a role in MFG adsorption at the protein and air interface of air bubbles formed during whipping; hence, they govern the dynamics of fat network formation and influencing whipping properties.

2024-02-22·Diabetes, obesity & metabolism

TEAD1, MYO7A and NDUFC2 are novel functional genes associated with glucose metabolism in BXD recombinant inbred population.

Article

作者: Yingying Wu ; Chao Zhang ; Shaofei Duan ; Yushan Li ; Lu Lu ; Akhilesh Bajpai ; Chunhua Yang ; Jia Mi ; Geng Tian ; Fuyi Xu ; Donglai Qi ; Zhaowei Xu ; Xiao Dong Chi

AIM:

The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause non-alcoholic fatty liver disease, type 2 diabetes mellitus, dyslipidaemia, etc. We aimed use systematic investigation of the key factors related to hepatic glucose metabolism, which may be beneficial for understanding the underlying pathogenic mechanisms for obesity and diabetes mellitus.

MATERIALS AND METHODS:

Oral glucose tolerance test (OGTT) phenotypes and liver transcriptomes of BXD mice under chow and high-fat diet conditions were collected from GeneNetwork. QTL mapping was conducted to pinpoint genomic regions associated with glucose homeostasis. Candidate genes were further nominated using a multi-criteria approach and in vitro validated to confirm their functional relevance.

RESULTS:

Our results showed that plasma glucose levels in the oral glucose tolerance test were significantly affected by both diet and genetic background. To identify further the candidate genes associated with hepatic glucose metabolism, the results revealed nine genetic regulating loci on chromosomes 1, 4, 7 and 11, respectively, by quantitative trait loci mapping. Moreover, TEA Domain Transcription Factor 1 (TEAD1), myosin VIIA (MYO7A) and NADH:ubiquinone oxidoreductase subunit C2 (NDUFC2) were identified as the candidate functional genes. Functionally, siRNA-mediated TEAD1, MYO7A and NDUFC2 significantly decreased glucose uptake. Reverse transcription-polymerase chain reaction assays confirmed that the downregulation of those three candidates inhibited the transcription of genes related to insulin and glucose metabolism pathways.

CONCLUSIONS:

Our study contributes novel insights to the understanding of hepatic glucose metabolish, demonstrating the impact of TEAD1, MYO7A and NDUFC2 on mitochondrial function in the liver and their regulatory role in maintaining in glucose homeostasis.

2024-02-21·Biochimica et biophysica acta. General subjects

Alpha-fetoprotein upregulates hepatocellular carcinoma cell-intrinsic PD-1 expression through the LATS2/YAP/TEAD1 pathway.

Article

作者: Guangxian Leng ; Hongxia Gong ; Guiyuan Liu ; Yin Kong ; Liuqing Guo ; Youcheng Zhang

BACKGROUND:

Hepatocellular carcinoma (HCC) cell-intrinsic programmed death 1 (PD-1) promotes tumor progression. However, the mechanisms that regulate its expression are unclear. This study investigated the impact of alpha-fetoprotein (AFP) on HCC cell-intrinsic PD-1 expression.

METHODS:

The expression of PD-1 and AFP at the gene and protein levels was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Proteins interacting with AFP were examined by co-immunoprecipitation (CO-IP). Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were used to identify transcription-enhanced association domain 1 (TEAD1) binding to the promoter of PD-1.

RESULTS:

The expression of HCC cell-intrinsic PD-1 was positively correlated with AFP. Mechanistically, AFP inhibited the phosphorylation of large tumor suppressor 2 (LATS2) and yes-associated protein (YAP). As a result, YAP is transferred to the nucleus and forms a transcriptional complex with TEAD1, promoting PD-1 transcription by binding to its promoter.

CONCLUSION:

AFP is an upstream regulator of the HCC cell-intrinsic PD-1 and increases PD-1 expression via the LATS2/YAP/TEAD1 axis.

GENERAL SIGNIFICANCE:

Our findings provide insight into the mechanisms of HCC development and offer new ideas for further in-depth studies of HCC.

项与 TEAD1 相关的新闻（医药）

2024-03-26

·生物探索

JCI | 澄清争议！周兆才/赵世民等合作发现丙烯酰tRNA合成酶AARS1作为一种乳酸转移酶在胃癌中促进YAP信号传导

引言乳酸酰化是一种新的翻译后修饰，广泛发生在组蛋白和非组蛋白的赖氨酸残基上。乙酰基转移酶p300被认为介导蛋白质的乳酸化，然而，所提出的乙酰基供体乙酰辅酶A的细胞浓度比乙酰辅酶A低约1000倍，这就提出了p300是否是真正的乙酰基转移酶的问题。2024年3月21日，同济大学、复旦大学及安徽科技大学等多单位合作，周兆才、赵世民及Shi Jiao共同通讯在 Journal of clinical Investigation 在线发表题为“The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer”的研究论文，该研究报道了Alanyl-tRNA合成酶1 (AARS1)作为一种真正的乳酸转移酶，直接使用乳酸和ATP来催化蛋白质的乳酸化。在候选底物中，该研究关注的是Hippo通路，它在肿瘤发生中具有明确的作用。具体来说，AARS1被发现能感知细胞内乳酸并转运到细胞核内以乳酸化并激活YAP-TEAD复合物；而AARS1本身被鉴定为Hippo靶基因，与YAP-TEAD形成正反馈回路，促进胃癌(GC)细胞增殖。与此一致的是，AARS1在GC中表达上调，且AARS1表达升高与GC患者预后不良相关。总的来说，这项工作在体外和体内发现了AARS1具有乳酸转移酶活性，并揭示了代谢物乳酸是如何转化为细胞增殖信号的。乳酸是一种众所周知的代谢物，几乎存在于所有类型的细胞中，由于Warburg效应，在增殖的肿瘤细胞中含量很高。尽管许多研究表明，肿瘤分泌的乳酸可以进入多种类型的免疫细胞，形成有利于肿瘤生长的微环境，但细胞内乳酸是如何表现为或转化为有利于肿瘤生长的信号的，仍然是未知的。最近，赖氨酸残基的乳酸化已被确定为组蛋白的一种新的翻译后修饰，为乳酸的非代谢功能提供了新的视角。例如，组蛋白乳酸化已被发现在干细胞多能性、神经兴奋、阿尔茨海默病、巨噬细胞极化和肿瘤发展中发挥重要作用。最近，在非组蛋白中也发现了乳酸化。例如，对肝癌的一项综合乳酸组学和蛋白质组学分析发现，在非组蛋白中有9000多种乳酸化赖氨酸。尽管蛋白质乳酸化越来越被认为是一种广泛存在的翻译后修饰，尤其是在肿瘤细胞中，但这种酶直接催化这种修饰，以及催化的确切化学反应过程仍然存在争议。具体来说，乙酰转移酶p300被认为是一种乳酸转移酶，因此介导组蛋白的乳酸化，但缺乏使用纯化的p300蛋白和底物的直接体外证据。更重要的是，在提出的催化系统中，p300需要使用乳酸辅酶A (lactyl-CoA)作为乳酸供体，但在哺乳动物细胞中负责产生乳酸辅酶A的酶仍然不明确，并且肿瘤细胞中乳酸辅酶A的水平几乎无法检测到。事实上，细胞内乳酸辅酶A的浓度至少比哺乳动物细胞中的乙酰辅酶A低1000倍，这可能会大大限制p300在体内的乙酰转移酶活性(如果有的话)。因此，一种真正的乳酸转移酶，能够直接使用乳酸作为乳酸供体来催化底物的体外和体内的乳酸化，还有待于鉴定。机理模式图（图源自Journal of clinical Investigation ）进化保守的Hippo信号通路在器官大小控制、组织稳态和肿瘤发生中发挥重要作用。在这一途径中，MST1/2 (Hippo)-LATS1/2激酶级联控制亚细胞定位，从而控制转录辅激活因子YAP/TAZ 的活性。然而，在各种环境刺激下，上游激酶级联可以失活，使YAP/TAZ进入核，并与TEAD家族转录因子相互作用，调节下游靶基因的表达。Hippo通路的失调，特别是YAP的过度激活，已被证明与异常细胞生长和肿瘤发生密切相关。据推测，Hippo通路也可能直接感知某些代谢线索。然而，将细胞内乳酸与Hippo-YAP信号联系起来的特定分子机制(如果有的话)尚未被发现，特别是在乳酸含量丰富且YAP过度活跃的肿瘤细胞中。该研究鉴定了通常催化L-丙氨酸与tRNA连接的AARS1是一种真正的乳酸转移酶，可以直接利用乳酸和ATP来催化蛋白质的乳酸化。此外，研究发现，为了响应细胞内乳酸的积累，AARS1易位进入细胞核，直接催化K90位点的YAP和K108位点的TEAD1的乳酸化，从而激活下游靶基因的表达，从而促进肿瘤细胞的增殖。此外，AARS1被证明是YAP-TEAD1的一个直接靶基因，形成一个正反馈回路，将高水平的细胞内乳酸作为生长信号。在胃癌(GC)中，AARS1表达上调并与YAP-TEAD1乳酸化相关，并且AARS1表达升高与TNM分期和不良临床结果密切相关。总的来说，这项工作发现AARS1在体外和体内具有乳酸转移酶活性，并揭示了代谢物乳酸是如何转化为细胞增殖的信号的。原文链接https://www.jci.org/articles/view/174587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CRISPR技术进化史 | 24年Cell综述

抗体药物偶联物

2024-03-22

·生物谷

Cell Systems封面论文：中科院深圳先进院戴卓君团队实现合成生物学赋能的接枝反应

团队开发了能够自主生产、裂解和释放特定MutS的大肠杆菌，进而生成接枝了TaMutS或TmMutS的MELG系统。近日，中国科学院深圳先进技术研究院戴卓君团队在 Cell 子刊 Cell Systems 发表了题为：Engineering Functional Materials through Bacteria-assisted Living Grafting 的研究性工作。该研究借鉴化学接枝反应的策略，通过合成生物学手段编程微生物，实现了功能蛋白的持续生产与原位接枝，赋予了材料多样的生物学功能。在传统化学接枝反应中，虽可实现大分子或其表面的功能化修饰，但赋予的性质往往受限于亲疏水性、pH值、温度敏感性等物理化学属性，缺乏生物学功能（例如结合错配DNA等）。相较之下，该研究借鉴了植物嫁接中供体植物可生长并提供多个接穗的理念，通过调控工程细菌持续的生长及释放功能蛋白模块，增强了接枝反应的稳定性和自我修复能力，获得了一系列动态可调、可再生的生物功能。该工作也被选为 Cell Systems 的封面文章。研究团队通过聚合物支架封装了工程细菌，支架内含有大约20微米的带有活性接枝位点的微粒；这些经过基因线路调控的微生物能够在支架内生长，感知到自我密度，并自主裂解释放特定的功能蛋白；携带标签的目标蛋白能够有效地接枝至支架内的活性位点，从而组装为MELG（Materials Engineered by Living Grafting）（如图1）。系统具备高度的模块化特性：提供蛋白模块的底盘细胞、可定制的基因线路、多种功能蛋白模块以及接枝化学反应，所有这些都可以灵活调节。得益于活体微生物可源源不断的提供接枝蛋白，这套系统展现出对外部干扰的高度稳定性和可再生能力。在此基础上，团队进一步开发了多种功能性MELG：如能够响应生物信号进行蛋白质的可控释放、合成高值化学品橄榄醇酸，以及修正错配的DNA序列。图1. MELG的模块、系统及下游应用活体接枝材料消除错配DNA 以识别并结合错配DNA，从而降低合成DNA错误率的MELG系统为例。合成生物学的快速进展得益于DNA合成技术的突破。然而，通过芯片合成核苷酸池并组装双链DNA的方法在提高合成效率的同时也积累了错误率。自然界的生物为了维持自身遗传物质的完整性和稳定性，天然具有DNA 错配修复系统。其中DNA结合蛋白MutS即是细菌错配修复系统的关键成分。同时，不同物种来源的MutS对不同类型的DNA错配具有区别化的结合特异性。团队开发了能够自主生产、裂解和释放特定MutS（来自Thermus aquaticus的TaMutS和来自Thermotoga maritima的TmMutS）的大肠杆菌，进而生成接枝了TaMutS或TmMutS的MELG系统（图2a-b）。实验数据显示，接枝了TmMutS的MELG对GG错配具有较强的结合能力，而接枝了TaMutS的MELG则对AA错配有更高的亲和力（图2c）。因此，结合使用这两种MELG能够有效消除含有AA和GG错配的DNA片段（图2d）。此外，MELG系统可被长期存储，并根据需要进行组装使用（图2e）。所接枝的功能蛋白可以再生，例如：团队制造了大肠杆菌来源EcMutS 接枝的MELG，并捕获了标记有荧光信号的错配DNA；系统在随后进行了洗脱，去除了接枝的EcMutS，但是在培养基中重新培养系统后，再生的MELG可以再次捕获错误片段，证明了系统可再生的特性（图2f）。

微生物疗法寡核苷酸

2024-03-21

·生物谷

Mol Syst Biol：新研究揭示雌激素可以预防脂肪肝病的产生

研究人员发现，阻断TEAD1可以保护肝细胞免受脂肪的有害积累。接受雌激素治疗的小鼠 TEAD1 活性较低，肝脏中的脂肪积累也较少。在一项新的研究中，来自瑞典卡罗林斯卡医学院的研究人员通过研究，证实了雌激素是如何防止代谢功能障碍相关脂肪变性肝病（metabolic dysfunction-associated steatotic liver disease, MASLD）。他们还发现一种正在开发的新药，其未来可能成为治疗脂肪肝病和肝癌的药物。相关研究结果于2024年3月8日发表在Molecular Systems Biology期刊上，论文标题为“Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis”。全球肥胖症的流行导致脂肪肝病患者急剧增加。从去年开始，由肥胖（而非过量饮酒）引起的脂肪肝病被称为MASLD。根据以往的研究，每三名成年人中就有一人患有不同程度的 MASLD，最严重的可发展为肝硬化和肝癌。女性在绝经前受到保护然而，MASLD在两性之间的分布非常不均衡，绝大多数患者都是男性。论文通讯作者、卡罗林斯卡医学院微生物学、肿瘤与细胞生物学系高级研究员Claudia Kutter解释说，“由于女性性激素雌激素的作用，女性在绝经前一直受到天然保护。” 虽然女性激素的保护作用早已为人所知，但这种保护作用背后的机制却不太清楚。如今，Kutter及其团队可能已经找到了答案。图片来自Molecular Systems Biology, 2024, doi:10.1038/s44320-024-00024-x 通过对喂食高脂肪饮食的雌雄小鼠（其中的一些雄性小鼠还接受了雌激素治疗）进行基因分析，这些作者发现了脂肪肝病发生过程中的一种关键蛋白。他们发现，这种名为 TEAD1 的蛋白在调节肝细胞摄取脂肪的过程中发挥着关键作用。阻断TEAD1可以保护肝细胞免受脂肪的有害积累。接受雌激素治疗的小鼠 TEAD1 活性较低，肝脏中的脂肪积累也较少。正在开发的新药接下来，这些作者测试了在人类肝细胞中阻断 TEAD1 的效果。不过，能做到这一点还真有点运气。Kutter说，“一家制药公司正在开发一种能阻断TEAD1的抗癌药物，这让我们得以验证我们的假设。” TEAD1与癌症有关的事实并没有让她担心，恰恰相反。她说，“由于 TEAD 蛋白的活性在癌症中会升高，因此从癌症的角度来看，在早期阻断 TEAD 也是有积极意义的。目前，肝癌患者的诊断非常晚。如果在早期给病人服用这种药物来预防脂肪肝病，也有望防止肝癌的发生。” 制药公司现在将开始对这种药物进行临床试验，以预防脂肪肝病，而Kutter团队将继续研究应对这种疾病的进一步方法。她说，“我们希望把重点放在如何更早地发现这种疾病和确定新的治疗靶标上。根据不同患者的性别和激素状况，可能需要采取不同的方法。”（生物谷 Bioon.com）参考资料： Christian Sommerauer et al. Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis. Molecular Systems Biology, 2024, doi:10.1038/s44320-024-00024-x. Study shows how estrogen protects against fatty liverhttps://medicalxpress.com/news/2024-03-estrogen-fatty-liver.html