更新于：2024-09-19

HIF3A

更新于：2024-09-19

基本信息

别名

Basic-helix-loop-helix-PAS protein MOP7、bHLHe17、Class E basic helix-loop-helix protein 17

+ [12]

简介

Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity). Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression. Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation (PubMed:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395). May act as a tumor suppressor and inhibits malignant cell transformation (PubMed:17998805). Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.

关联

100 项与 HIF3A 相关的临床结果

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100 项与 HIF3A 相关的转化医学

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0 项与 HIF3A 相关的专利（医药）

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272

项与 HIF3A 相关的文献（医药）

2024-09-01·Anticancer Research

Hypoxia-induced Factor-1α and its Role in Endometrial Cancer

Review

作者: Romanowicz, Hanna ; Samulak, Dariusz ; Kołaciński, Radosław ; Langner, Sara ; Łukasiewicz, Honorata ; Smolarz, Beata

The transcription factor hypoxia inducible factor-1 (HIF-1) is one of the main factors in the cell's response to a lack of oxygen. Hypoxia is a typical feature of a growing cancerous tumor. Increased activity of HIF-1 is observed in many cancers, including endometrial cancer. HIF-1 functions as a heterodimer consisting of three subunits HIF-1α, HIF-2α, and HIF-3α and one subunit β. HIF-1α is a subunit that is sensitive to oxygen concentration and is constitutively expressed. The HIF-1α gene is highly polymorphic. Literature data suggest that single nucleotide polymorphisms (SNPs) of the HIF-1α gene may be risk factors for endometrial cancer. A better understanding of the molecular mechanisms of cancer development, progression and prognosis, including the role of SNPs, could lead to the development of new anti-cancer therapies.

2024-09-01·Pflügers Archiv - European Journal of Physiology

Hypoxia-inducible factors in postnatal mouse molar dental pulp development: insights into expression patterns, localisation and metabolic pathways

Article

作者: Matalová, Eva ; Lesot, Hervé ; Dadáková, Kateřina ; Veselá, Barbora ; Sharpe, Paul T ; Holomková, Kateřina ; Švandová, Eva

Hypoxia is relevant to several physiological and pathological processes and this also applies for the tooth. The adaptive response to lowering oxygen concentration is mediated by hypoxia-inducible factors (HIFs). Since HIFs were shown to participate in the promotion of angiogenesis, stem cell survival, odontoblast differentiation and dentin formation, they may play a beneficial role in the tooth reparative processes. Although some data were generated in vitro, little is known about the in vivo context of HIFs in tooth development. In order to contribute to this field, the mouse mandibular first molar was used as a model.The expression and in situ localisation of HIFs were examined at postnatal (P) days P0, P7, P14, using RT-PCR and immunostaining. The expression pattern of a broad spectrum of hypoxia-related genes was monitored by customised PCR Arrays. Metabolic aspects were evaluated by determination of the lactate level and mRNA expression of the mitochondrial marker Nd1.The results show constant high mRNA expression of Hif1a, increasing expression of Hif2a, and very low expression of Hif3a during early postnatal molar development. In the examined period the localisation of HIFs in the nuclei of odontoblasts and the subodontoblastic layer identified their presence during odontoblastic differentiation. Additionally, the lower lactate level and higher expression of mitochondrial Nd1 in advanced development points to decreasing glycolysis during differentiation. Postnatal nuclear localisation of HIFs indicates a hypoxic state in specific areas of dental pulp as oxygen demands depend on physiological events such as crown and root dentin mineralization.

2024-08-02·Expert Opinion on Therapeutic Patents

A patent review on hypoxia-inducible factor (HIF) modulators (2021–2023)

Review

作者: Gao, Yinli ; Liu, Jiaming ; Zhang, Xiaojin

INTRODUCTIONHypoxia-inducible factor (HIF) is a central regulatory factor in detecting and adapting to cellular oxygen stress. Dysregulation of HIF is associated with various human diseases. Seven HIF modulators, including six prolyl hydroxylase (PHD) inhibitors and one HIF-2α inhibitor, have already been approved for the treatment of renal anemia and cancer, respectively.AREAS COVEREDThis review summarizes HIF modulators patented in the 2021-2023 period. This review provides an overview of HIF downregulators, including HIF-1α inhibitors, HIF-2α inhibitors, and HIF-2α degraders, as well as HIF upregulators, including PHD, FIH, and VHL inhibitors, and HIF-2α and HIF-3α agonists.EXPERT OPINIONEfforts should be made to address the adverse clinical effects associated with approved HIF-modulating drugs, including PHD inhibitors and HIF-2α inhibitors. Identification of the specific buried cavity in the HIF-2α and an opened pocket in HIF-3α offer an avenue for designing novel modulators for HIF-2α or HIF-3α. Given the similarities observed in the binding cavities of HIF-2α and HIF-3α, it should be considered whether the approved HIF-2α inhibitors also inhibit HIF-3α. A comprehensive understanding of the HIF signaling pathway biology would lead to the development of novel small-molecule HIF modulators as innovative therapeutic approaches for a wide range of human diseases.

项与 HIF3A 相关的新闻（医药）

2023-12-12

·今日头条

双靶向抑制剂！沈阳药科大学陈国良/王立辉团队发现癌症发展最新分子机制

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读：肺癌是全球最常见的癌症之一，也是导致癌症相关死亡的主要原因，每年估计有200万新病例和176万人死亡。 12月10日，沈阳药科大学陈国良、王立辉共同通讯在期刊《ADVANCED SCIENCE》上在线发表题为“The Interplay Between HIF-1α and EZH2 in Lung Cancer and Dual-Targeted Drug Therapy”的研究论文，研究证明了表观遗传修饰酶EZH2参与了HIF-1α抑制剂耐药过程。抑制HIF-1α会导致PRC2复合物中SUZ12的转录抑制丧失，进而增加EZH2酶活性。同时，EZH2作为HIF-1α的转录抑制因子。HIF-1α和EZH2相互作用形成负向反馈环路，促进癌症发展。双靶向抑制剂DYB-03在体外和体内结合EZH2和HIF-1α，发挥抗肿瘤作用。结果为双靶向HIF-1α和EZH2提供了药理学基础。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202303904 研究背景 01 肺癌是全球最常见的癌症之一，也是导致癌症相关死亡的主要原因，每年估计有200万新病例和176万人死亡。非小细胞肺癌（NSCLC）根据组织病理类型的诊断约占所有病例的85%。NSCLC的治疗异常复杂，原因在于存在同时发生的基因组变异、代谢重编程和表观遗传异常。低氧是NSCLC等实体肿瘤的一个显著特征。肿瘤内低氧和反应性氧化物种、细胞因子和生长因子等信号分子的参与导致HIF（低氧诱导因子）高度活化。HIF是一个转录因子，由两个亚基组成，即HIF-1α（或其类似物HIF-2α和HIF-3α）和HIF-1β。表观遗传修饰是一种生物学过程，其中DNA序列保持不变，但由于可逆的调节作用，主要包括DNA甲基化和组蛋白修饰，表型被改变。表观遗传失调在肿瘤的发展、进展和获得治疗抵抗中发挥着重要作用，包括实体肿瘤和血液系统恶性肿瘤。除了在单药治疗中潜在的作用外，表观遗传药物可能在与其他抗癌疗法协同作用或逆转耐药方面发挥重要作用。 DYB-03通过靶向 HIF-1和EZH2发挥抗肿瘤功能 02 研究人员建立了一个稳定的EZH2/HIF-1α双基因敲除细胞系。与亲本细胞相比，EZH2/HIF-1α双基因敲除细胞在增殖和迁移能力上部分丧失，表明这两种蛋白在肿瘤发生中起到了作用。集落形成和划痕愈合实验显示，与对照相比，DYB-03对双基因敲除细胞的增殖和迁移没有显著影响。Transwell实验显示，DYB-03抑制细胞迁移的能力消失，但当重新输入HIF-1α和EZH2时，这种抑制效果被逆转，表明DYB-03作用于HIF-1和EZH2。研究人员在体内验证了DYB-03的靶向特异性，并显示双基因敲除HIF-1α和EZH2可以减缓A549的肿瘤生长，类似于DYB-03对亲本细胞的抑制效果。此外，DYB-03的给药对A549双基因敲除细胞的肿瘤生长没有显著抑制作用，表明DYB-03通过作用于HIF-1α和EZH2发挥其抗肿瘤活性。免疫印迹验证了A549双基因敲除细胞的蛋白稳定性。肿瘤组织的组织学分析还检测了Ki67和CD31的表达。双基因敲除肿瘤组织中Ki67和CD31的表达要比亲本肿瘤组织低得多。DYB-03的给药在亲本组中显示出明显的抗增殖和抗血管生成作用，而在A549双基因敲除组中作用较小。上述结果表明，DYB-03通过作用于HIF-1和EZH2在体内也发挥其抑制肿瘤的效果。研究结果 03 综上所述，研究证明了表观遗传修饰酶EZH2参与了HIF-1α抑制剂耐药过程。抑制HIF-1α会导致PRC2复合物中SUZ12的转录抑制丧失，进而增加EZH2酶活性。同时，EZH2作为HIF-1α的转录抑制因子。HIF-1α和EZH2相互作用形成负向反馈环路，促进癌症发展。双靶向抑制剂DYB-03在体外和体内结合EZH2和HIF-1α，发挥抗肿瘤作用。结果为双靶向HIF-1α和EZH2提供了药理学基础。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202303904 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

临床结果临床研究

2022-09-22

·生物谷

Mol Psych：即使少量饮酒也会诱发大脑回路中表观基因组和转录组学的改变

来自伊利诺伊大学等机构的科学家们通过对啮齿类动物进行研究后发现，即使少量饮酒或许也会诱发特定大脑回路中表观基因组和转录组学的改变，该大脑回路对于机体成瘾症的发生至关重要。诸如抗焦虑和欣快感等饮酒所产生的积极作用似乎是酒精使用障碍（AUD，alcohol use disorder）开始和维持的一个关键因素，然而，急性乙醇暴露后从染色质重组到转录组改变的机制，目前研究人员尚不清楚。近日，一篇发表在国际杂志Molecular Psychiatry上题为“Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis”的研究报告中，来自伊利诺伊大学等机构的科学家们通过对啮齿类动物进行研究后发现，即使少量饮酒或许也会诱发特定大脑回路中表观基因组和转录组学的改变，该大脑回路对于机体成瘾症的发生至关重要。更重要的是，研究者表示，参与激发大脑成瘾的途径或许和与大量饮酒（能产生欣快感和抗焦虑反应）相关的途径相同。研究者Subhash Pandey表示，当大脑经历饮酒所产生的抗焦虑作用和情绪提升时（放松感），其或许也在为酒精使用障碍的发生做准备。尽管这项研究并未阐明这一点，比如，一杯酒会导致人类上瘾，但其确实提供了一些线索表明，为何某些人对酒精使用障碍非常易感。研究者指出，这种依赖性行为可能并不总是来自长期、高数量的习惯，而是大脑中快速表观遗传学变化的结果，本文研究结果表明，即使在低剂量时也可能会开始发生。这篇研究报告中，研究人员在控制和酒精暴露的条件下对老鼠进行了研究，实验中，啮齿类动物暴露于低浓度的酒精中，当其在探索迷宫时研究人员对其行为进行观察，随后利用RNA测序分析其在安乐死后大脑的组织样本，并寻找基因表达的模式。当研究人员分析样本后，他们发现，名为Hif3a（hypoxia inducible factor 3 alpha subunit，缺氧诱导因子3α亚单位）的基因或许与酒精暴露后大脑的改变和机体行为改变相关，比如，老鼠在迷宫中被封闭（高度焦虑）或张开双臂（低度焦虑）的区域停留多长时间等。酒精会增加Hif3a的表达，即使是在低剂量接触后也会帮助减少焦虑症，而且，尽管酒精的多种影响在雄性和雌性之间是不同的，但在这项研究中两者之间并没有区别。喝多少酒才算喝多了？科学家们给出答案。图片来源：Molecular Psychiatry (2022). DOI: 10.1038/s41380-022-01732-2 研究者Pandey说道，我们发现，低剂量（也就是我们所说的社交饮酒）能改变大脑杏仁核中的基因表达，杏仁核是大脑中负责调节焦虑症的特殊区域，换句话说，其能为成瘾创造一条表观遗传学途径。研究人员还进行了额外的实验，即在暴露或未暴露于酒精的情况下阻断老鼠大脑杏仁核中的基因表达来验证其调节机体焦虑症的作用，当Hif3a被阻断后，焦虑症就会在对照老鼠机体中增加，这或许就模拟了慢性酒精暴露的戒断作用，从另一方面来讲，这还能够预防酒精所产生的抗焦虑作用。研究者还揭示了为何Hif3a的染色质是松散的，这意味着其基因很容易发生转录的改变，然而，本文研究并没有揭示对于啮齿类动物而言什么程度的酒精暴露是安全的，但重要的是我们要知道，低剂量的饮酒会产生成瘾的诱因，对于人们而言，他们的收获或许很简单，即不要认为社交饮酒甚至大范围的饮酒是没有风险的。酒精使用障碍是复杂且具有挑战性的，本文研究结果或能帮助更好地理解大脑中正在发生的事情，而且未来还有望被科学家们用来开发更好的疗法和药物。（生物谷Bioon.com）原始出处： Krishnan, H.R., Zhang, H., Chen, Y. et al. Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis. Mol Psychiatry (2022). doi：10.1038/s41380-022-01732-2