Advances in biological regulation最新文献_第4页

The wheat VIH2-3B, a functional PPIP5K controls the localization of fasciclin-like arabinogalactan protein 小麦VIH2-3B是一个功能性的PPIP5K，它控制着筋状蛋白样阿拉伯半乳聚糖蛋白的定位

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-07-25 DOI: 10.1016/j.jbior.2025.101103

Anuj Shukla , Reshma Gopal , Riya Ghosh , Ankur Chaudhuri , Kanupriya Agrwal , Rahul Tanwar , Henning Jacob Jessen , Debabrata Laha , Ajay Kumar Pandey

Inositol pyrophosphates (PP-InsPs) are important signalling molecules that participate in multiple physiological processes across a wide range of eukaryotes. Metabolic pathway kinases (VIP1/VIHs) leading to the production of PP-InsPs are now well characterized in yeast and plants. Previously, the wheat (Triticum aestivum L.) inositol pyrophosphate kinase (TaVIH2) was shown to encode a catalytic active kinase domain. Heterologous expression of TaVIH2 in Arabidopsis thaliana was shown to enhance drought tolerance by modulating the cell composition. In this study, we attempted to identify the interacting protein targets of wheat VIH2-3B using a yeast two-hybrid (Y2H) cDNA library screen, which led to the identification of 52 putative interactors that are primarily involved in cell wall-related functions. Notably, fasciclin-like arabinogalactan protein (FLA7), a glycosylphosphatidyl inositol (GPI)-anchored protein, emerged as the most frequently interacting partner. Further analysis using pulldown assays validated the interaction between TaVIH2-3B and TaFLA7 in vivo. Using the reporter fusion studies, we observed the localization of TaFLA7 to be a plasma membrane and this localization of the TaFLA7 was perturbed in the yeast vip1Δ strain. The expression of TaVIH2-3B bearing PPIP5K enzymatic activity in yeast mutants rescued the level of IP₈ and restore the localization of the TaFLA7 to the membrane. Expression analysis of TaFLA7 revealed a differential expression response to drought in wheat shoot tissues. TaFLA7 was also found to be highly expressed during grain development, particularly in the endosperm and seed coat during grain maturation. Taken together, these findings highlight the potential role of TaVIH2 in cell wall remodelling and stress response pathways, offering new insights into the functional roles of VIH proteins in plants.

肌醇焦磷酸（PP-InsPs）是一种重要的信号分子，参与多种真核生物的多种生理过程。导致PP-InsPs产生的代谢途径激酶（VIP1/VIHs）现在已经在酵母和植物中得到了很好的表征。此前，小麦（Triticum aestivum L.）肌醇焦磷酸激酶（TaVIH2）编码一个催化活性激酶结构域。TaVIH2在拟南芥中的异源表达通过调节细胞组成来增强耐旱性。在这项研究中，我们试图利用酵母双杂交（Y2H） cDNA文库筛选小麦VIH2-3B的相互作用蛋白靶点，从而鉴定出52个主要参与细胞壁相关功能的推定相互作用蛋白。值得注意的是，一种糖基磷脂酰肌醇（GPI）锚定蛋白fasicillin -样阿拉伯半乳聚糖蛋白（fl7）是最常见的相互作用伙伴。进一步的下拉实验验证了tvih2 - 3b和TaFLA7在体内的相互作用。通过报告融合研究，我们观察到TaFLA7定位为质膜，并且在酵母vip1Δ菌株中TaFLA7的定位受到干扰。携带PPIP5K酶活性的TaVIH2-3B在酵母突变体中的表达挽救了IP8水平，恢复了TaFLA7在膜上的定位。TaFLA7的表达分析揭示了干旱对小麦茎部组织的差异表达响应。TaFLA7在籽粒发育过程中也被发现高表达，尤其是在籽粒成熟过程中的胚乳和种皮中。综上所述，这些发现突出了TaVIH2在细胞壁重塑和胁迫反应途径中的潜在作用，为植物中VIH蛋白的功能作用提供了新的见解。

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引用次数: 0

In-depth review of breast cancer and inflammation pre-and post-treatment strategies with conventional and novel Steroid agents 深入回顾乳腺癌和炎症治疗前后的策略与传统和新型类固醇药物

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-07-15 DOI: 10.1016/j.jbior.2025.101102

Panneerselvam Theivendren , Punitha Narayanasamy , Kumarappan Chidamabaram , Sangeetha Menon , Josephin Arockia Dhivya Antony Sahayaraj , Natarajan Kiruthiga , Balaji Pandiyan

Breast cancer leads to many women's cancer deaths worldwide and inflammation is essential for tumors to develop, advance and spread within the body. High levels of ongoing inflammation within the tumor help cancer cells multiply, encourage blood vessel formation and allow the cancer cells to evade detection by the immune system, so it is a target of choice for many cancer treatments. The relationship between breast cancer and inflammation is explored, stressing how important both early and late stages are, with both traditional and novel steroid options. For many years, corticosteroids and other conventional steroids have been used to help relieve side effects of treatment and boost the well-being of patients. Even so, steroids only working in certain patients and side effects have pushed scientists to discover new type of steroid derivatives that are better and safer. Targeted inflammation control and altered immune response in tumors by these new steroids could make therapy more successful. This review looks at current evidence from different types of studies to determine steroids' role in treating breast cancer-related inflammation. It also reviews options for using steroids together with chemotherapy, radiotherapy and immunotherapy, focusing on achieving the best anti-inflammatory results while keeping the inability to respond to treatment low. The study also looks at potential future progress in developing steroids, personalized medicine and therapies guided by biomarkers that could greatly improve how breast cancer is managed. Knowing how steroids affect tumors as well as inflammation is necessary for creating good treatment plans that improve breast cancer patients' chances of survival and lower their risk of disease recurrence.

乳腺癌导致全世界许多妇女因癌症死亡，而炎症是肿瘤在体内发展、发展和扩散的必要条件。肿瘤内持续的高水平炎症有助于癌细胞繁殖，促进血管形成，并使癌细胞逃避免疫系统的检测，因此它是许多癌症治疗的首选目标。探讨了乳腺癌和炎症之间的关系，强调了早期和晚期的重要性，以及传统和新型类固醇选择。多年来，皮质类固醇和其他常规类固醇一直被用来帮助减轻治疗的副作用，提高患者的健康水平。即便如此，类固醇只对某些病人有效，而且还有副作用，这促使科学家们去发现更好、更安全的新型类固醇衍生物。通过这些新的类固醇靶向炎症控制和改变肿瘤的免疫反应可以使治疗更加成功。这篇综述着眼于目前来自不同类型研究的证据，以确定类固醇在治疗乳腺癌相关炎症中的作用。它还回顾了类固醇与化疗、放疗和免疫疗法一起使用的选择，重点是实现最佳的抗炎效果，同时保持对治疗的无反应性。该研究还展望了未来在类固醇、个性化药物和生物标志物指导下的治疗方面的潜在进展，这些将极大地改善乳腺癌的治疗方式。了解类固醇如何影响肿瘤和炎症对于制定良好的治疗计划，提高乳腺癌患者的生存机会和降低疾病复发的风险是必要的。

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引用次数: 0

Norepinephrine mediates adrenergic receptor transcription and oncogenic gene expression in pancreatic ductal adenocarcinoma 去甲肾上腺素介导胰腺导管腺癌中肾上腺素能受体转录和致癌基因表达

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-05 DOI: 10.1016/j.jbior.2025.101097

Henry H. Brak, Noelle R.J. Thielman

Adrenergic stimulation of β₂ receptors has shown to increase pancreatic ductal adenocarcinoma (PDAC) proliferation and migration in an in vitro setting; however, the role of α₁ receptors in these adrenergic signaling pathways is unclear. Previous research has suggested that the MAPK signaling pathway is upregulated in response to β-adrenergic signaling, but other signaling pathways and downstream targets of mutant KRAS have yet to be investigated. This study investigates the role of adrenergic signaling through α₁ and β-receptors in two human-derived PDAC cell lines, examining proliferation, wound healing, and protein expression after treatment with norepinephrine (NE) and in the presence of β and α₁-receptor antagonism. Using RT-qPCR, the expression of adrenergic receptors and downstream KRAS effector proteins was evaluated. We found that NE has varying effects on proliferation and wound healing in different PDAC cell lines. Moreover, adrenergic receptor expression is under negative feedback control through α₁ signaling in both cell lines. Furthermore, NE decreases expression of MMP9 while also affecting expression of VIM, CCND1, mTOR, and rhoA. We demonstrate genotype dependent effects of adrenergic stimulation on downstream molecular signaling pathways in PDAC that are important for oncogenicity. Based on our findings, genotypic characterization of cell signaling pathways in PDAC may aid further research in effective therapeutics for PDAC.

在体外环境中，肾上腺素能刺激β2受体可增加胰腺导管腺癌（PDAC）的增殖和迁移；然而，α1受体在这些肾上腺素能信号通路中的作用尚不清楚。先前的研究表明，MAPK信号通路响应β-肾上腺素能信号而上调，但突变体KRAS的其他信号通路和下游靶点尚未被研究。本研究探讨了肾上腺素能信号通过α1和β-受体在两种人源性PDAC细胞系中的作用，检测了去甲肾上腺素（NE）处理后以及β和α -受体拮抗剂存在下的增殖、伤口愈合和蛋白表达。RT-qPCR检测肾上腺素能受体和KRAS下游效应蛋白的表达。我们发现NE对不同PDAC细胞系的增殖和伤口愈合有不同的影响。此外，肾上腺素能受体的表达在两种细胞系中均受α1信号的负反馈控制。此外，NE降低MMP9的表达，同时也影响VIM、CCND1、mTOR和rhoA的表达。我们证明了肾上腺素能刺激对PDAC下游分子信号通路的基因型依赖性作用，这对致癌性很重要。基于我们的发现，PDAC细胞信号通路的基因型表征可能有助于进一步研究PDAC的有效治疗方法。

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引用次数: 0

Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association 脂质磷脂酸磷酸酶：结构、功能、调节和疾病关联。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101082

Franceine S. Welcome, Taisha C.M. Elizaire, Michael V. Airola

Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.

脂质作为细胞膜的结构屏障、长期能量储存和信号分子发挥着重要作用。参与脂质合成的一类酶是脂质酶。脂质是镁依赖性磷脂酸磷酸酶，产生二酰基甘油，在TAG合成、新生磷脂合成和代谢中起关键作用。在这里，我们回顾了最近在脂质结构、功能和调控方面的进展，特别关注与横纹肌溶解、马吉德综合征和神经病变相关的错义突变的结构影响。结构洞察揭示，虽然一些疾病相关突变直接破坏催化，但许多错义突变不在活性位点附近，但仍在PAP活性中发挥关键作用。随着脂质同源物Tt Pah2、AlphaFold和AlphaMissense的晶体结构的解析，预测单个残基和突变的致病性和结构贡献变得越来越可能。展望未来，这些结构信息可以用来预测和理解新突变的出现。

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引用次数: 0

Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions 溶血磷脂酸（LPA）受体信号在氯化钴诱导的缺氧条件下调节结肠癌细胞的细胞功能

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101098

Mao Yamamoto, Miwa Takai, Narumi Yashiro, Moemi Tamura, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Nanami Shimomura, Toshifumi Tsujiuchi

In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl₂) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA₁ to LPA₆) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl₂. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl₂. CoCl₂ treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl₂ was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl₂-treated DLD-1 cells was suppressed by AM966 (LPA₁ antagonist) and enhanced by GRI-977143 (LPA₂ agonist). Conversely, CoCl₂ treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl₂-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl₂-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl₂-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl₂ treatment.

在肿瘤微环境（TME）中，缺氧是促进肿瘤侵袭和进展的关键。氯化钴（CoCl2）通过诱导类似的细胞反应来模拟缺氧。溶血磷脂酸（LPA）受体（LPA1 ~ LPA6）在调节癌细胞功能中起关键作用。在本研究中，我们研究了在CoCl2诱导的缺氧条件下LPA受体信号传导对结肠癌DLD-1细胞恶性特性的影响。在CoCl2处理的DLD-1细胞中，LPAR1和LPAR2表达水平升高。CoCl2处理也刺激了DLD-1细胞的运动。CoCl2诱导的这种增强的运动性被LW6 （HIF-1抑制剂）所降低。此外，cocl2处理的DLD-1细胞的运动性被AM966 （LPA1拮抗剂）抑制，而被GRI-977143 （LPA2激动剂）增强。相反，CoCl2处理降低了DLD-1细胞的侵袭。AM966进一步抑制细胞侵袭，而GRI-977143则提高细胞侵袭。cocl2处理的DLD-1细胞对氟尿嘧啶（5-FU）的存活率较高。AM966和GRI-977143进一步增强了对5-FU的活性。当cocl2处理的DLD-1细胞在低糖培养基中培养时，与高糖培养基相比，LPAR1表达上调，而LPAR2表达下调。此外，在低糖条件下，cocl2处理的DLD-1细胞的运动性和侵袭性进一步受到刺激。这些结果表明，在CoCl2诱导的缺氧环境下，LPA受体信号传导有助于DLD-1细胞的恶性潜能。

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引用次数: 0

Solid pancancer analysis reveals immune and hematopoietic stem cell and DNA damage repair signatures to distinguish different cancer subtypes 实体胰腺癌分析揭示了免疫和造血干细胞和DNA损伤修复特征，以区分不同的癌症亚型

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101090

Nayila Abulimiti , Rongzhuo Long , Yin He , Junze Dong , Xiaosheng Wang

Purpose

Immunity, stemness, and DNA damage repair (DDR) are crucial for cancer development and therapy resistance. With advancements in multiomics technology, the exploration of cancers related to immunity, stemness, and the DDR has triggered interest, but the combination of these levels for analyzing multiple cancers remains insufficient.

Methods

In this study, 9906 solid tumor samples from 31 TCGA cancer types were clustered on the basis of the enrichment levels of 13 gene sets associated with stemness, immunity, and DDR. Moreover, a soft ensemble model was constructed on the basis of the enrichment levels of these 13 gene sets to predict cancer subtypes via other omics data.

Results

We identified four pancancer subtypes, termed C1, C2, C3, and C4, which presented distinct molecular and clinical features, including the immune microenvironment, stemness, genome instability, intratumor heterogeneity, methylation levels, tumor progression, sensitivity to chemotherapy and immunotherapy, and survival prognosis. The soft ensemble model validated this subtyping method in two breast cancer datasets (gene expression level), a pancancer proteomic dataset (protein expression level), and a pancancer cell line dataset (cell line gene expression level).

Conclusion

Our findings indicate that immune, stemness, and DDR signature-based subtyping offers new perspectives on cancer biology and holds promise for improving the clinical management of cancers.

目的免疫、干细胞和DNA损伤修复（DDR）是肿瘤发生和耐药的关键。随着多组学技术的进步，对与免疫、干细胞和DDR相关的癌症的探索引发了人们的兴趣，但将这些水平结合起来分析多种癌症仍然不足。方法基于13个与干性、免疫和DDR相关的基因集的富集水平，对31种TCGA肿瘤类型的9906个实体瘤样本进行聚类。此外，基于这13个基因集的富集水平，构建了一个软集合模型，通过其他组学数据预测癌症亚型。结果我们确定了四种胰腺癌亚型，分别为C1、C2、C3和C4，它们具有不同的分子和临床特征，包括免疫微环境、干性、基因组不稳定性、肿瘤内异质性、甲基化水平、肿瘤进展、对化疗和免疫治疗的敏感性以及生存预后。软集成模型在两个乳腺癌数据集（基因表达水平）、一个胰腺癌蛋白质组学数据集（蛋白质表达水平）和一个胰腺癌细胞系数据集（细胞系基因表达水平）中验证了这种亚型方法。结论基于免疫、干性和DDR特征的亚型为研究癌症生物学提供了新的视角，并有望改善癌症的临床管理。

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引用次数: 0

Fructose 1,6-bisphosphatase as a promising target of anticancer treatment 果糖-1,6-二磷酸酶有望成为抗癌治疗的靶点。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101057

Agnieszka Gizak, Bartosz Budziak, Aleksandra Domaradzka, Łukasz Pietras, Dariusz Rakus

Fructose 1,6-bisphosphatase (FBP) is a regulatory enzyme of gluconeogenesis that also influences in a non-catalytic manner – via protein-protein interactions – cell cycle-dependent events, mitochondria biogenesis and polarization, synaptic plasticity and even cancer progression. FBP reduces glycolytic capacity of cells via blocking HIF-1α transcriptional activity and modulating NF-κB action, and influences oxidative metabolism by binding to c-MYC. Because FBP limits the energy-producing potential of cells and because a reduction of FBP amounts is observed in cancer cells, FBP is considered to be an anti-oncogenic protein. This is supported by the observation that cancer cells overexpress aldolase A (ALDOA), a pro-oncogenic protein that can bind to FBP and potentially block its anti-oncogenic activity. Interestingly, only the muscle isozyme of FBP (FBP2) interacts strongly with ALDOA, whereas the binding of the liver isozyme (FBP1) to ALDOA is more than an order of magnitude weaker.

Here, we briefly review the most important evidence supporting the anti-oncogenic function of FBP and discuss what structural properties of the two FBP isozymes allow FBP2, rather than FBP1, to exert more flexible anticancer functions.

果糖-1,6-二磷酸酶（FBP）是葡萄糖生成的一种调节酶，它还通过蛋白质之间的相互作用，以非催化的方式影响细胞周期依赖性事件、线粒体生物生成和极化、突触可塑性甚至癌症进展。FBP 通过阻断 HIF-1α 的转录活性和调节 NF-κB 的作用来降低细胞的糖酵解能力，并通过与 c-MYC 结合来影响氧化代谢。由于 FBP 限制了细胞产生能量的潜力，而且在癌细胞中观察到 FBP 数量减少，因此 FBP 被认为是一种抗癌蛋白。癌细胞过量表达醛缩酶 A（ALDOA）也证明了这一点，醛缩酶 A 是一种促癌蛋白，可与 FBP 结合，并有可能阻断其抗癌活性。有趣的是，只有 FBP 的肌肉同工酶（FBP2）与 ALDOA 有强烈的相互作用，而肝脏同工酶（FBP1）与 ALDOA 的结合力要弱一个数量级以上。在此，我们简要回顾了支持 FBP 抗癌功能的最重要证据，并讨论了两种 FBP 同工酶的哪些结构特性使 FBP2 而不是 FBP1 能够发挥更灵活的抗癌功能。

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引用次数: 0

A budding yeast-centric view of oxysterol binding protein family function 以芽殖酵母为中心的氧甾醇结合蛋白家族功能的观点。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101061

Xiaohan Yu , Carl J. Mousley , Vytas A. Bankaitis , Prasanna Iyer

The Trans Golgi Network (TGN)/endosomal system is a sorting center for cargo brought via the anterograde secretory pathway and the endocytic pathway that internalizes material from the plasma membrane. As many of the cargo that transit this central trafficking hub are components of key homeostatic signaling pathways, TGN/endosomes define a critical signaling hub for cellular growth control. A particularly interesting yet incompletely understood aspect of regulation of TGN/endosome function is control of this system by two families of lipid exchange/lipid transfer proteins. The phosphatidylinositol transfer proteins promote pro-trafficking phosphoinositide (i.e. phosphatidylinositol-4-phosphate) signaling pathways whereas proteins of the oxysterol binding protein family play reciprocal roles in antagonizing those arms of phosphoinositide signaling. The precise mechanisms for how these lipid binding proteins execute their functions remain to be resolved. Moreover, information regarding the coupling of individual members of the oxysterol binding protein family to specific biological activities is particularly sparse. Herein, we review what is being learned regarding functions of the oxysterol binding protein family in the yeast model system. Focus is primarily directed at a discussion of the Kes1/Osh4 protein for which the most information is available.

跨高尔基网络(TGN)/内体系统是通过顺行分泌途径和内化质膜物质的内吞途径带来的货物的分拣中心。由于许多经过这个中心运输枢纽的货物是关键稳态信号通路的组成部分，TGN/核内体定义了细胞生长控制的关键信号枢纽。TGN/内体功能调控的一个特别有趣但尚未完全了解的方面是脂质交换/脂质转移蛋白的两个家族对该系统的控制。磷脂酰肌醇转移蛋白促进前运输磷酸肌醇（即磷脂酰肌醇-4-磷酸）信号通路，而氧甾醇结合蛋白家族的蛋白质在拮抗磷酸肌醇信号通路中发挥相互作用。这些脂质结合蛋白如何执行其功能的确切机制仍有待解决。此外，关于氧甾醇结合蛋白家族的个体成员与特定生物活性的偶联的信息尤其稀少。在此，我们回顾了酵母模型系统中关于氧甾醇结合蛋白家族功能的研究进展。重点主要集中在Kes1/Osh4蛋白的讨论上，这是可获得信息最多的蛋白。

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引用次数: 0

Sixty-fifth international symposium on biological regulation and enzyme activity in normal and neoplastic tissues 第65届正常和肿瘤组织的生物调控和酶活性国际研讨会

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101077

引用次数: 0

The perinucleolar compartment and the oncogenic super-enhancers are part of the same phase-separated structure filled with phosphatidylinositol 4,5-bisphosphate and long non-coding RNA HANR 核仁周围区室和致癌超增强子是同一相分离结构的一部分，充满磷脂酰肌醇4,5二磷酸和长链非编码RNA HANR。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101069

Ana Miladinović , Ludovica Antiga , Tomáš Venit , Andrea Bayona-Hernandez , Jakub Červenka , Rajendra Kumar Labala , Michal Kolář , Enrique Castaño , Martin Sztacho , Pavel Hozák

The liquid-liquid phase separation in the cell nucleus regulates various processes such as gene regulation and transcription control, chromatin organization, and DNA repair. A plethora of proteins and RNAs contribute to the formation of biomolecular condensates and recently, several nuclear phosphoinositides were shown to be a part of these membrane-less complexes within the nucleus as well. Here we lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to uncover the RNA-binding capacity and localization of phosphatidylinositol 4,5 bisphosphate (PIP2). We discovered the consensus PIP2-binding AU-rich RNA motif and identified long non-coding RNA HANR (lncHANR) to colocalize with PIP2 in the proximity to the nucleolus in the perinucleolar compartment (PNC). Colocalization studies with different nuclear markers reveal that PIP2-HANR presence in the PNC correlates with oncogenic super-enhancers, and both PNC and oncogenic enhancers are part of the same structure. As lncHANR, PNC, and oncogenic super-enhancers are associated with cancer cell lines and tumors, we suggest that they can serve as interchangeable prognostic markers. Understanding of the interplay between lipid metabolism, and lncRNAs in subnuclear compartment phase separation can lead to future improvement in treatment strategies and personalized cancer management approaches.

细胞核中的液-液相分离调节着基因调控和转录控制、染色质组织和DNA修复等多种过程。过多的蛋白质和rna有助于生物分子凝聚物的形成，最近，几种核磷酸肌苷也被证明是核内这些无膜复合物的一部分。在这里，我们通过脂质相互作用RNA测序（LIPRNAseq）和共聚焦显微镜来揭示磷脂酰肌醇4,5二磷酸（PIP2）的RNA结合能力和定位。我们发现了一致的PIP2结合富au RNA基序，并鉴定了长链非编码RNA HANR （lncHANR）与PIP2共定位在核仁周围室（PNC）的核仁附近。不同核标记的共定位研究表明，PIP2-HANR在PNC中的存在与致癌超增强子相关，PNC和致癌增强子都是同一结构的一部分。由于lncHANR、PNC和致癌超级增强子与癌细胞系和肿瘤相关，我们认为它们可以作为可互换的预后标志物。了解脂质代谢和lncrna在亚核室相分离中的相互作用可以改善治疗策略和个性化癌症管理方法。

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引用次数: 0