Advances in biological regulation最新文献

英文中文

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

Signaling pathways and bone marrow microenvironment in myelodysplastic neoplasms 骨髓增生异常肿瘤的信号通路和骨髓微环境。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101071

Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo

Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.

骨髓微环境（BMM）中的关键信号通路，如Notch、磷酸肌苷特异性磷脂酶C （pi - plc）、转化生长因子β (TGF-β)和核因子κB (NF-κB)，在骨髓增生异常肿瘤（MDS）的进展中发挥重要作用。在各种BMM细胞类型中，间充质基质细胞（MSCs）在这些途径中尤其重要。虽然这些信号通路可以独立影响MSCs和造血干细胞（hsc），但它们最重要的是改变它们相互作用的动力学，导致生存、分化和静止的异常变化。Notch和PI-PLC信号通路促进细胞间通讯，TGF-β促进静止和抑制造血，NF-κ b驱动的炎症反应营造了一个不利于正常造血的环境。这篇综述强调了这些通路在MDS微环境中的作用，推动了疾病的发展和进展，并为新的可能的治疗策略铺平了道路。

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引用次数: 0

Making PI3K superfamily enzymes run faster 让 PI3K 超家族酶跑得更快

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101060

Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams

The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.

磷酸肌酸 3-激酶（PI3K）超家族包括脂质激酶（PI3Ks 和 III 型 PI4Ks）和一组类似 PI3K 的 Ser/Thr 蛋白激酶（PIKKs：mTOR、ATM、ATR、DNA-PKcs、SMG1 和 TRRAP），它们都有一个保守的 C 端激酶结构域。该超家族的一个共同特点是，它们的基础活性很低，但可以通过一系列调节因子大大提高。激活因子会重新配置活性位点，使激酶结构域的 N-叶相对于 C-叶发生微妙的重新排列。这种重新排列使 N 环的 ATP 结合环更接近 C 环的催化残基。此外，被称为 PIKK 调节结构域（PRD）的保守的 C-lobe 特征也会改变构象，PI3K 激活剂也会改变类似的 PRD 区域。最近的结构显示，各种激活影响因素都能引发这些构象变化，而夹在激酶结构域上的螺旋区域则能传递调控相互作用，使活性位点重新排列，从而提高催化效率。最近一份关于应用于神经再生的 PI3Kα 小分子激活剂的报告表明，可以利用这些调节元件的灵活性来开发所有 PI3K 超家族成员的特异性激活剂。这些激活剂可在伤口愈合、抗中风治疗和治疗神经变性方面发挥作用。我们回顾了 PI3K 超家族的共同结构特征，这些特征可能使它们适于激活。

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引用次数: 0

Tissue specific roles of fatty acid oxidation 脂肪酸氧化在组织中的特殊作用。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101070

Danielle M. Smith , Joseph Choi , Michael J. Wolfgang

Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.

线粒体长链脂肪酸β-氧化是一个关键的中心碳分解代谢过程。脂肪酸氧化的重要性通过与该途径中各种先天性错误相关的危及生命的疾病得到了证明。虽然先天性缺陷显示出脂肪酸氧化的多系统需求，但从这些酶缺乏的临床表现来看，尚不清楚该途径的组织特异性作用与继发性全身效应相比。为了了解脂肪酸氧化对系统生理的细胞或组织特异性贡献，在小鼠中使用条件敲除来确定不同细胞类型对脂肪酸氧化的需求。这产生了许多令人惊讶的结果，有时与这种代谢途径的规范观点背道而驰。条件敲除的严谨性也为先前利用体外细胞系或具有可疑特异性的小分子抑制剂的研究提供了清晰度。在这里，我们将总结目前使用肉碱棕榈酰基转移酶小鼠模型的研究，以确定长链线粒体脂肪酸β-氧化的组织特异性作用和需求。

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引用次数: 0

Insights into phosphatidic acid phosphatase and its potential role as a therapeutic target 磷脂酸磷酸酶及其作为治疗靶点的潜在作用。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101074

George M. Carman, Geordan J. Stukey, Ruta Jog, Gil-Soo Han

Phosphatidic acid phosphatase, a conserved eukaryotic enzyme that catalyzes the Mg²⁺-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol, has emerged as a vital regulator of lipid homeostasis. By controlling the balance of phosphatidic acid and diacylglycerol, the enzyme governs the use of the lipids for synthesis of the storage lipid triacylglycerol and the membrane phospholipids needed for cell growth. The mutational, biochemical, and cellular analyses of yeast phosphatidic acid phosphatase have provided insights into the structural determinants of enzyme function with the understanding of its regulation by phosphorylation and dephosphorylation. The key role that the enzyme plays in triacylglycerol synthesis indicates it may be a potential drug target to ameliorate obesity in humans. The enzyme activity, which is critical to the growth and virulence of pathogenic fungi, is a proposed target for therapeutic development to ameliorate fungal infections.

磷脂酸磷酸酶是一种保守的真核酶，催化磷脂酸的Mg2+依赖性去磷酸化产生二酰基甘油，已成为脂质稳态的重要调节因子。通过控制磷脂酸和二酰基甘油的平衡，酶控制脂质的使用，用于合成储存脂质三酰基甘油和细胞生长所需的膜磷脂。酵母磷脂酸磷酸酶的突变、生化和细胞分析提供了对酶功能的结构决定因素的见解，以及对其磷酸化和去磷酸化调控的理解。该酶在三酰甘油合成中所起的关键作用表明，它可能是改善人类肥胖的潜在药物靶点。该酶活性对致病真菌的生长和毒力至关重要，是改善真菌感染的治疗开发的一个拟议目标。

引用次数: 0

Photo of special symposium lecturer - Vytas Bankaitis 专题研讨会讲师Vytas Bankaitis的照片

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2025.101080

引用次数: 0

Expanding functions of the phosphatidylinositol/phosphatidate lipid transporter, PITPNC1 in physiology and in pathology 磷脂酰肌醇/磷脂酸脂质转运体 PITPNC1 在生理学和病理学中的扩展功能。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-01-01 DOI: 10.1016/j.jbior.2024.101056

Shamshad Cockcroft

PITPNC1 was the last of the PITPs to be identified and has been characterized as a binding protein for phosphatidylinositol and phosphatidate. In mammals, PITPNC1 is expressed as two splice variants whilst in zebrafish is expressed from two separate genes. The two splice variants have different expression profiles with the long splice variant having a prominent role in the brain. Several physiological functions have been identified including neuronal and metabolic functions. PITPNC1 also plays a significant role in cancer and has been identified as a risk factor in type 2 diabetes. Here, we review our current understanding of PITPNC1 in cell physiology and pathology.

PITPNC1 是最后一种被确认的 PITPs，其特征是磷脂酰肌醇和磷脂酸的结合蛋白。在哺乳动物中，PITPNC1 以两种剪接变体的形式表达，而在斑马鱼中则由两个独立的基因表达。这两种剪接变体有不同的表达谱，其中长剪接变体在大脑中的作用突出。目前已经确定了几种生理功能，包括神经元和新陈代谢功能。PITPNC1 在癌症中也发挥着重要作用，并被确定为 2 型糖尿病的风险因素。在此，我们回顾了我们目前对 PITPNC1 在细胞生理学和病理学中作用的理解。

引用次数: 0

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