Lei Wang, S. Broussy, N. Gagey-Eilstein, M. Reille‐Seroussi, F. Huguenot, M. Vidal, Wang-Qing Liu
Inhibition of the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) is a validated therapeutic strategy of anti-cancer treatment. This approach consists in indirect blockage of the kinase activity on VEGFR with inhibitors of protein-protein interactions, which showed great interests in oncology. The FDA approved anti-cancer agents bevacizumab (Avastin®) and ziv-aflibercept (Zaltrap®) bind specifically to VEGF are from anti-VEGF strategy. The very recently approved agent ramucirumab (Cyramza®), a recombinant humanized monoclonal antibody that specifically binds to VEGFR2 is from anti-VEGFR strategy. Based on a cyclic peptide antagonist of VEGFR1 designed from VEGF fragments, we developed, by a new synthesis process, a series of C-terminal modified cyclic peptides to improve their receptor binding ability. Three of such peptides with aromatic groups showed greatly increased VEGFR1 binding affinity in a competition ELISA-based test. This research highlight discusses the processing and findings of the recent study.
{"title":"Inhibition of VEGF/VEGFR1 interaction by a series of C-terminal modified cyclic peptides","authors":"Lei Wang, S. Broussy, N. Gagey-Eilstein, M. Reille‐Seroussi, F. Huguenot, M. Vidal, Wang-Qing Liu","doi":"10.14800/RCI.534","DOIUrl":"https://doi.org/10.14800/RCI.534","url":null,"abstract":"Inhibition of the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) is a validated therapeutic strategy of anti-cancer treatment. This approach consists in indirect blockage of the kinase activity on VEGFR with inhibitors of protein-protein interactions, which showed great interests in oncology. The FDA approved anti-cancer agents bevacizumab (Avastin®) and ziv-aflibercept (Zaltrap®) bind specifically to VEGF are from anti-VEGF strategy. The very recently approved agent ramucirumab (Cyramza®), a recombinant humanized monoclonal antibody that specifically binds to VEGFR2 is from anti-VEGFR strategy. Based on a cyclic peptide antagonist of VEGFR1 designed from VEGF fragments, we developed, by a new synthesis process, a series of C-terminal modified cyclic peptides to improve their receptor binding ability. Three of such peptides with aromatic groups showed greatly increased VEGFR1 binding affinity in a competition ELISA-based test. This research highlight discusses the processing and findings of the recent study.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"24 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72761953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The paper we recently published in PNAS, entitled “Neurite outgrowth induced by NGF or L1CAM via activation of the TrkA receptor is sustained also by the exocytosis of enlargeosomes” (Colombo et al., 2014), reported studies carried out in clones isolated from the PC12 line, frequently employed as a neuronal model. Two original and integrated findings were obtained, concerning the vesicle traffic and fusion processes necessary for neurite outgrowth, and the activation of TrkA, the tyrosine kinase receptor of NGF, by the adhesion protein L1CAM. Both these findings provide an explanation to results previously obtained in our and other laboratories.
我们最近在PNAS上发表的论文题为“NGF或L1CAM通过激活TrkA受体诱导的神经突生长也由增大体的胞外作用维持”(Colombo et al.， 2014)，报告了从PC12系分离的克隆中进行的研究，该克隆经常被用作神经元模型。我们获得了两个原始而完整的发现，关于神经突生长所需的囊泡运输和融合过程，以及粘附蛋白L1CAM对NGF酪氨酸激酶受体TrkA的激活。这两项发现都为我们和其他实验室先前获得的结果提供了解释。
{"title":"New mechanisms of neurite outgrowth and TrkA receptor activation/signaling","authors":"F. Colombo, J. Meldolesi","doi":"10.14800/RCI.542","DOIUrl":"https://doi.org/10.14800/RCI.542","url":null,"abstract":"The paper we recently published in PNAS, entitled “Neurite outgrowth induced by NGF or L1CAM via activation of the TrkA receptor is sustained also by the exocytosis of enlargeosomes” (Colombo et al., 2014), reported studies carried out in clones isolated from the PC12 line, frequently employed as a neuronal model. Two original and integrated findings were obtained, concerning the vesicle traffic and fusion processes necessary for neurite outgrowth, and the activation of TrkA, the tyrosine kinase receptor of NGF, by the adhesion protein L1CAM. Both these findings provide an explanation to results previously obtained in our and other laboratories.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75499381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N-type voltage-gated Ca 2+ (Ca V 2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as Gbg, calmodulin, arachidonic acid and PIP 2 . However, the molecular mechanism by which G q/11 -coupled receptors (G q PCRs) suppress Ca V 2.2 currents remains unclear. In this research highlight, we review our recent finding that M 1 muscarinic receptors inhibit Ca V 2.2 channels through both Gbg-mediated voltage-dependent (VD) and Gα q/11 /PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of Ca V 2.2 channels initiates approximately 3s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized Ca V b subunits. Our observations demonstrate a novel mechanism for Ca V 2.2 channel modulation by G q PCRs where the subcellular location of Ca V b subunits plays a critical role in determining the voltage-dependence of current suppression by M 1 receptors.
n型电压门控ca2 + (Ca v2.2)通道通过触发神经递质释放来实现突触传递，由G蛋白偶联受体(gpcr)通过几个下游信号信使，如Gbg、钙调素、花生四烯酸和PIP 2紧密调节。然而，gq /11偶联受体(gq pcr)抑制Ca V 2.2电流的分子机制尚不清楚。在本研究重点中，我们回顾了我们最近的发现，m1毒蕈碱受体通过gbg介导的电压依赖性(VD)和Gα q/11 / plc介导的电压依赖性(VI)途径抑制Ca v2.2通道。我们的光度测定结果还表明，gbg介导的VD对Ca v2.2通道的抑制比VI抑制早大约3秒，并且在表达质膜定位的Ca vb亚基的细胞中被强烈增强。我们的观察结果证明了gq pcr调制Ca V 2.2通道的新机制，其中Ca V b亚基的亚细胞位置在决定m1受体电流抑制的电压依赖性中起着关键作用。
{"title":"Molecular basis for N-type voltage-gated Ca2+ channel modulation by Gq protein-coupled receptors","authors":"D. Keum, B. Suh","doi":"10.14800/RCI.515","DOIUrl":"https://doi.org/10.14800/RCI.515","url":null,"abstract":"N-type voltage-gated Ca 2+ (Ca V 2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as Gbg, calmodulin, arachidonic acid and PIP 2 . However, the molecular mechanism by which G q/11 -coupled receptors (G q PCRs) suppress Ca V 2.2 currents remains unclear. In this research highlight, we review our recent finding that M 1 muscarinic receptors inhibit Ca V 2.2 channels through both Gbg-mediated voltage-dependent (VD) and Gα q/11 /PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of Ca V 2.2 channels initiates approximately 3s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized Ca V b subunits. Our observations demonstrate a novel mechanism for Ca V 2.2 channel modulation by G q PCRs where the subcellular location of Ca V b subunits plays a critical role in determining the voltage-dependence of current suppression by M 1 receptors.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81390564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Postural tachycardia syndrome (POTS) is a type of chronic orthostatic intolerance. Acetylcholine receptor antibodies (AChR-ab) mediated autonomic dysfunction is common in POTS patients. Therefore, it is important to explore the value of serum AChR-ab in those patients. In a recent paper published in Pediatric Cardiology, we compared POTS patients with different AChR-ab status and found preceding infection, syncope and fatigue as main clinical features of POTS patients with AChR-ab positive. Thus, clinicians can determine targeted therapy of acetylcholinesterase inhibitors or immunotherapy according to both the specific clinical features and the results of AChR-ab detecting.
{"title":"Acetylcholine receptors antibodies in postural tachycardia syndrome","authors":"Jiawei Li, Qing-you Zhang, Junbao Du","doi":"10.14800/RCI.516","DOIUrl":"https://doi.org/10.14800/RCI.516","url":null,"abstract":"Postural tachycardia syndrome (POTS) is a type of chronic orthostatic intolerance. Acetylcholine receptor antibodies (AChR-ab) mediated autonomic dysfunction is common in POTS patients. Therefore, it is important to explore the value of serum AChR-ab in those patients. In a recent paper published in Pediatric Cardiology, we compared POTS patients with different AChR-ab status and found preceding infection, syncope and fatigue as main clinical features of POTS patients with AChR-ab positive. Thus, clinicians can determine targeted therapy of acetylcholinesterase inhibitors or immunotherapy according to both the specific clinical features and the results of AChR-ab detecting.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87800091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purinergic P2X receptors are a family of nonselective cation channels gated by extracellular adenosine 5′-triphosphate. They are important drug targets primarily because of their involvement in neuropathic pain and inflammation. ATP binds allows Na + and Ca 2+ to pass through the channel pore, thus causing membrane depolarization and affecting various downstream Ca 2+ -dependent signaling processes. A concerted effort by investigators over the last two decades has culminated in significant advances in our understanding of where ATP binds and how ATP binding leads to channel opening and ion flux. The recent publication of the crystal structures for both the closed and open channel conformations of the zebrafish P2X4 receptor sheds new light on how P2X receptors work. In this review, we will attempt to present the existing functional data regarding ATP binding with the available crystal structure data and different experimental approaches that have been used to explore the ATP-binding sites.
{"title":"ATP Binding and Channel Activation in P2X Receptors","authors":"Longmei Zhang, Sihao Deng, Zhiyuan Li","doi":"10.14800/RCI.527","DOIUrl":"https://doi.org/10.14800/RCI.527","url":null,"abstract":"Purinergic P2X receptors are a family of nonselective cation channels gated by extracellular adenosine 5′-triphosphate. They are important drug targets primarily because of their involvement in neuropathic pain and inflammation. ATP binds allows Na + and Ca 2+ to pass through the channel pore, thus causing membrane depolarization and affecting various downstream Ca 2+ -dependent signaling processes. A concerted effort by investigators over the last two decades has culminated in significant advances in our understanding of where ATP binds and how ATP binding leads to channel opening and ion flux. The recent publication of the crystal structures for both the closed and open channel conformations of the zebrafish P2X4 receptor sheds new light on how P2X receptors work. In this review, we will attempt to present the existing functional data regarding ATP binding with the available crystal structure data and different experimental approaches that have been used to explore the ATP-binding sites.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78667469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The binding of a protein to its target is a major mode of action for most biopharmaceutical therapies with over 70% of biopharmaceuticals involved in binding between the protein and its target. The interfaces between a biopharmaceutical and its target are key regions for its efficacy. Any modifications to the amino acids at the interfaces invariably affect interactions between the biopharmaceutical and its receptor and may result in lowering therapeutic efficacy. Degradations of biopharmaceuticals by asparagine (Asn) deamidation and/or aspartate (Asp) isomerization have been well characterized and those modifications at the interfaces have resulted in a loss of activity. To characterize modification hot-spots on the interfaces, it is necessary to identify the amino acid residues on the interfaces. We recently addressed a visualization tool for amino acids on the interfaces between a protein ligand and its receptor. This tool was applied to visualize ligand protein-receptor interaction and antigen-antibody interaction. As a model system for ligand protein-receptor interaction, erythropoietin (EPO) and its receptor were selected and amino acids on the interfaces were identified. Modifications on the interfaces were then investigated. Deamidation of Asn was identified at two amino acid residues, Asn47 and Asp147, on Interface 1 of EPO. The relative contents of deamidated residues on the interface of EPO were in the range of 3-5% of the total. As a model system for antigen-antibody interaction, Herceptin and its receptor, HER2, were chosen and amino acids on the interfaces were identified. Then modifications on the interfaces were assessed. Deamidation of the light chain Asn30 and heavy chain Asn55 were identified. The relative contents of the deamidated residues on the interfaces were in the range of 8-9% of the total. Along with deamidation, another modification, isomerization, was identified at the amino acid residue Asp102 of the heavy chain, and the level of oxidation was 13.5% of the total. Our studies provide a targeted method focusing on the interface between a protein and its target that can be coupled with other applications, for example, identification of modified amino acids on the interfaces.
{"title":"Structural Characterization of Modification on the Interface between a Ligand and its Receptor for Biopharmaceuticals","authors":"Jae-Young Byeon, Yoo-Joo Choi, J. Suh","doi":"10.14800/RCI.536","DOIUrl":"https://doi.org/10.14800/RCI.536","url":null,"abstract":"The binding of a protein to its target is a major mode of action for most biopharmaceutical therapies with over 70% of biopharmaceuticals involved in binding between the protein and its target. The interfaces between a biopharmaceutical and its target are key regions for its efficacy. Any modifications to the amino acids at the interfaces invariably affect interactions between the biopharmaceutical and its receptor and may result in lowering therapeutic efficacy. Degradations of biopharmaceuticals by asparagine (Asn) deamidation and/or aspartate (Asp) isomerization have been well characterized and those modifications at the interfaces have resulted in a loss of activity. To characterize modification hot-spots on the interfaces, it is necessary to identify the amino acid residues on the interfaces. We recently addressed a visualization tool for amino acids on the interfaces between a protein ligand and its receptor. This tool was applied to visualize ligand protein-receptor interaction and antigen-antibody interaction. As a model system for ligand protein-receptor interaction, erythropoietin (EPO) and its receptor were selected and amino acids on the interfaces were identified. Modifications on the interfaces were then investigated. Deamidation of Asn was identified at two amino acid residues, Asn47 and Asp147, on Interface 1 of EPO. The relative contents of deamidated residues on the interface of EPO were in the range of 3-5% of the total. As a model system for antigen-antibody interaction, Herceptin and its receptor, HER2, were chosen and amino acids on the interfaces were identified. Then modifications on the interfaces were assessed. Deamidation of the light chain Asn30 and heavy chain Asn55 were identified. The relative contents of the deamidated residues on the interfaces were in the range of 8-9% of the total. Along with deamidation, another modification, isomerization, was identified at the amino acid residue Asp102 of the heavy chain, and the level of oxidation was 13.5% of the total. Our studies provide a targeted method focusing on the interface between a protein and its target that can be coupled with other applications, for example, identification of modified amino acids on the interfaces.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74829235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Serum soluble urokinase-type plasminogen activator receptor (suPAR) is a glycoprotein secreted during infections and inflammation [1]. Urokinase-type plasminogen activator (uPA) is secreted by polymorphonuclear neutrophils (PMN) and macrophages; then uPA binds to membrane urokinase-type plasminogen activator receptor (uPAR) [2]. suPAR is formed by cleaved from the uPAR [2]. suPAR is expressed in various cell types, such as macrophages monocytes, endothelial cells and neutrophils [3]. suPAR can be potentially cause or modulate various diseases in patients with cancer, various infectious and inflammatory diseases (including infections with human immunodeficiency virus (HIV), tuberculosis, liver fibrosis and inflammatory bowel disease) [2, 3]. suPAR can convert plasminogen to plasmin, which degrades fibrin, activates matrix metalloproteases and mediates proteolysis of extracellular matrix proteins during cellular invasion [4]. suPAR modulate the functions of integrins (including activating intracellular signals, monocyte chemotaxis, cell adhesion and proliferation) [4, 5]. So suPAR contributes to cell adhesion, migration, proliferation inflammation, chemotaxis, proteolysis, immune system activation, tissue remodeling and signal transduction [5, 6]. Several studies have identified that suPAR level is a important marker in patients with various diseases and associated with a poorer outcome in a range of non-infectious and infectious diseases [2]. Biomarkers of lung disease are required to aid diagnosis, define clinical phenotypes and monitor the response to existing and new therapeutic strategies. Our review aims to explore the potential of suPAR as a general marker in the diagnosis, prognosis and follow-up of therapy of lung disease.
{"title":"Soluble urokinase-type plasminogen activator receptor (suPAR) in multiple respiratory diseases","authors":"Ü. Can","doi":"10.14800/RCI.473","DOIUrl":"https://doi.org/10.14800/RCI.473","url":null,"abstract":"Serum soluble urokinase-type plasminogen activator receptor (suPAR) is a glycoprotein secreted during infections and inflammation [1]. Urokinase-type plasminogen activator (uPA) is secreted by polymorphonuclear neutrophils (PMN) and macrophages; then uPA binds to membrane urokinase-type plasminogen activator receptor (uPAR) [2]. suPAR is formed by cleaved from the uPAR [2]. suPAR is expressed in various cell types, such as macrophages monocytes, endothelial cells and neutrophils [3]. suPAR can be potentially cause or modulate various diseases in patients with cancer, various infectious and inflammatory diseases (including infections with human immunodeficiency virus (HIV), tuberculosis, liver fibrosis and inflammatory bowel disease) [2, 3]. suPAR can convert plasminogen to plasmin, which degrades fibrin, activates matrix metalloproteases and mediates proteolysis of extracellular matrix proteins during cellular invasion [4]. suPAR modulate the functions of integrins (including activating intracellular signals, monocyte chemotaxis, cell adhesion and proliferation) [4, 5]. So suPAR contributes to cell adhesion, migration, proliferation inflammation, chemotaxis, proteolysis, immune system activation, tissue remodeling and signal transduction [5, 6]. Several studies have identified that suPAR level is a important marker in patients with various diseases and associated with a poorer outcome in a range of non-infectious and infectious diseases [2]. Biomarkers of lung disease are required to aid diagnosis, define clinical phenotypes and monitor the response to existing and new therapeutic strategies. Our review aims to explore the potential of suPAR as a general marker in the diagnosis, prognosis and follow-up of therapy of lung disease.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"644 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79002799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Farnesoid X alpha receptors (FXRα or NR1H4) are present in male and female reproductive tissues. The aim of the present review is to describe those actions of the most relevant ligands of FXRα on reproduction and the interaction of this receptor with other nuclear receptors, for understanding the possible role of FXRα in reproductive events. Thus, although the relevance of the FXRα on reproduction is widely unknown, its endogenous ligands like farnesol, chenodeoxycholic acid (CDCA), and cholate acid (CA) participate in proliferation, apoptosis, differentiation, and steroidogenesis in reproductive tissues. In these tissues FXRα modulates estrogen and androgen actions. Since FXRα is stretched related to other nuclear receptors, also present in reproductive tissues, such as the liver X receptors (LXR), peroxisome proliferation-activated receptor (PPAR), liver receptors homolog-1 (LRH-1), small heterodimer partner (SHP), and dosage-sensitive sex reversal (DAX1), the FXRα actions on reproductive tissues might be directly or indirectly mediated by its interaction with these nuclear receptors.
Farnesoid X α受体(FXRα或NR1H4)存在于男性和女性生殖组织中。本文综述了FXRα最相关的配体在生殖中的作用及其与其他核受体的相互作用，以期进一步了解FXRα在生殖活动中的可能作用。因此，尽管FXRα与生殖的相关性尚不清楚，但其内源性配体如法尼醇、鹅去氧胆酸(CDCA)和胆酸(CA)参与生殖组织的增殖、凋亡、分化和甾体生成。在这些组织中，FXRα调节雌激素和雄激素的作用。由于FXRα与其他核受体相关，也存在于生殖组织中，如肝脏X受体(LXR)、过氧化物酶体增殖激活受体(PPAR)、肝脏受体同源物-1 (LRH-1)、小异二聚体伴侣(SHP)和剂量敏感性逆转(DAX1)，因此FXRα对生殖组织的作用可能通过与这些核受体的相互作用直接或间接介导。
{"title":"Farnesoid X receptor and reproduction","authors":"Cuevas Estela, M. Martínez-Gómez, F. Castelán","doi":"10.14800/RCI.463","DOIUrl":"https://doi.org/10.14800/RCI.463","url":null,"abstract":"Farnesoid X alpha receptors (FXRα or NR1H4) are present in male and female reproductive tissues. The aim of the present review is to describe those actions of the most relevant ligands of FXRα on reproduction and the interaction of this receptor with other nuclear receptors, for understanding the possible role of FXRα in reproductive events. Thus, although the relevance of the FXRα on reproduction is widely unknown, its endogenous ligands like farnesol, chenodeoxycholic acid (CDCA), and cholate acid (CA) participate in proliferation, apoptosis, differentiation, and steroidogenesis in reproductive tissues. In these tissues FXRα modulates estrogen and androgen actions. Since FXRα is stretched related to other nuclear receptors, also present in reproductive tissues, such as the liver X receptors (LXR), peroxisome proliferation-activated receptor (PPAR), liver receptors homolog-1 (LRH-1), small heterodimer partner (SHP), and dosage-sensitive sex reversal (DAX1), the FXRα actions on reproductive tissues might be directly or indirectly mediated by its interaction with these nuclear receptors.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"459 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76499016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver X Receptors (LXRs) have been proposed to have some anticancer properties. LXRs affect cancer cell proliferation and cell death through mechanisms that seems mostly to rely on its transcriptional activities. We recently identified a new non-genomic role of LXRβ in colon cancer cells. Under LXR agonist treatment, LXRβ induces an atypical cell death called pyroptosis in vitro and in vivo. Together with other reports, we raise the importance of targeting LXRs in cancer treatment.
{"title":"Transcriptional and non-transcriptional roles of LXRs in cancer cells","authors":"C. Rébé, V. Derangère, F. Ghiringhelli","doi":"10.14800/RCI.444","DOIUrl":"https://doi.org/10.14800/RCI.444","url":null,"abstract":"Liver X Receptors (LXRs) have been proposed to have some anticancer properties. LXRs affect cancer cell proliferation and cell death through mechanisms that seems mostly to rely on its transcriptional activities. We recently identified a new non-genomic role of LXRβ in colon cancer cells. Under LXR agonist treatment, LXRβ induces an atypical cell death called pyroptosis in vitro and in vivo. Together with other reports, we raise the importance of targeting LXRs in cancer treatment.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79162550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men in North America. With the rate of new cases rising each year, prostate cancer poses a heavy burden on both the economy and society. While the first line of treatment for metastatic prostate cancer is androgen deprivation therapy, it has become evident that tumors eventually become castration resistant. One of the proposed mechanisms by which tumors overcome androgen deprivation therapy is through the expression and activation of glucocorticoid receptors. However, whether the glucocorticoid receptor functions as a key driver for castration resistant progression or a biomarker reflecting androgen receptor activity remains elusive. In our recent study, we utilized tissue microarrays and multiple prostate cancer xenograft and cell models to investigate the roles of the glucocorticoid receptor during castration resistant progression. As a result, we determined that the expression of the glucocorticoid receptor is inversely correlated with androgen receptor activity and is not associated with castration resistant phenotypes. In addition, we identified a negative androgen responsive element in the promoter region of the glucocorticoid receptor gene through chromatin immunoprecipitation analysis combined with DNA sequencing technology. We showed that the androgen receptor interacted directly to this response element to exert suppressive effects on the transcription of the glucocorticoid receptor gene. In conclusion, the expression of the glucocorticoid receptor is negatively regulated by the androgen receptor and can potentially serve as a biomarker to monitor prostate tumor progression.
{"title":"Driver or Passenger - Roles of the Glucocorticoid Receptor in Castration Resistance Prostate Cancers","authors":"Ahn R. Lee, Xuesen Dong","doi":"10.14800/RCI.431","DOIUrl":"https://doi.org/10.14800/RCI.431","url":null,"abstract":"Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men in North America. With the rate of new cases rising each year, prostate cancer poses a heavy burden on both the economy and society. While the first line of treatment for metastatic prostate cancer is androgen deprivation therapy, it has become evident that tumors eventually become castration resistant. One of the proposed mechanisms by which tumors overcome androgen deprivation therapy is through the expression and activation of glucocorticoid receptors. However, whether the glucocorticoid receptor functions as a key driver for castration resistant progression or a biomarker reflecting androgen receptor activity remains elusive. In our recent study, we utilized tissue microarrays and multiple prostate cancer xenograft and cell models to investigate the roles of the glucocorticoid receptor during castration resistant progression. As a result, we determined that the expression of the glucocorticoid receptor is inversely correlated with androgen receptor activity and is not associated with castration resistant phenotypes. In addition, we identified a negative androgen responsive element in the promoter region of the glucocorticoid receptor gene through chromatin immunoprecipitation analysis combined with DNA sequencing technology. We showed that the androgen receptor interacted directly to this response element to exert suppressive effects on the transcription of the glucocorticoid receptor gene. In conclusion, the expression of the glucocorticoid receptor is negatively regulated by the androgen receptor and can potentially serve as a biomarker to monitor prostate tumor progression.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85186736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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