Acinetobacter baumannii, a top-priority WHO pathogen, causes life-threatening infections in immunocompromised patients, leading to prolonged hospitalisation and high mortality. Here, we used the Galleria mellonella model to investigate community strain C98 (Ab-C98) virulence via transcriptomic analysis. Ab-C98 showed greater killing and faster colonisation in larvae than the clinical reference strain (ATCC BAA1605). Genes in three iron clusters, acinetobactin, baumannoferrin and the Feo system, were significantly up-regulated. Targeted knockout of siderophore genes (basC, bfnD, and the gene encoding isochorismatase) significantly increased the survival of infected larvae by at least 35.16%, identifying these genes as potential targets for developing anti-virulence agents against A. baumannii.
{"title":"Transcriptomic insights into the virulence of Acinetobacter baumannii during infection-role of iron uptake and siderophore production genes.","authors":"Kah Ern Ten, Sadequr Rahman, Hock Siew Tan","doi":"10.1002/1873-3468.15061","DOIUrl":"https://doi.org/10.1002/1873-3468.15061","url":null,"abstract":"<p><p>Acinetobacter baumannii, a top-priority WHO pathogen, causes life-threatening infections in immunocompromised patients, leading to prolonged hospitalisation and high mortality. Here, we used the Galleria mellonella model to investigate community strain C98 (Ab-C98) virulence via transcriptomic analysis. Ab-C98 showed greater killing and faster colonisation in larvae than the clinical reference strain (ATCC BAA1605). Genes in three iron clusters, acinetobactin, baumannoferrin and the Feo system, were significantly up-regulated. Targeted knockout of siderophore genes (basC, bfnD, and the gene encoding isochorismatase) significantly increased the survival of infected larvae by at least 35.16%, identifying these genes as potential targets for developing anti-virulence agents against A. baumannii.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1-/- mice (99%) exhibited embryonic lethality with severe growth retardation. Electron microscopy revealed that Iqsec1-/- embryos at embryonic day 8.5 lacked large apical vacuoles in visceral endoderm cells of the yolk sac, compared with controls. These findings suggest that Iqsec1 plays a critical role in embryogenesis, likely through regulation of membrane trafficking in visceral endoderm cells.
Iqsec1(IQ motif and Sec7 domain-containing protein 1)又称BRAG2(Brefeldin A-resistant Arf-GEF 2),是一种鸟嘌呤核苷酸交换因子,它通过激活II类和III类ADP-核糖基化因子来调节膜贩运、细胞骨架组织和信号转导。为了研究Iqsec1在整个动物水平上的生理作用,我们利用CRISPR/Cas9介导的基因编辑技术产生了Iqsec1缺陷小鼠。几乎所有 Iqsec1-/- 小鼠(99%)都表现出胚胎致死和严重的生长迟缓。电子显微镜显示,与对照组相比,Iqsec1-/-胚胎在胚胎第8.5天时,卵黄囊内脏内胚层细胞缺乏大的顶端空泡。这些研究结果表明,Iqsec1 在胚胎发生过程中发挥着关键作用,很可能是通过调节内脏内胚层细胞的膜运输。
{"title":"Disruption of Iqsec1 in mice leads to embryonic lethality with reduced large apical vacuoles in the visceral endoderm.","authors":"Hiroyuki Sakagami, Tomoko Shiroshima, Noriko Nemoto, Tomoko Niimura, Takeyuki Sugawara, Yoshinobu Hara, Koji Saito, Tadashi Okubo, Masahiro Fukaya","doi":"10.1002/1873-3468.15058","DOIUrl":"https://doi.org/10.1002/1873-3468.15058","url":null,"abstract":"<p><p>Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1<sup>-/-</sup> mice (99%) exhibited embryonic lethality with severe growth retardation. Electron microscopy revealed that Iqsec1<sup>-/-</sup> embryos at embryonic day 8.5 lacked large apical vacuoles in visceral endoderm cells of the yolk sac, compared with controls. These findings suggest that Iqsec1 plays a critical role in embryogenesis, likely through regulation of membrane trafficking in visceral endoderm cells.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The tumor suppressor p53 plays a central role in suppressing tumor formation. Mouse double minute 2 homolog (Mdm2) serves as the principal ubiquitin E3 ligase responsible for the ubiquitination and subsequent degradation of p53. However, the regulatory mechanisms governing the Mdm2-p53 pathway are not comprehensively understood. Here, we report that F-box only protein 46 (FBXO46) directly binds to Mdm2 and inhibits its self-ubiquitination and degradation, leading to Mdm2 stabilization and subsequent Mdm2-mediated ubiquitination and degradation of p53. Functionally, FBXO46 promotes cell proliferation, accelerates G1/S cell cycle progression, and increases anchorage-independent cell growth by inhibiting p53. Collectively, these findings reveal a critical role for FBXO46 in controlling Mdm2 stability and establish FBXO46 as an important regulator of the Mdm2-p53 pathway.
{"title":"FBXO46 negatively regulates p53 activity by stabilizing Mdm2.","authors":"Lai Wei, Ning Yu, Bo Yao, Yide Mei, Kailiang Zhao","doi":"10.1002/1873-3468.15055","DOIUrl":"https://doi.org/10.1002/1873-3468.15055","url":null,"abstract":"<p><p>The tumor suppressor p53 plays a central role in suppressing tumor formation. Mouse double minute 2 homolog (Mdm2) serves as the principal ubiquitin E3 ligase responsible for the ubiquitination and subsequent degradation of p53. However, the regulatory mechanisms governing the Mdm2-p53 pathway are not comprehensively understood. Here, we report that F-box only protein 46 (FBXO46) directly binds to Mdm2 and inhibits its self-ubiquitination and degradation, leading to Mdm2 stabilization and subsequent Mdm2-mediated ubiquitination and degradation of p53. Functionally, FBXO46 promotes cell proliferation, accelerates G1/S cell cycle progression, and increases anchorage-independent cell growth by inhibiting p53. Collectively, these findings reveal a critical role for FBXO46 in controlling Mdm2 stability and establish FBXO46 as an important regulator of the Mdm2-p53 pathway.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity. Additionally, we highlighted the roles of both conserved and unique residues in ubiquitin binding. These findings advance our understanding of the interactions between the HUWE1 HECT domain and ubiquitin, and highlight potential targets for therapeutic intervention in the ubiquitin-proteasome pathway.
{"title":"The E3 ligase HUWE1 interacts with ubiquitin non-covalently via key residues in the HECT domain.","authors":"Li Sun, Haoran Zhang, Yan Li","doi":"10.1002/1873-3468.15050","DOIUrl":"https://doi.org/10.1002/1873-3468.15050","url":null,"abstract":"<p><p>HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity. Additionally, we highlighted the roles of both conserved and unique residues in ubiquitin binding. These findings advance our understanding of the interactions between the HUWE1 HECT domain and ubiquitin, and highlight potential targets for therapeutic intervention in the ubiquitin-proteasome pathway.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
d-Galactofuranose (Galf) is widely distributed in glycoconjugates of pathogenic microbes. β-d-Galactofuranosidase (Galf-ase) from Streptomyces sp. JHA19 (ORF1110) belongs to glycoside hydrolase (GH) family 2 and is the first identified Galf-specific degradation enzyme. Here, the crystal structure of ORF1110 in complex with a mechanism-based potent inhibitor, d-iminogalactitol (Ki = 65 μm) was solved. ORF1110 binds to the C5-C6 hydroxy groups of d-iminogalactitol with an extensive and integral hydrogen bond network, a key interaction that discriminates the substrates. The active site structure of ORF1110 is largely different from those of β-glucuronidases and β-galactosidases in the same GH2 family. A C-terminal domain of ORF1110 is predicted to be a carbohydrate-binding module family 42 that may bind Galf. The structural insights into Galf-ase will contribute to the investigation of therapeutic tools against pathogens.
{"title":"Crystal structure of β-d-galactofuranosidase from Streptomyces sp. JHA19 in complex with an inhibitor provides insights into substrate specificity.","authors":"Noriki Fujio, Chihaya Yamada, Toma Kashima, Emiko Matsunaga, Robert J Nash, Kaoru Takegawa, Shinya Fushinobu","doi":"10.1002/1873-3468.15056","DOIUrl":"https://doi.org/10.1002/1873-3468.15056","url":null,"abstract":"<p><p>d-Galactofuranose (Galf) is widely distributed in glycoconjugates of pathogenic microbes. β-d-Galactofuranosidase (Galf-ase) from Streptomyces sp. JHA19 (ORF1110) belongs to glycoside hydrolase (GH) family 2 and is the first identified Galf-specific degradation enzyme. Here, the crystal structure of ORF1110 in complex with a mechanism-based potent inhibitor, d-iminogalactitol (K<sub>i</sub> = 65 μm) was solved. ORF1110 binds to the C5-C6 hydroxy groups of d-iminogalactitol with an extensive and integral hydrogen bond network, a key interaction that discriminates the substrates. The active site structure of ORF1110 is largely different from those of β-glucuronidases and β-galactosidases in the same GH2 family. A C-terminal domain of ORF1110 is predicted to be a carbohydrate-binding module family 42 that may bind Galf. The structural insights into Galf-ase will contribute to the investigation of therapeutic tools against pathogens.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA is modified by > 170 chemical modifications that affect its structure and function. Accordingly, RNA modifications have been implicated in regulation of gene expression and cellular outcomes in a variety of species spanning the phylogenetic tree. The study of RNA modifications is accelerated by generation of high-throughput methods for detecting RNA modifications at single base resolution. Here, we review recent advancement in next generation sequencing based approaches for detection of 14 distinct RNA modifications present in rRNA, tRNA and mRNA. We further outline the molecular and computational principles underlying currently available methods.
{"title":"High-throughput detection of RNA modifications at single base resolution.","authors":"Keren Ron, Joshua Kahn, Nofar Malka-Tunitsky, Aldema Sas-Chen","doi":"10.1002/1873-3468.15052","DOIUrl":"10.1002/1873-3468.15052","url":null,"abstract":"<p><p>RNA is modified by > 170 chemical modifications that affect its structure and function. Accordingly, RNA modifications have been implicated in regulation of gene expression and cellular outcomes in a variety of species spanning the phylogenetic tree. The study of RNA modifications is accelerated by generation of high-throughput methods for detecting RNA modifications at single base resolution. Here, we review recent advancement in next generation sequencing based approaches for detection of 14 distinct RNA modifications present in rRNA, tRNA and mRNA. We further outline the molecular and computational principles underlying currently available methods.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yomna Soliman, Jana Al-Khodor, Gülnaz Yildirim Köken, Nur Mustafaoglu
Understanding the intricate mechanisms underlying brain-related diseases hinges on unraveling the pivotal role of the blood-brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.
{"title":"A guide for blood-brain barrier models.","authors":"Yomna Soliman, Jana Al-Khodor, Gülnaz Yildirim Köken, Nur Mustafaoglu","doi":"10.1002/1873-3468.15053","DOIUrl":"https://doi.org/10.1002/1873-3468.15053","url":null,"abstract":"<p><p>Understanding the intricate mechanisms underlying brain-related diseases hinges on unraveling the pivotal role of the blood-brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor-like-like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH-dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2-ROBO3 signaling could be regulated by extracellular pH.
{"title":"Glu592 of the axon guidance receptor ROBO3 mediates a pH-dependent interaction with NELL2 ligand.","authors":"Kimihiko Mizutani, Mayuko Toyoda, Teruyo Ojima-Kato, Andrés D Maturana, Tomoaki Niimi","doi":"10.1002/1873-3468.15054","DOIUrl":"https://doi.org/10.1002/1873-3468.15054","url":null,"abstract":"<p><p>There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor-like-like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH-dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2-ROBO3 signaling could be regulated by extracellular pH.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz
FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).
FoxO 转录因子(FoxO1、FoxO3a、FoxO4、FoxO6)是 "叉头 "盒蛋白亚家族中一个高度进化保守的亚家族。它们历来被认为是肿瘤抑制因子,但 FoxO1 也具有致癌特性。FoxO1 在 B 细胞发育和分化、免疫球蛋白基因重排和细胞表面 B 细胞受体(BCR)结构、DNA 损伤控制、细胞周期调控和生殖中心反应中的各种作用说明了 FoxO1 的复杂性。FoxO1 在转录水平(STAT3、HEB、EBF、FoxOs)和转录后水平(Akt、AMPK、CDK2、GSK3、IKKs、JNK、MAPK/Erk、SGK1、miRNA)受到严格调控。在 B 细胞恶性肿瘤中,FoxO1 的活化突变(S22/T24)和异常核输出及活性反复出现,这突显了其治疗抑制的潜力。在此,我们回顾了 FoxO1 在 B 细胞和髓系恶性肿瘤中的作用,即急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、滤泡性淋巴瘤(FL)、弥漫大 B 细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、伯基特淋巴瘤(BL)、霍奇金淋巴瘤(HL)和多发性骨髓瘤(MM)。我们还讨论了目前可用的抑制剂(AS1708727、AS1842856、cpd10)靶向 FoxO1 的临床前证据。
{"title":"FoxO1 signaling in B cell malignancies and its therapeutic targeting.","authors":"Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz","doi":"10.1002/1873-3468.15057","DOIUrl":"https://doi.org/10.1002/1873-3468.15057","url":null,"abstract":"<p><p>FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steven Lawrence, Jialiang Lin, Asma Khurshid, Wahyu Utami, Richa Singhania, Sadaf Ashraf, Graeme J Thorn, Irengbam Rocky Mangangcha, Keith Spriggs, Dong-Hyun Kim, David Barrett, Cornelia H de Moor
Cordycepin (3' deoxyadenosine) has been widely researched as a potential cancer therapy, but many diverse mechanisms of action have been proposed. Here, we confirm that cordycepin triphosphate is likely to be the active metabolite of cordycepin and that it consistently represses growth factor-induced gene expression. Bioinformatic analysis, quantitative PCR and western blotting confirmed that cordycepin blocks the PI3K/AKT/mTOR and/or MEK/ERK pathways in six cell lines and that AMPK activation is not required. The effects of cordycepin on translation through mTOR pathway repression were detectable within 30 min, indicating a rapid process. These data therefore indicate that cordycepin has a universal mechanism of action, acting as cordycepin triphosphate on an as yet unknown target molecule involved in growth factor signalling.
{"title":"Cordycepin generally inhibits growth factor signal transduction in a systems pharmacology study.","authors":"Steven Lawrence, Jialiang Lin, Asma Khurshid, Wahyu Utami, Richa Singhania, Sadaf Ashraf, Graeme J Thorn, Irengbam Rocky Mangangcha, Keith Spriggs, Dong-Hyun Kim, David Barrett, Cornelia H de Moor","doi":"10.1002/1873-3468.15046","DOIUrl":"https://doi.org/10.1002/1873-3468.15046","url":null,"abstract":"<p><p>Cordycepin (3' deoxyadenosine) has been widely researched as a potential cancer therapy, but many diverse mechanisms of action have been proposed. Here, we confirm that cordycepin triphosphate is likely to be the active metabolite of cordycepin and that it consistently represses growth factor-induced gene expression. Bioinformatic analysis, quantitative PCR and western blotting confirmed that cordycepin blocks the PI3K/AKT/mTOR and/or MEK/ERK pathways in six cell lines and that AMPK activation is not required. The effects of cordycepin on translation through mTOR pathway repression were detectable within 30 min, indicating a rapid process. These data therefore indicate that cordycepin has a universal mechanism of action, acting as cordycepin triphosphate on an as yet unknown target molecule involved in growth factor signalling.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}