The FEBS journal最新文献_第5页

The AXL inhibitor bemcentinib overcomes microenvironment-mediated resistance to pioglitazone in acute myeloid leukemia. AXL抑制剂bemcentinib克服了微环境介导的急性髓性白血病患者对吡格列酮的耐药性。

The FEBS journal Pub Date : 2024-09-26 DOI: 10.1111/febs.17263

Jaja Zhu, Hippolyte Guérineau, Anne-Margaux Lefebvre-Fortané, Laetitia Largeaud, Juliette Lambert, Philippe Rousselot, Maèva Boudouin, Julien Calvo, Stéphane Prost, Sylvain Clauser, Valérie Bardet

{"title":"The AXL inhibitor bemcentinib overcomes microenvironment-mediated resistance to pioglitazone in acute myeloid leukemia.","authors":"Jaja Zhu, Hippolyte Guérineau, Anne-Margaux Lefebvre-Fortané, Laetitia Largeaud, Juliette Lambert, Philippe Rousselot, Maèva Boudouin, Julien Calvo, Stéphane Prost, Sylvain Clauser, Valérie Bardet","doi":"10.1111/febs.17263","DOIUrl":"https://doi.org/10.1111/febs.17263","url":null,"abstract":"Prognosis of acute myeloid leukemia (AML) remains poor especially in older patients who are ineligible for standard chemotherapy or have refractory disease. Here, we study the potential of Peroxisome Proliferator-Activated Receptor (PPAR)-γ agonist pioglitazone to improve the treatment of AML. We show that pioglitazone exerts an anti-proliferative and anti-clonogenic effect on AML cell lines KG-1a, MOLM-14 and OCI-AML3 and on primary cultures from AML patients. However, co-culture of AML cells with stromal cells mimicking the bone marrow microenvironment counteracts this effect, suggesting the existence of a stroma-mediated resistance mechanism to pioglitazone. We show that pioglitazone treatment upregulates the receptor AXL in AML cells at the mRNA and protein level, allowing AXL to be phosphorylated by its ligand Gas6, which is secreted by the stroma. Addition of exogenous Gas6 or stromal cell conditioned medium also abolishes the anti-proliferative effect of pioglitazone, with an increase in AXL phosphorylation observed in both conditions. Co-incubation with the AXL inhibitor bemcentinib restored the anti-leukemic activity of pioglitazone in the presence of stromal cells by reducing AXL phosphorylation to its baseline level. We also confirm that this resistance mechanism is PPAR-γ-dependent as stromal cells invalidated for PPAR-γ are unable to inhibit the antileukemic effect of pioglitazone. Altogether, we suggest that pioglitazone treatment exerts an anti-leukemic effect but concomitantly triggers a stroma-mediated resistance mechanism involving the Gas6/AXL axis. We demonstrate that a combination of pioglitazone with an AXL inhibitor overcomes this mechanism in primary cultures and AML cell lines and exerts potent anti-leukemic activity requiring further evaluation in vivo through murine xenograft pre-clinical models.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335505","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}

引用次数: 0

Senescence in the ageing skin: a new focus on mTORC1 and the lysosome. 老化皮肤的衰老：mTORC1 和溶酶体的新焦点。

The FEBS journal Pub Date : 2024-09-26 DOI: 10.1111/febs.17281

Phineas Smith, Bernadette Carroll

引用次数: 0

Structural and molecular insights of two unique enzymes involved in the biosynthesis of a natural halogenated nitrile. 参与天然卤代腈生物合成的两种独特酶的结构和分子见解。

The FEBS journal Pub Date : 2024-09-22 DOI: 10.1111/febs.17279

Chun-Chi Chen, Hao Li, Jian-Wen Huang, Rey-Ting Guo

{"title":"Structural and molecular insights of two unique enzymes involved in the biosynthesis of a natural halogenated nitrile.","authors":"Chun-Chi Chen, Hao Li, Jian-Wen Huang, Rey-Ting Guo","doi":"10.1111/febs.17279","DOIUrl":"https://doi.org/10.1111/febs.17279","url":null,"abstract":"Organohalogen compounds exhibit wide-ranging bioactivities and potential applications. Understanding natural biosynthetic pathways and improving the production of halogenated compounds has garnered significant attention. Recently, the biosynthetic pathway of a cyanobacterial neurotoxin, aetokthonotoxin, was reported. It contains two unique enzymes: a single-component flavin-dependent halogenase AetF and a new type of nitril synthase AetD. The crystal structures of these enzymes in complex with their cofactors and substrates that were recently reported will be presented here. The AetF structures reveal a tri-domain architecture, the transfer direction of the hydride ion, a possible path to deliver the hypohalous acid, and the unusual bispecific substrate-recognition mode. The AetD structures demonstrate that the nitrile formation should occur through the action of a diiron cluster, implying that the enzyme should be capable of catalyzing the nitrile formation of alternative amino acids. This information is of central importance for understanding the mechanism of action as well as the applications of these two the-first-of-its-kind enzymes.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305294","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}

引用次数: 0

Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective. 利用癌症中的核苷酸代谢和免疫：肿瘤微环境视角。

The FEBS journal Pub Date : 2024-09-22 DOI: 10.1111/febs.17278

Hadil Sulieman, Alexandra Emerson, Peter M Wilson, Karl A Mulligan, Robert D Ladner, Melissa J LaBonte

{"title":"Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.","authors":"Hadil Sulieman, Alexandra Emerson, Peter M Wilson, Karl A Mulligan, Robert D Ladner, Melissa J LaBonte","doi":"10.1111/febs.17278","DOIUrl":"https://doi.org/10.1111/febs.17278","url":null,"abstract":"The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305292","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}

引用次数: 0

What's in a name: the multifaceted function of DNA- and RNA-binding proteins in T cell responses. 名字的含义：DNA 和 RNA 结合蛋白在 T 细胞反应中的多方面功能。

The FEBS journal Pub Date : 2024-09-20 DOI: 10.1111/febs.17273

Kaspar Bresser, Branka Popović, Monika C Wolkers

{"title":"What's in a name: the multifaceted function of DNA- and RNA-binding proteins in T cell responses.","authors":"Kaspar Bresser, Branka Popović, Monika C Wolkers","doi":"10.1111/febs.17273","DOIUrl":"https://doi.org/10.1111/febs.17273","url":null,"abstract":"Cellular differentiation allows cells to transition between different functional states and adapt to various environmental cues. The diversity and plasticity of this process is beautifully exemplified by T cells responding to pathogens, which undergo highly specialized differentiation tailored to the ongoing infection. Such antigen-induced T cell differentiation is regulated at the transcriptional level by DNA-binding proteins and at the post-transcriptional level by RNA-binding proteins. Although traditionally defined as separate protein classes, a growing body of evidence indicates an overlap between these two groups of proteins, collectively coined DNA/RNA-binding proteins (DRBPs). In this review, we describe how DRBPs might bind both DNA and RNA, discuss the putative functional relevance of this dual binding, and provide an exploratory analysis into characteristics that are associated with DRBPs. To exemplify the significance of DRBPs in T cell biology, we detail the activity of several established and putative DRBPs during the T cell response. Finally, we highlight several methodologies that allow untangling of the distinct functionalities of DRBPs at the DNA and RNA level, including key considerations to take into account when applying such methods.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305295","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}

引用次数: 0

Neural control of tumor immunity 肿瘤免疫的神经控制

The FEBS journal Pub Date : 2024-09-20 DOI: 10.1111/febs.17280

Burak Kizil, Francesco De Virgiliis, Christoph Scheiermann

引用次数: 0

Research highlights 研究重点

The FEBS journal Pub Date : 2024-09-19 DOI: 10.1111/febs.17267

Hajrah Khawaja

引用次数: 0

Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression 雌激素受体和细胞外基质：癌症发生和发展过程中的关键相互作用

The FEBS journal Pub Date : 2024-09-17 DOI: 10.1111/febs.17270

Sylvia Mangani, Zoi Piperigkou, Nikolaos E. Koletsis, Paraskevi Ioannou, Nikos K. Karamanos

{"title":"Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression","authors":"Sylvia Mangani, Zoi Piperigkou, Nikolaos E. Koletsis, Paraskevi Ioannou, Nikos K. Karamanos","doi":"10.1111/febs.17270","DOIUrl":"https://doi.org/10.1111/febs.17270","url":null,"abstract":"Cancer remains a significant global health concern. Breast cancer is a multifaceted and prevalent disease influenced by several factors, among which estrogen receptors (ERs) and the extracellular matrix (ECM) play pivotal roles. ERs, encompassing ERα and ERβ, exert significant diversity on tumor behavior, cell signaling, invasion, and metastatic potential, thus guiding breast cancer prognosis. Understanding the multifunctional connections between ERs and ECM that mediate the dynamics of tumor microenvironment is vital for unraveling the complexity of breast cancer pathobiology and identifying novel therapeutic targets. This critical review delves into the intricate nature of ERs, emphasizing their structural isoforms and the consequential impact on breast cancer outcomes. A detailed examination of ER‐mediated cell signaling pathways reveals how differential expression of ERα and ERβ isoforms influence breast cancer cell behavior. The functional ERs‐matrix interactions emerge as a pivotal factor in modulating epigenetic mechanisms of breast cancer cells, orchestrating changes in cellular phenotype and expression patterns of matrix modulators. Specifically, ERα isoforms are shown to regulate ECM signaling cascades, while the effects of ECM components on ERα activity highlight a bidirectional regulatory axis. The diversity of ERβ isoforms is also highlighted, illustrating their distinct contribution to ECM‐mediated cellular responses. This review underscores the complex interplay between ERα/β isoforms and the ECM, shedding light onto the potential therapeutic strategies targeting these interactions to improve breast cancer management.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266853","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}

引用次数: 0

Mouse polyomavirus infection induces lamin reorganisation 小鼠多瘤病毒感染诱导片层重组

The FEBS journal Pub Date : 2024-09-17 DOI: 10.1111/febs.17275

Kateřina Bruštíková, Boris Ryabchenko, Sandra Žáčková, Vojtěch Šroller, Jitka Forstová, Lenka Horníková

{"title":"Mouse polyomavirus infection induces lamin reorganisation","authors":"Kateřina Bruštíková, Boris Ryabchenko, Sandra Žáčková, Vojtěch Šroller, Jitka Forstová, Lenka Horníková","doi":"10.1111/febs.17275","DOIUrl":"https://doi.org/10.1111/febs.17275","url":null,"abstract":"The nuclear lamina is a dense network of intermediate filaments beneath the inner nuclear membrane. Composed of A‐type lamins (lamin A/C) and B‐type lamins (lamins B1 and B2), the nuclear lamina provides a scaffold for the nuclear envelope and chromatin, thereby maintaining the structural integrity of the nucleus. A‐type lamins are also found inside the nucleus where they interact with chromatin and participate in gene regulation. Viruses replicating in the cell nucleus have to overcome the nuclear envelope during the initial phase of infection and during the nuclear egress of viral progeny. Here, we focused on the role of lamins in the replication cycle of a dsDNA virus, mouse polyomavirus. We detected accumulation of the major capsid protein VP1 at the nuclear periphery, defects in nuclear lamina staining and different lamin A/C phosphorylation patterns in the late phase of mouse polyomavirus infection, but the nuclear envelope remained intact. An absence of lamin A/C did not affect the formation of replication complexes but did slow virus propagation. Based on our findings, we propose that the nuclear lamina is a scaffold for replication complex formation and that lamin A/C has a crucial role in the early phases of infection with mouse polyomavirus.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266851","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}

引用次数: 0

Mycobacterial peptidyl prolyl isomerase A activates STING‐TBK1‐IRF3 signaling to promote IFNβ release in macrophages 分枝杆菌肽基脯氨酰异构酶 A 激活 STING-TBK1-IRF3 信号，促进巨噬细胞释放 IFNβ

The FEBS journal Pub Date : 2024-09-17 DOI: 10.1111/febs.17261

Arun Kumar Sharma, Soumya Mal, Sanjaya Kumar Sahu, Shreya Bagchi, Debayan Majumder, Debangana Chakravorty, Sudipto Saha, Manikuntala Kundu, Joyoti Basu

{"title":"Mycobacterial peptidyl prolyl isomerase A activates STING‐TBK1‐IRF3 signaling to promote IFNβ release in macrophages","authors":"Arun Kumar Sharma, Soumya Mal, Sanjaya Kumar Sahu, Shreya Bagchi, Debayan Majumder, Debangana Chakravorty, Sudipto Saha, Manikuntala Kundu, Joyoti Basu","doi":"10.1111/febs.17261","DOIUrl":"https://doi.org/10.1111/febs.17261","url":null,"abstract":"Peptidyl prolyl isomerases (PPIases) are well‐conserved protein‐folding enzymes that moonlight as regulators of bacterial virulence. Peptidyl prolyl isomerase A, PPiA (Rv0009) is a secretory protein of Mycobacterium tuberculosis that possesses sequence and structural similarity to eukaryotic cyclophilins. In this study, we validated the interaction of PPiA with stimulator of interferon genes (STING) using both, Escherichia coli‐based and mammalian in vitro expression systems. In vitro pull‐down assays confirmed that the cytosolic domain of STING interacts with PPiA, and moreover, we found that PPiA could induce dimerization of STING in macrophages. In silico docking analyses suggested that the PXXP (PDP) motif of PPiA is crucial for interaction with STING, and concordantly, mutations in the PDP domain (PPiA MUT‐II) abrogated this interaction, as well as the ability of PPiA to facilitate STING dimerization. In agreement with these observations, fluorescence microscopy demonstrated that STING and wild‐type PPiA, but not PPiA MUT‐II, could colocalize when expressed in HEK293 cells. Highlighting the importance of the PDP domain further, PPiA, but not PPiA MUT‐II could activate Tank binding kinase 1 (TBK1)‐interferon regulatory factor 3 (IRF3) signaling to promote the release of interferon‐beta (IFNβ). PPiA, but not PPiA MUT‐II expressed in Mycobacterium smegmatis induced IFNβ release and facilitated bacterial survival in macrophages in a STING‐dependent manner. The PPiA‐induced release of IFNβ was c‐GAS independent. We conclude that PPiA is a previously undescribed mycobacterial regulator of STING‐dependent type I interferon production from macrophages.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266852","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}

引用次数: 0