Life Science Alliance最新文献_第9页

Early Atf4 activity drives airway club and goblet cell differentiation. 早期 Atf4 活性驱动气道俱乐部和鹅口疮细胞分化。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-01-04 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302284

Juan F Barrera-Lopez, Guadalupe Cumplido-Laso, Marcos Olivera-Gomez, Sergio Garrido-Jimenez, Selene Diaz-Chamorro, Clara M Mateos-Quiros, Dixan A Benitez, Francisco Centeno, Sonia Mulero-Navarro, Angel C Roman, Jose M Carvajal-Gonzalez

{"title":"Early Atf4 activity drives airway club and goblet cell differentiation.","authors":"Juan F Barrera-Lopez, Guadalupe Cumplido-Laso, Marcos Olivera-Gomez, Sergio Garrido-Jimenez, Selene Diaz-Chamorro, Clara M Mateos-Quiros, Dixan A Benitez, Francisco Centeno, Sonia Mulero-Navarro, Angel C Roman, Jose M Carvajal-Gonzalez","doi":"10.26508/lsa.202302284","DOIUrl":"10.26508/lsa.202302284","url":null,"abstract":"Activating transcription factor 4 (Atf4), which is modulated by the protein kinase RNA-like ER kinase (PERK), is a stress-induced transcription factor responsible for controlling the expression of a wide range of adaptive genes, enabling cells to withstand stressful conditions. However, the impact of the Atf4 signaling pathway on airway regeneration remains poorly understood. In this study, we used mouse airway epithelial cell culture models to investigate the role of PERK/Atf4 in respiratory tract differentiation. Through pharmacological inhibition and silencing of ATF4, we uncovered the crucial involvement of PERK/Atf4 in the differentiation of basal stem cells, leading to a reduction in the number of secretory cells. ChIP-seq analysis revealed direct binding of ATF4 to regulatory elements of genes associated with osteoblast differentiation and secretory cell function. Our findings provide valuable insights into the role of ATF4 in airway epithelial differentiation and its potential involvement in innate immune responses and cellular adaptation to stress.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10766780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter. 普利多哌啶巧妙地改善了白质消失小鼠模型的运动技能。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-01-03 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302199

Ellen Oudejans, Diede Witkamp, Gino V Hu-A-Ng, Leoni Hoogterp, Gemma van Rooijen-van Leeuwen, Iris Kruijff, Pleun Schonewille, Zeinab Lalaoui El Mouttalibi, Imke Bartelink, Marjo S van der Knaap, Truus Em Abbink

{"title":"Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter.","authors":"Ellen Oudejans, Diede Witkamp, Gino V Hu-A-Ng, Leoni Hoogterp, Gemma van Rooijen-van Leeuwen, Iris Kruijff, Pleun Schonewille, Zeinab Lalaoui El Mouttalibi, Imke Bartelink, Marjo S van der Knaap, Truus Em Abbink","doi":"10.26508/lsa.202302199","DOIUrl":"10.26508/lsa.202302199","url":null,"abstract":"The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate clinical and neuropathological disease hallmarks. It is unclear which ISR components are suitable therapeutic targets. In this study, effects of 4-phenylbutyric acid, tauroursodeoxycholic acid, or pridopidine (PDPD), with ISR targets upstream or downstream of eIF2B, were assessed in VWM mice. In addition, it was found that the composite ataxia score represented motor decline of VWM mice more accurately than the previously used neuroscore. 4-phenylbutyric acid and tauroursodeoxycholic acid did not improve VWM disease hallmarks, whereas PDPD had subtle beneficial effects on motor skills. PDPD alone does not suffice as treatment in VWM mice but may be considered for combination therapy. Also, treatments aimed at ISR components upstream of eIF2B do not improve chronic neurological deterioration; effects on acute episodic decline remain to be investigated.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport. Tmprss2 可维持上皮屏障的完整性和经上皮钠转运。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-01-03 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302304

Olivia J Rickman, Emma Guignard, Thomas Chabanon, Giovanni Bertoldi, Muriel Auberson, Edith Hummler

{"title":"Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport.","authors":"Olivia J Rickman, Emma Guignard, Thomas Chabanon, Giovanni Bertoldi, Muriel Auberson, Edith Hummler","doi":"10.26508/lsa.202302304","DOIUrl":"10.26508/lsa.202302304","url":null,"abstract":"The mouse cortical collecting duct cell line presents a tight epithelium with regulated ion and water transport. The epithelial sodium channel (ENaC) is localized in the apical membrane and constitutes the rate-limiting step for sodium entry, thereby enabling transepithelial transport of sodium ions. The membrane-bound serine protease Tmprss2 is co-expressed with the alpha subunit of ENaC. αENaC gene expression followed the Tmprss2 expression, and the absence of Tmprss2 resulted not only in down-regulation of αENaC gene and protein expression but also in abolished transepithelial sodium transport. In addition, RNA-sequencing analyses unveiled drastic down-regulation of the membrane-bound protease CAP3/St14, the epithelial adhesion molecule EpCAM, and the tight junction proteins claudin-7 and claudin-3 as also confirmed by immunohistochemistry. In summary, our data clearly demonstrate a dual role of Tmprss2 in maintaining not only ENaC-mediated transepithelial but also EpCAM/claudin-7-mediated paracellular barrier; the tight epithelium of the mouse renal mCCD cells becomes leaky. Our working model proposes that Tmprss2 acts via CAP3/St14 on EpCAM/claudin-7 tight junction complexes and through regulating transcription of αENaC on ENaC-mediated sodium transport.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene architecture is a determinant of the transcriptional response to bulky DNA damages. 基因结构决定了对大块 DNA 损伤的转录反应。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-01-02 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302328

May Merav, Elnatan M Bitensky, Elisheva E Heilbrun, Tamar Hacohen, Ayala Kirshenbaum, Hadar Golan-Berman, Yuval Cohen, Sheera Adar

{"title":"Gene architecture is a determinant of the transcriptional response to bulky DNA damages.","authors":"May Merav, Elnatan M Bitensky, Elisheva E Heilbrun, Tamar Hacohen, Ayala Kirshenbaum, Hadar Golan-Berman, Yuval Cohen, Sheera Adar","doi":"10.26508/lsa.202302328","DOIUrl":"10.26508/lsa.202302328","url":null,"abstract":"Bulky DNA damages block transcription and compromise genome integrity and function. The cellular response to these damages includes global transcription shutdown. Still, active transcription is necessary for transcription-coupled repair and for induction of damage-response genes. To uncover common features of a general bulky DNA damage response, and to identify response-related transcripts that are expressed despite damage, we performed a systematic RNA-seq study comparing the transcriptional response to three independent damage-inducing agents: UV, the chemotherapy cisplatin, and benzo[a]pyrene, a component of cigarette smoke. Reduction in gene expression after damage was associated with higher damage rates, longer gene length, and low GC content. We identified genes with relatively higher expression after all three damage treatments, including NR4A2, a potential novel damage-response transcription factor. Up-regulated genes exhibit higher exon content that is associated with preferential repair, which could enable rapid damage removal and transcription restoration. The attenuated response to BPDE highlights that not all bulky damages elicit the same response. These findings frame gene architecture as a major determinant of the transcriptional response that is hardwired into the human genome.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

2',3' cyclic nucleotide 3' phosphodiesterase 1 functional isoform antagonizes HIV-1 particle assembly. 2',3'环核苷酸 3'磷酸二酯酶 1 功能同工酶能拮抗 HIV-1 颗粒的组装。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-01-02 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302188

Shuntao Liang, Qin Zhang, Fang Wang, Shiwei Wang, Guoli Li, Dong Jiang, Hui Zeng

{"title":"2',3' cyclic nucleotide 3' phosphodiesterase 1 functional isoform antagonizes HIV-1 particle assembly.","authors":"Shuntao Liang, Qin Zhang, Fang Wang, Shiwei Wang, Guoli Li, Dong Jiang, Hui Zeng","doi":"10.26508/lsa.202302188","DOIUrl":"10.26508/lsa.202302188","url":null,"abstract":"IFN-stimulated gene 2',3' cyclic nucleotide 3' phosphodiesterase (CNP) comprises two isoforms: the short CNP1 and the long CNP2, featuring an additional N-terminal segment of 20 amino acids (N20aa) proposed as a mitochondrial targeting sequence. Notably, CNP1 can be produced by cleaving the N20aa segment from CNP2. Although previous investigations have recognized the HIV-1 particle assembly impairment capability of CNP2, the antiviral activity of CNP1 remains ambiguous. Our study clarifies that CNP1, as opposed to CNP2, serves as the primary isoform exerting anti-HIV-1 activity. Both CNP1 and CNP2 can localize to the cell membrane, but the N20aa segment of CNP2 impedes CNP2-HIV-1 Gag interaction. Cleavage of the N20aa segment from CNP2 results in the formation of a functional, truncated form known as CNP1. Intriguingly, this posttranslational processing of CNP2 N20aa occurs within the cytoplasmic matrix rather than the mitochondria. Regulated by CTII motif prenylation, CNP1 proteins translocate to the cell membrane and engage with HIV-1 Gag. In conclusion, our findings underscore the pivotal role of posttranslational modification in governing the inhibitory potential of CNP in HIV-1 replication.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sterile protection against P. vivax malaria by repeated blood stage infection in the Aotus monkey model. 在奥特斯猴模型中通过重复血期感染对间皮细胞疟的无菌保护。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2023-12-29 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302524

Nicanor Obaldía, Joao Luiz Da Silva Filho, Marlon Núñez, Katherine A Glass, Tate Oulton, Fiona Achcar, Grennady Wirjanata, Manoj Duraisingh, Philip Felgner, Kevin Ka Tetteh, Zbynek Bozdech, Thomas D Otto, Matthias Marti

{"title":"Sterile protection against P. vivax malaria by repeated blood stage infection in the Aotus monkey model.","authors":"Nicanor Obaldía, Joao Luiz Da Silva Filho, Marlon Núñez, Katherine A Glass, Tate Oulton, Fiona Achcar, Grennady Wirjanata, Manoj Duraisingh, Philip Felgner, Kevin Ka Tetteh, Zbynek Bozdech, Thomas D Otto, Matthias Marti","doi":"10.26508/lsa.202302524","DOIUrl":"10.26508/lsa.202302524","url":null,"abstract":"The malaria parasite Plasmodium vivax remains a major global public health challenge, and no vaccine is approved for use in humans. Here, we assessed whether P. vivax strain-transcendent immunity can be achieved by repeated infection in Aotus monkeys. Sterile immunity was achieved after two homologous infections, whereas subsequent heterologous challenge provided only partial protection. IgG levels based on P. vivax lysate ELISA and protein microarray increased with repeated infections and correlated with the level of homologous protection. Parasite transcriptional profiles provided no evidence of major antigenic switching upon homologous or heterologous challenge. However, we observed significant sequence diversity and transcriptional differences in the P. vivax core gene repertoire between the two strains used in the study, suggesting that partial protection upon heterologous challenge is due to molecular differences between strains rather than immune evasion by antigenic switching. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated homologous blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139074472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The memory of airway epithelium damage in smokers and COPD patients. 吸烟者和慢性阻塞性肺病患者气道上皮细胞损伤的记忆。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2023-12-29 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302341

François M Carlier, Bruno Detry, Marylène Lecocq, Amandine M Collin, Thomas Planté-Bordeneuve, Ludovic Gérard, Stijn E Verleden, Monique Delos, Benoît Rondelet, Wim Janssens, Jérôme Ambroise, Bart M Vanaudenaerde, Sophie Gohy, Charles Pilette

{"title":"The memory of airway epithelium damage in smokers and COPD patients.","authors":"François M Carlier, Bruno Detry, Marylène Lecocq, Amandine M Collin, Thomas Planté-Bordeneuve, Ludovic Gérard, Stijn E Verleden, Monique Delos, Benoît Rondelet, Wim Janssens, Jérôme Ambroise, Bart M Vanaudenaerde, Sophie Gohy, Charles Pilette","doi":"10.26508/lsa.202302341","DOIUrl":"10.26508/lsa.202302341","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139074473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extreme trait GWAS (Et-GWAS): Unraveling rare variants in the 3,000 rice genome. 极端性状 GWAS（Et-GWAS）：揭示 3000 个水稻基因组中的罕见变异。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2023-12-26 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302352

Niranjani Gnanapragasam, Vinukonda Vishnu Prasanth, Krishna Tesman Sundaram, Ajay Kumar, Bandana Pahi, Anoop Gurjar, Challa Venkateshwarlu, Sanjay Kalia, Arvind Kumar, Shalabh Dixit, Ajay Kohli, Uma Maheshwer Singh, Vikas Kumar Singh, Pallavi Sinha

{"title":"Extreme trait GWAS (Et-GWAS): Unraveling rare variants in the 3,000 rice genome.","authors":"Niranjani Gnanapragasam, Vinukonda Vishnu Prasanth, Krishna Tesman Sundaram, Ajay Kumar, Bandana Pahi, Anoop Gurjar, Challa Venkateshwarlu, Sanjay Kalia, Arvind Kumar, Shalabh Dixit, Ajay Kohli, Uma Maheshwer Singh, Vikas Kumar Singh, Pallavi Sinha","doi":"10.26508/lsa.202302352","DOIUrl":"10.26508/lsa.202302352","url":null,"abstract":"Identifying high-impact, rare genetic variants associated with specific traits is crucial for crop improvement. The 3,010 rice genome (3K RG) dataset offers a valuable resource for discovering genomic regions with potential applications in crop breeding. We used Extreme Trait GWAS (Et-GWAS), employing bulk pooling and allele frequency measurement to efficiently extract rare variants from the 3K RG. This innovative approach facilitates the detection of associations between genetic variants and target traits, concentrating and quantifying rare alleles. In our study, on grain yield under drought stress, Et-GWAS successfully identified five key genes (OsPP2C11, OsK5.2, OsIRO2, OsPEX1, and OsPWA1) known for enhancing yield under drought. In addition, we examined the overlap of our results with previously reported qDTY-QTLs and observed that OsUCH1 and OsUCH2 genes were located within qDTY2.2 We compared Et-GWAS with conventional GWAS, finding it effectively capturing most candidate genes associated with the target trait. Validation with resistant starch showed similar results. To enhance user-friendliness, we developed a GUI for Et-GWAS; https://et-gwas.shinyapps.io/Et-GWAS/.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis. 初始淋巴管中的VE-cadherin连接动态促进淋巴结转移。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2023-12-26 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302168

Miguel Sáinz-Jaspeado, Sarah Ring, Steven T Proulx, Mark Richards, Pernilla Martinsson, Xiujuan Li, Lena Claesson-Welsh, Maria H Ulvmar, Yi Jin

{"title":"VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis.","authors":"Miguel Sáinz-Jaspeado, Sarah Ring, Steven T Proulx, Mark Richards, Pernilla Martinsson, Xiujuan Li, Lena Claesson-Welsh, Maria H Ulvmar, Yi Jin","doi":"10.26508/lsa.202302168","DOIUrl":"10.26508/lsa.202302168","url":null,"abstract":"The endothelial junction component vascular endothelial (VE)-cadherin governs junctional dynamics in the blood and lymphatic vasculature. Here, we explored how lymphatic junction stability is modulated by elevated VEGFA signaling to facilitate metastasis to sentinel lymph nodes. Zippering of VE-cadherin junctions was established in dermal initial lymphatic vessels after VEGFA injection and in tumor-proximal lymphatics in mice. Shape analysis of pan-cellular VE-cadherin fragments revealed that junctional zippering was accompanied by accumulation of small round-shaped VE-cadherin fragments in the lymphatic endothelium. In mice expressing a mutant VEGFR2 lacking the Y949 phosphosite (Vegfr2 Y949F/Y949F ) required for activation of Src family kinases, zippering of lymphatic junctions persisted, whereas accumulation of small VE-cadherin fragments was suppressed. Moreover, tumor cell entry into initial lymphatic vessels and subsequent metastatic spread to lymph nodes was reduced in mutant mice compared with WT, after challenge with B16F10 melanoma or EO771 breast cancer. We conclude that VEGFA mediates zippering of VE-cadherin junctions in initial lymphatics. Zippering is accompanied by increased VE-cadherin fragmentation through VEGFA-induced Src kinase activation, correlating with tumor dissemination to sentinel lymph nodes.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor. EIF4G2 非典型翻译起始因子中与癌症相关的功能缺失突变。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2023-12-21 Print Date: 2024-03-01 DOI: 10.26508/lsa.202302338

Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi

{"title":"Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor.","authors":"Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi","doi":"10.26508/lsa.202302338","DOIUrl":"10.26508/lsa.202302338","url":null,"abstract":"Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed because of cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site (IRES)- and uORF-dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here, we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein-protein interactions and, importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near-complete loss of function. Two other mutations within the MIF4G domain specifically affected EIF4G2's ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure-function of EIF4G2 and its potential tumor suppressor effects.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10746786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138830313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0