Proceedings of the National Academy of Sciences of the United States of America最新文献_第10页

JunB–HBZ nuclear translocation by TGF-β is a key driver in HTLV-1-mediated leukemogenesis TGF-β介导的JunB-HBZ核易位是htlv -1介导的白血病发生的关键驱动因素

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2420756122

Wenyi Zhang, Takafumi Shichijo, Xueda Chen, Miho Watanabe, Kisato Nosaka, Masao Matsuoka, Jun-ichirou Yasunaga

{"title":"JunB–HBZ nuclear translocation by TGF-β is a key driver in HTLV-1-mediated leukemogenesis","authors":"Wenyi Zhang, Takafumi Shichijo, Xueda Chen, Miho Watanabe, Kisato Nosaka, Masao Matsuoka, Jun-ichirou Yasunaga","doi":"10.1073/pnas.2420756122","DOIUrl":"https://doi.org/10.1073/pnas.2420756122","url":null,"abstract":"The HTLV-1 bZIP factor ( HBZ ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia–lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1–infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1–infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-β activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-β stimulation. JUNB knockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1–infected nonleukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-β-induced nuclear translocation of HBZ–JunB complexes is associated with ATL oncogenesis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural mechanism for the recognition of E2F1 by the ubiquitin ligase adaptor Cyclin F 泛素连接酶接头细胞周期蛋白F识别E2F1的结构机制

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2501057122

Peter Ngoi, Xianxi Wang, Sivasankar Putta, Ricardo F. Da Luz, Vitor Hugo B. Serrão, Michael J. Emanuele, Seth M. Rubin

{"title":"Structural mechanism for the recognition of E2F1 by the ubiquitin ligase adaptor Cyclin F","authors":"Peter Ngoi, Xianxi Wang, Sivasankar Putta, Ricardo F. Da Luz, Vitor Hugo B. Serrão, Michael J. Emanuele, Seth M. Rubin","doi":"10.1073/pnas.2501057122","DOIUrl":"https://doi.org/10.1073/pnas.2501057122","url":null,"abstract":"Cyclin F, a noncanonical member of the cyclin protein family, plays a critical role in regulating transitions in the cell division cycle. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1–Cullin-F-box E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryoelectron microscopy to elucidate the structure of a Cyclin F–Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies between Cyclin F and Cyclin A. These results advance our understanding of E2F1 regulation and may inform strategies for selectively targeting Cyclin F in cancer or neurodegeneration.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"30 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling 骨形态发生蛋白9控制肺血管生长和重塑

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2410229122

Nihel Berrebeh, Yvon Mbouamboua, Raphaël Thuillet, Mina Ottaviani, Fabien Robert, Mustapha Kamel Chelgham, Virginie Magnone, Agnès Desroches-Castan, Nicolas Ricard, Ignacio Anegon, Séverine Remy, Ralph Theo Schermuly, Kevin Lebrigand, Baktybek Kojonazarov, Laurent Savale, Marc Humbert, Sabine Bailly, Pascal Barbry, Ly Tu, Christophe Guignabert

{"title":"Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling","authors":"Nihel Berrebeh, Yvon Mbouamboua, Raphaël Thuillet, Mina Ottaviani, Fabien Robert, Mustapha Kamel Chelgham, Virginie Magnone, Agnès Desroches-Castan, Nicolas Ricard, Ignacio Anegon, Séverine Remy, Ralph Theo Schermuly, Kevin Lebrigand, Baktybek Kojonazarov, Laurent Savale, Marc Humbert, Sabine Bailly, Pascal Barbry, Ly Tu, Christophe Guignabert","doi":"10.1073/pnas.2410229122","DOIUrl":"https://doi.org/10.1073/pnas.2410229122","url":null,"abstract":"Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we demonstrate a role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings reveal that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Calcineurin targets that mediate Cryptococcus thermotolerance. 钙调磷酸酶靶点介导隐球菌的耐热性。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2511623122

Aaron P Mitchell

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Onset of extensive human fire use 50,000 y ago. 人类开始广泛使用火是在5万年前。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2500042122

Shoushu Jiang,Debo Zhao,Stefanie Kaboth-Bahr,Luc Beaufort,Hua Tu,Zhengyao Lu,Zhongjing Cheng,Shanjia Zhang,Yi Zhong,Xiudong Hao,Wenqiang Pei,Guangqiang Cui,Yifei Yang,Anni Lin,Jie Huang,Shiming Wan

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The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate. 雌激素受体β在维持前列腺基底细胞和调节免疫环境中的作用。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-23 DOI: 10.1073/pnas.2505797122

Wan-Fu Wu,Xiao-Yu Song,Margaret Warner,Otabeck Imamov,Per Antonson,Jan-Ake Gustafsson

{"title":"The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate.","authors":"Wan-Fu Wu,Xiao-Yu Song,Margaret Warner,Otabeck Imamov,Per Antonson,Jan-Ake Gustafsson","doi":"10.1073/pnas.2505797122","DOIUrl":"https://doi.org/10.1073/pnas.2505797122","url":null,"abstract":"Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with 5-α reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERβ-/- mice. By comparing RNA-Seq of the ventral prostates (VP) of ERβ knockout mice (ERβcrispr-/-) and wild-type (WT) mice, we confirmed that ERβ modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERβcrispr-/- mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERβcrispr-/- mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERβcrispr-/- mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERβcrispr-/- mice. We conclude that ERβ is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERβ agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"88 1","pages":"e2505797122"},"PeriodicalIF":11.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multistage nucleation pathway in LiF molten salt mirrors the crystal–melt interface structure LiF熔盐的多阶段成核路径反映了晶体-熔体界面结构

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-20 DOI: 10.1073/pnas.2425702122

Zhao Fan, Deepak Rawat, Piotr Zarzycki, Michael L. Whittaker, Mark Asta

{"title":"Multistage nucleation pathway in LiF molten salt mirrors the crystal–melt interface structure","authors":"Zhao Fan, Deepak Rawat, Piotr Zarzycki, Michael L. Whittaker, Mark Asta","doi":"10.1073/pnas.2425702122","DOIUrl":"https://doi.org/10.1073/pnas.2425702122","url":null,"abstract":"Despite over a century of studies, fundamental questions remain about the processes governing crystal nucleation from melts or solutions. Research over the past three decades has presented mounting evidence for kinetic pathways of crystal nucleation that are more complex than envisioned by the simplest forms of classical theory. Such observations have been presented for colloidal and elemental systems with covalent and metallic bonding. Despite the technological and geochemical importance of molten salts, similar studies for these ionically bonded systems are currently lacking. Here we develop a machine learning interatomic potential for a model ionic system: LiF. The potential features quantum-level accuracy for both liquid and multiple solid polymorphs over wide temperature and pressure ranges and accurately reproduces experimentally measured properties. Thanks to the efficiency of the potential, which enables microsecond-scale molecular dynamics simulations, induction times for nucleation of LiF solids from their melts are computed over a range of undercoolings. With the aid of a set of robust local order parameters established here, the simulations reveal that homogeneous crystal nucleation in undercooled melts preferentially initiates from liquid regions showing slow dynamics and high bond orientational order simultaneously, and the second-shell order of both precritical nuclei and the surface of postcritical nuclei is dominated by hexagonal close packing and body-centered cubic local structure, even though the nucleus core is dominated by face-centered cubic structure corresponding to the stable rocksalt crystal structure. Finally, we establish a connection between the crystallization pathway and the equilibrium crystal–melt interface structure.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"25 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction for Chihoub et al., The evolution of robustness and fragility during long-term bacterial adaptation. 对Chihoub等人的修正，细菌长期适应过程中稳健性和脆弱性的演变。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-20 DOI: 10.1073/pnas.2512470122

引用次数: 0

Correction for Maher et al., Intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus. 修正Maher等人，冥想诱导的杏仁核和海马体神经调节的颅内底物。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-20 DOI: 10.1073/pnas.2511043122

引用次数: 0

Beyond additive genetic effects: Explaining family resemblance in school performance across millions of pairs of Norwegian relatives 超越加性基因效应：解释数百万对挪威亲属在学校表现上的家庭相似性

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-20 DOI: 10.1073/pnas.2419627122

Nikolai Haahjem Eftedal, Espen Moen Eilertsen, Hans Fredrik Sunde, Thomas Haarklau Kleppestø, Eivind Ystrom, Nikolai Olavi Czajkowski

{"title":"Beyond additive genetic effects: Explaining family resemblance in school performance across millions of pairs of Norwegian relatives","authors":"Nikolai Haahjem Eftedal, Espen Moen Eilertsen, Hans Fredrik Sunde, Thomas Haarklau Kleppestø, Eivind Ystrom, Nikolai Olavi Czajkowski","doi":"10.1073/pnas.2419627122","DOIUrl":"https://doi.org/10.1073/pnas.2419627122","url":null,"abstract":"We investigate the hypothesis that family resemblance on school performance can be fully explained by additive genetic effects and assortative mating. Our sample consists of all schoolchildren who took Norwegian national standardized tests between 2007 and 2019 (N = 936,708). These tests measure aptitude in math and reading comprehension, and are taken the years children turn 10, 13, and 14 y old. We identify millions of pairs of relatives within our sample (82 different kinds, in total), including not only conventional biological relatives such as siblings and cousins, but also relatives-in-law, relatives through adoption, twins, and relatives connected through twins. When fitting models which assume that family resemblance arises solely from additive genetic effects and assortative mating, we find that they describe much of our data well, but that they systematically underestimate the similarity of close relatives (particularly monozygotic twins), maternal relatives, relatives-in-law, and relatives through adoption. We discuss potential explanations for these deviations, including shared-environmental effects, nonadditive genetic effects, and gene–environment interplay.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0