Science Signaling最新文献

Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer eIF2 激酶 GCN2 和 p53 信号之间的协调支持嘌呤代谢和前列腺癌的进展。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-26 DOI: 10.1126/scisignal.adp1375

Ricardo A. Cordova, Noah R. Sommers, Andrew S. Law, Angela J. Klunk, Katherine E. Brady, David W. Goodrich, Tracy G. Anthony, Jeffrey J. Brault, Roberto Pili, Ronald C. Wek, Kirk A. Staschke

{"title":"Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer","authors":"Ricardo A. Cordova, Noah R. Sommers, Andrew S. Law, Angela J. Klunk, Katherine E. Brady, David W. Goodrich, Tracy G. Anthony, Jeffrey J. Brault, Roberto Pili, Ronald C. Wek, Kirk A. Staschke","doi":"10.1126/scisignal.adp1375","DOIUrl":"10.1126/scisignal.adp1375","url":null,"abstract":"<div >Cancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death. Here, we discovered that the loss of GCN2 in PCa induces prosenescent p53 signaling. This p53 activation occurred through GCN2 inhibition–dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint. p53 signaling induced cell cycle arrest and senescence that promoted the survival of GCN2-deficient PCa cells. Depletion of GCN2 combined with loss of p53 or pharmacological inhibition of de novo purine biosynthesis reduced proliferation and enhanced cell death in PCa cell lines, organoids, and xenograft models. Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for PCa.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 864","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142734125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microbes help honeybees learn 微生物帮助蜜蜂学习

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-26 DOI: 10.1126/scisignal.adu7439

Annalisa M. VanHook

引用次数: 0

TYK2 on tau TYK2 就是 tau。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-19 DOI: 10.1126/scisignal.adu6085

Leslie K. Ferrarelli

引用次数: 0

Promiscuous Janus kinase binding to cytokine receptors modulates signaling efficiencies and contributes to cytokine pleiotropy 杂合 Janus 激酶与细胞因子受体的结合可调节信号传递效率，并促进细胞因子的多效性。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-19 DOI: 10.1126/scisignal.adl1892

Eyal Zoler, Thomas Meyer, Junel Sotolongo Bellón, Mia Mönnig, Boyue Sun, Jacob Piehler, Gideon Schreiber

{"title":"Promiscuous Janus kinase binding to cytokine receptors modulates signaling efficiencies and contributes to cytokine pleiotropy","authors":"Eyal Zoler, Thomas Meyer, Junel Sotolongo Bellón, Mia Mönnig, Boyue Sun, Jacob Piehler, Gideon Schreiber","doi":"10.1126/scisignal.adl1892","DOIUrl":"10.1126/scisignal.adl1892","url":null,"abstract":"<div >Janus kinases (JAKs) bind to class I and II cytokine receptors, activating signaling and regulating gene transcription through signal transducer and activator of transcription (STAT) proteins. Type I interferons (IFNs) require the JAK members TYK2 and JAK1, which bind to the receptor subunits IFNAR1 and IFNAR2, respectively. We investigated the role of JAKs in regulating IFNAR signaling activity. Synthetic IFNARs in which the extracellular domains of IFNAR1 and IFNAR2 are replaced with nanobodies had near-native type I IFN signaling, whereas the homomeric variant of IFNAR2 initiated much weaker signaling, despite harboring docking sites for JAKs and STATs. Cells with JAK1 and TYK2 knockout (KO) showed residual signaling, suggesting partial complementation by the remaining JAKs, particularly when they were overexpressed. Live-cell micropatterning experiments confirmed the promiscuous binding of JAK1, JAK2, and TYK2 to IFNAR1 and IFNAR2, and their recruitment correlated with their relative cellular abundances. However, each JAK had a different efficacy in inducing cross-phosphorylation and downstream signaling. JAK binding was also promiscuous for other cytokine receptors, including IFN-L1, IL-10Rβ, TPOR, and GHR, but not for EPOR, which activated different downstream signaling pathways. These findings suggest that competitive binding of JAKs to cytokine receptors together with the varying absolute and relative abundances of the JAKs in different cell types can account for the cell type–dependent signaling pleiotropy of cytokine receptors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 863","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas 将可乐定达罗帕特用于治疗 MYC 驱动的高级别浆液性卵巢癌。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-19 DOI: 10.1126/scisignal.ado8303

Matthew J. Knarr, Jamie Moon, Priyanka Rawat, Analisa DiFeo, David S. B. Hoon, Ronny Drapkin

{"title":"Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas","authors":"Matthew J. Knarr, Jamie Moon, Priyanka Rawat, Analisa DiFeo, David S. B. Hoon, Ronny Drapkin","doi":"10.1126/scisignal.ado8303","DOIUrl":"10.1126/scisignal.ado8303","url":null,"abstract":"<div >High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids but had negligible cytotoxicity in immortalized, nontumorigenic fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface epithelial cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in subcutaneous and intraperitoneal xenograft models. These antitumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 863","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolically inducing defects in DNA repair sensitizes BRCA–wild-type cancer cells to replication stress 代谢诱导 DNA 修复缺陷会使 BRCA 野生型癌细胞对复制压力敏感。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-12 DOI: 10.1126/scisignal.adl6445

Kenji Watanabe, Tatsuro Yamamoto, Tomoko Fujita, Shinjiro Hino, Yuko Hino, Kanami Yamazaki, Yoshimi Ohashi, Shun Sakuraba, Hidetoshi Kono, Mitsuyoshi Nakao, Koji Ochiai, Shingo Dan, Noriko Saitoh

{"title":"Metabolically inducing defects in DNA repair sensitizes BRCA–wild-type cancer cells to replication stress","authors":"Kenji Watanabe, Tatsuro Yamamoto, Tomoko Fujita, Shinjiro Hino, Yuko Hino, Kanami Yamazaki, Yoshimi Ohashi, Shun Sakuraba, Hidetoshi Kono, Mitsuyoshi Nakao, Koji Ochiai, Shingo Dan, Noriko Saitoh","doi":"10.1126/scisignal.adl6445","DOIUrl":"10.1126/scisignal.adl6445","url":null,"abstract":"<div >Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration—using glyceollin I, metformin, or phenformin—induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)–associated DNA repair genes. These serial events created so-called “BRCAness,” in which cells exhibit an HR deficiency phenotype despite lacking germline mutations in HR genes such as <i>BRCA1</i> and <i>BRCA2</i>, and, thus, sensitized the cancer cells to clinically available poly(ADP-ribose) polymerase inhibitors. The increase in lactate repressed HR-associated gene expression by decreasing histone acetylation. These effects were selective to breast cancer cells; normal epithelial cells retained HR proficiency and cell viability. These mechanistic insights into the BRCAness-prone properties of breast cancer cells support the therapeutic utility and cancer cell–specific potential of mitochondria-targeting drugs.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 862","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cholesterol sensing goes vegetarian 胆固醇传感变成了 "素食"。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-12 DOI: 10.1126/scisignal.adu4398

John F. Foley

引用次数: 0

Extracellular proximal interaction profiling by cell surface–targeted TurboID reveals LDLR as a partner of liganded EGFR 通过细胞表面靶向 TurboID 进行细胞外近端相互作用分析，发现 LDLR 是配体表皮生长因子受体的伙伴。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-05 DOI: 10.1126/scisignal.adl6164

Rasha Al Mismar, Payman Samavarchi-Tehrani, Brendon Seale, Vesal Kasmaeifar, Claire E. Martin, Anne-Claude Gingras

{"title":"Extracellular proximal interaction profiling by cell surface–targeted TurboID reveals LDLR as a partner of liganded EGFR","authors":"Rasha Al Mismar, Payman Samavarchi-Tehrani, Brendon Seale, Vesal Kasmaeifar, Claire E. Martin, Anne-Claude Gingras","doi":"10.1126/scisignal.adl6164","DOIUrl":"10.1126/scisignal.adl6164","url":null,"abstract":"<div >Plasma membrane proteins play pivotal roles in receiving and transducing signals from other cells and from the environment and are vital for cellular functionality. Enzyme-based, proximity-dependent approaches, such as biotin identification (BioID), combined with mass spectrometry have begun to illuminate the landscape of proximal protein interactions within intracellular compartments. To extend the potential of these approaches to study the extracellular environment, we developed extracellular TurboID (ecTurboID), a method designed to profile the interactions between proteins on the surfaces of living cells over short timescales using the fast-acting biotin ligase TurboID. After optimizing our experimental and data analysis strategies to capture extracellular proximity interactions, we used ecTurboID to reveal the proximal interactomes of several plasma membrane proteins, including the epidermal growth factor receptor (EGFR). We found that EGF stimulation induced an association between EGFR and the low-density lipoprotein receptor (LDLR) and changed the interactome of LDLR by increasing its proximity with proteins that regulate EGFR signaling. The identification of this interaction between two well-studied and clinically relevant receptors illustrates the utility of our modified proximity labeling methodology for identifying dynamic extracellular associations between plasma membrane proteins.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 861","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The cancer risk of repeat RNAs 重复 RNA 的致癌风险

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-11-05 DOI: 10.1126/scisignal.adu2651

Wei Wong

引用次数: 0

The de novo purine synthesis enzyme Adssl1 promotes cardiomyocyte proliferation and cardiac regeneration 新嘌呤合成酶 Adssl1 促进心肌细胞增殖和心脏再生

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-10-29 DOI: 10.1126/scisignal.adn3285

Zhigang Li, Xiaxi Dong, Lingfang Zhuang, Kangni Jia, Haomai Cheng, Hang Sun, Yuke Cui, Wenqi Ma, Keying Wei, Pupu Zhang, Hongyang Xie, Lei Yi, Zhiyong Chen, Lin Lu, Tao Li, Ruiyan Zhang, Xiaoxiang Yan

{"title":"The de novo purine synthesis enzyme Adssl1 promotes cardiomyocyte proliferation and cardiac regeneration","authors":"Zhigang Li, Xiaxi Dong, Lingfang Zhuang, Kangni Jia, Haomai Cheng, Hang Sun, Yuke Cui, Wenqi Ma, Keying Wei, Pupu Zhang, Hongyang Xie, Lei Yi, Zhiyong Chen, Lin Lu, Tao Li, Ruiyan Zhang, Xiaoxiang Yan","doi":"10.1126/scisignal.adn3285","DOIUrl":"10.1126/scisignal.adn3285","url":null,"abstract":"<div >There is a short window during which the neonatal heart has the proliferative capacity to completely repair damage, an ability that is lost in adulthood. Inducing proliferation in adult cardiomyocytes by reactivating cell cycle reentry after myocardial infarction (MI) improves cardiac function. De novo purine synthesis is a critical source of nucleotides for cell proliferation. Here, using loss- and gain-of-function genetic approaches, we explored the role of the muscle-specific de novo purine synthesis enzyme Adssl1 in cardiac regeneration. Deletion of Adssl1 in mouse neonatal hearts reduced cardiomyocyte proliferation and attenuated heart regeneration after apical resection. Conversely, cardiomyocyte-specific Adssl1 overexpression extended the postnatal regenerative window and induced robust cell cycle reentry after MI, which decreased fibrotic scar size and improved cardiac function. RNA sequencing analysis suggested that Adssl1 overexpression induced strong dedifferentiation and cell cycle entry. Moreover, LC-MS/MS analysis showed that Adssl1 overexpression was associated with increased amounts of purine metabolites, including inosine, which is in clinical use. Administration of exogenous inosine promoted cardiac repair after MI in adult mice. At a molecular level, the increase in purine metabolite production mediated by Adssl1 enhanced the activity of the proliferation-promoting mTORC1 pathway. Our study identifies a role for Adssl1 in supporting cardiomyocyte proliferation and cardiac regeneration.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0