Science Signaling最新文献_第6页

Healing limited 治疗有限。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-03 DOI: 10.1126/scisignal.adu8280

Amy E. Baek

引用次数: 0

Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson’s disease 孤儿受体GPR6与帕金森病相关的高基础活性和逆激动作用的结构见解。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-03 DOI: 10.1126/scisignal.ado8741

Mahta Barekatain, Linda C. Johansson, Jordy H. Lam, Hao Chang, Anastasiia V. Sadybekov, Gye Won Han, Joseph Russo, Joshua Bliesath, Nicola L. Brice, Mark B. L. Carlton, Kumar S. Saikatendu, Hukai Sun, Sean T. Murphy, Holger Monenschein, Hans H. Schiffer, Petr Popov, Corinne A. Lutomski, Carol V. Robinson, Zhi-Jie Liu, Tian Hua, Vsevolod Katritch, Vadim Cherezov

{"title":"Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson’s disease","authors":"Mahta Barekatain, Linda C. Johansson, Jordy H. Lam, Hao Chang, Anastasiia V. Sadybekov, Gye Won Han, Joseph Russo, Joshua Bliesath, Nicola L. Brice, Mark B. L. Carlton, Kumar S. Saikatendu, Hukai Sun, Sean T. Murphy, Holger Monenschein, Hans H. Schiffer, Petr Popov, Corinne A. Lutomski, Carol V. Robinson, Zhi-Jie Liu, Tian Hua, Vsevolod Katritch, Vadim Cherezov","doi":"10.1126/scisignal.ado8741","DOIUrl":"10.1126/scisignal.ado8741","url":null,"abstract":"<div >GPR6 is an orphan G protein–coupled receptor with high constitutive activity found in D2-type dopamine receptor–expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson’s disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson’s disease in clinical trials. In addition, we obtained a cryo–electron microscopy structure of the signaling complex between GPR6 and its cognate G<sub>s</sub> heterotrimer. The pseudo-apo structure revealed a strong density in the orthosteric pocket of GPR6 corresponding to a lipid-like endogenous ligand. A combination of site-directed mutagenesis, native mass spectrometry, and computer modeling suggested potential mechanisms for high constitutive activity and inverse agonism in GPR6 and identified a series of lipids and ions bound to the receptor. The structures and results obtained in this study could guide the rational design of drugs that modulate GPR6 signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 865","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142773969","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

ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress 在慢性应激反应中，chrebp介导的Them1上调与糖酵解和脂肪生成协调产热。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-03 DOI: 10.1126/scisignal.adk7971

Xu Xu, Arturo Mendoza, Christopher S. Krumm, Shi Su, Mariana Acuña, Curtis J. Bare, Corey D. Holman, Marissa Cortopassi, Hayley T. Nicholls, Vincent Dartigue, Anthony N. Hollenberg, Ann-Hwee Lee, Susan J. Hagen, David E. Cohen

{"title":"ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress","authors":"Xu Xu, Arturo Mendoza, Christopher S. Krumm, Shi Su, Mariana Acuña, Curtis J. Bare, Corey D. Holman, Marissa Cortopassi, Hayley T. Nicholls, Vincent Dartigue, Anthony N. Hollenberg, Ann-Hwee Lee, Susan J. Hagen, David E. Cohen","doi":"10.1126/scisignal.adk7971","DOIUrl":"10.1126/scisignal.adk7971","url":null,"abstract":"<div >Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that <i>Them1</i> expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess. Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct cytoplasmic and nuclear activities. Targeted inhibition of Them1 could be a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 865","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142773928","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

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}

引用次数: 0

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