Science Signaling最新文献

{"title":"TB impairs DNA repair.","authors":"Annalisa M VanHook","doi":"10.1126/scisignal.adn5031","DOIUrl":"10.1126/scisignal.adn5031","url":null,"abstract":"<p><p>A <i>Mycobacterium tuberculosis</i> virulence factor promotes foam cell formation by inhibiting DNA repair.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812483","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}

{"title":"Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses.","authors":"Luca Mazzarella, Fabio Santoro, Roberto Ravasio, Valeria Fumagalli, Paul E Massa, Simona Rodighiero, Elena Gavilán, Mauro Romanenghi, Bruno A Duso, Emanuele Bonetti, Lara Manganaro, Rani Pallavi, Deborah Trastulli, Isabella Pallavicini, Claudia Gentile, Silvia Monzani, Tommaso Leonardi, Sebastiano Pasqualato, Gabriele Buttinelli, Angela Di Martino, Giorgio Fedele, Ilaria Schiavoni, Paola Stefanelli, Giuseppe Meroni, Raffaele de Francesco, Christian Steinkuhler, Gianluca Fossati, Matteo Iannacone, Saverio Minucci, Pier Giuseppe Pelicci","doi":"10.1126/scisignal.ade0326","DOIUrl":"10.1126/scisignal.ade0326","url":null,"abstract":"<p><p>Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB-dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812462","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}

{"title":"RHOA^L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling.","authors":"Antje Schaefer, Richard G Hodge, Haisheng Zhang, G Aaron Hobbs, Julien Dilly, Minh V Huynh, Craig M Goodwin, Feifei Zhang, J Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U Rashid, Emanuel F Petricoin, Adrienne D Cox, William C Hahn, Andrew J Aguirre, Adam J Bass, Channing J Der","doi":"10.1126/scisignal.adg5289","DOIUrl":"10.1126/scisignal.adg5289","url":null,"abstract":"<p><p>Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr⁴²-to-Cys (Y42C) and Leu⁵⁷-to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA^Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA^L57V promotes DGC growth. In mouse gastric organoids with deletion of <i>Cdh1</i>, which encodes the cell adhesion protein E-cadherin, the expression of RHOA^L57V, but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA^L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA^L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr⁴² and Leu⁵⁷ in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA^L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA^Y42C. Our results reveal that RHOA^L57V and RHOA^Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A noncanonical IRAK4-IRAK1 pathway counters DNA damage-induced apoptosis independently of TLR/IL-1R signaling.","authors":"Yuanyuan Li, Richa B Shah, Samanta Sarti, Alicia L Belcher, Brian J Lee, Andrej Gorbatenko, Francesca Nemati, Honglin Yu, Zoe Stanley, Mahbuba Rahman, Zhengping Shao, Jose M Silva, Shan Zha, Samuel Sidi","doi":"10.1126/scisignal.adh3449","DOIUrl":"10.1126/scisignal.adh3449","url":null,"abstract":"<p><p>Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage-induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88. Activated IRAK1 translocated to the nucleus in a Pellino2-dependent manner. In the nucleus, IRAK1 bound to the PIDD1 subunit of the proapoptotic PIDDosome and interfered with platform assembly, thus supporting cell survival. This noncanonical IRAK signaling pathway was also activated in response to other DSB-inducing agents. The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RHOA drivers take alternate routes in gastric cancer.","authors":"Dorothy Benton, Jonathan Chernoff","doi":"10.1126/scisignal.adk9171","DOIUrl":"10.1126/scisignal.adk9171","url":null,"abstract":"<p><p>Oncogenic small guanosine triphosphatases (GTPases) are often characterized by a limited set of activating mutations that affect their intrinsic biochemical function, but RHOA-which is frequently mutated in gastric cancer-appears not to have read the instruction manual. Having previously characterized the Y42C RHOA mutation in gastric cancer, in this issue of <i>Science Signaling</i>, Schaefer <i>et al.</i> take on the slightly less common L57V mutation and find that individual RHOA mutations can have different and unpredictable signaling outcomes.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812481","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}

{"title":"Abstract PR-009: Targeting the sterol regulatory element-binding protein pathway in pancreatic ductal adenocarcinoma","authors":"S. Myers, Meredith R. McGuire, W. Shao, Chin-Shei Liu, Theodore E. Ewachiw, Z. Rasheed, W. Matsui, Toni Sepalla, R. Burkhart, P. Espenshade","doi":"10.1158/1538-7445.panca21-pr-009","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-pr-009","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88822724","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}

{"title":"Abstract PO-094: Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition","authors":"M. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao N. D. Pham, H. Munshi","doi":"10.1158/1538-7445.panca21-po-094","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-094","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81191725","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}

{"title":"Abstract PO-091: Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors","authors":"C. Salmerón, K. Sriram, M. Javadi‐Paydar, P. Insel","doi":"10.1158/1538-7445.panca21-po-091","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-091","url":null,"abstract":"A recent study reported that patients taking HRH1 antihistamines have decreased progression of various tumors, including PDAC; the authors inferred that this was an immune effect (Fritz et al., PMID: 33550204). We have initiated studies to test an alternative hypothesis: HRH1 expressed by PDAC cells may contribute to the malignant phenotype and if so, FDA-approved HRH1 antihistamines might be therapeutics to treat or perhaps prevent PDAC. We have undertaken bioinformatic and experimental approaches to test this hypothesis. Our bioinformatic analysis revealed that PDAC tumors in The Cancer Genome Atlas (TCGA) have >30-fold higher HRH1 expression than in normal pancreas (GTEx database) and is highly expressed in PDAC cell lines in the Cancer Cell Line Encyclopedia (CCLE). HRH1 expression was selectively associated with markers of PDAC cells and not with markers of other cell types in the tumor microenvironment. Higher expression of HRH1 in TCGA-PDAC tumors negatively impacts on patient survival. Our experimental studies indicate that human and mouse PDAC cells express HRH1 mRNA, protein and signaling and that HRH1 is present on the surface of PDAC cells. We found that histamine prominently increases calcium [Ca2+] in multiple human PDAC cell lines with EC50 values comparable to that in other cell types. The histamine-stimulated increase in [Ca2+] occurs via a Gq/11 (heterotrimeric GTP binding protein)-dependent mechanism and is blocked by multiple FDA-approved HRH1 antihistamines (with pKi values similar to those of HRH1 inhibition of other cell types). HRH1 activation by histamine increases PDAC cell migration. Histamine also increases the production of numerous cytokines (including VEGF) from PDAC cells, and in preliminary studies, stimulates growth of multiple PDAC cell lines at low concentrations (1-10 nM). Together with published data indicating that mast cells (which synthesize and release histamine) in PDAC tumors are associated with PDAC cell growth/invasion, angiogenesis and worse prognosis, our findings suggest that independent of immune cells, a \"mast cell-histamine-PDAC cell HRH1 axis\" may contribute to the malignant phenotype of PDAC tumors. Importantly, HRH1 on PDAC cells could be targeted by repurposing approved HRH1 antihistamines as a novel therapeutic approach for PDAC tumors. Supported by grants from the University of California Cancer Research Coordinating Committee and Tobacco-Related Disease Research Program. Citation Format: Cristina Salmeron, Krishna Sriram, Mehrak Javadi-Paydar, Paul A. Insel. Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-091.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77781268","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}

{"title":"Abstract PO-092: Influence of the IL-13-receptor alpha 1 chain on the malignant phenotype of pancreatic cancer cells","authors":"Jingwei Shi, M. Kornmann, B. Traub","doi":"10.1158/1538-7445.panca21-po-092","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-092","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81718317","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}

{"title":"Abstract PO-081: Studying MYC's contribution to replication stress at the nuclear pore","authors":"G. Cohn, Colin J. Daniel, Daniel F. Liefwalker, R. Sears","doi":"10.1158/1538-7445.panca21-po-081","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-081","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88132474","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}