Science Signaling最新文献

{"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":"16 816","pages":"eadh3449"},"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":"16 816","pages":"eadk9171"},"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":"18 1","pages":""},"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":"31 1","pages":""},"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":"10 1","pages":""},"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":"148 1","pages":""},"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":"1 1","pages":""},"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}

{"title":"Abstract PO-082: Delineating the molecular basis of early dissemination of pancreatic cancer","authors":"Taelor Ekstrom, D. Grygoryev, T. Morgan, K. Zaret, Jungsun Kim","doi":"10.1158/1538-7445.panca21-po-082","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-082","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"21 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88850168","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-084: The role of p53 in the development of pancreatic ductal adenocarcinoma","authors":"Kathryn J Hanson, B. Flowers, N. Hughes, H. Vogel, L. Cong, L. Attardi","doi":"10.1158/1538-7445.panca21-po-084","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-084","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87337129","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-090: TGF-β induced EMT gene expression is associated with promoter demethylation in pancreatic cancer","authors":"Manjul Rana, A. Elahi, A. Ajidahun, R. Kansal, A. Berglund, D. Shibata, E. Glazer","doi":"10.1158/1538-7445.panca21-po-090","DOIUrl":"https://doi.org/10.1158/1538-7445.panca21-po-090","url":null,"abstract":"","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85264033","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}