Mahsa Zarei, Heng Du, Amin H Nassar, Rachel E Yan, Krinio Giannikou, Sneha H Johnson, Hilaire C Lam, Elizabeth P Henske, Yubao Wang, Tinghu Zhang, John Asara, David J Kwiatkowski
{"title":"Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion.","authors":"Mahsa Zarei, Heng Du, Amin H Nassar, Rachel E Yan, Krinio Giannikou, Sneha H Johnson, Hilaire C Lam, Elizabeth P Henske, Yubao Wang, Tinghu Zhang, John Asara, David J Kwiatkowski","doi":"10.1084/jem.20190251","DOIUrl":"10.1084/jem.20190251","url":null,"abstract":"<p><p>Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both <i>Tsc2<sup>+/</sup></i> <sup>-</sup> mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either <i>TSC1</i> or <i>TSC2</i>.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"216 1","pages":"2635-2652"},"PeriodicalIF":0.0,"publicationDate":"2019-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75371534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alvin Pratama, Alexandra Schnell, D. Mathis, C. Benoist
{"title":"Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells","authors":"Alvin Pratama, Alexandra Schnell, D. Mathis, C. Benoist","doi":"10.1084/jem.20190428","DOIUrl":"https://doi.org/10.1084/jem.20190428","url":null,"abstract":"Using a polyclonal Treg cell replacement system, Pratama et al. show that naive Tconv cells have the capacity to convert into both RORγ+ and Helios+ Treg cells in the colon. The developmental maturity (or cell states) of the starting Tconv cells determines the phenotype of the resulting pTreg cells.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79360490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dehong Yan, Jing-Horng Wang, Honghong Sun, Aliyeh Zamani, Hongling Zhang, Weihong Chen, A. Tang, Qingguo Ruan, Xiaolu Yang, Youhai H. Chen, X. Wan
{"title":"TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis","authors":"Dehong Yan, Jing-Horng Wang, Honghong Sun, Aliyeh Zamani, Hongling Zhang, Weihong Chen, A. Tang, Qingguo Ruan, Xiaolu Yang, Youhai H. Chen, X. Wan","doi":"10.1084/jem.20182005","DOIUrl":"https://doi.org/10.1084/jem.20182005","url":null,"abstract":"In this study, Yan et al. demonstrate that TIPE2, which is induced by tumor-derived ROS, promotes the functional polarization of protumoral myeloid-derived suppressor cells (MDSCs) during tumorigenesis by specifying the expression of MDSC signature genes such as Cebpb.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77515241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beibei Zhang, Hui Ma, Teka Khan, Ao Ma, Tao Li, Huan Zhang, Jianing Gao, Jianteng Zhou, Yang Li, Changping Yu, Jianqiang Bao, Asim Ali, G. Murtaza, Hao Yin, Qian Gao, Xiaohua Jiang, Feng Zhang, Chunyu Liu, Ihsan Khan, Muhammad Zubair, H. M. Hussain, R. Khan, A. Yousaf, Limin Yuan, Yan Lu, Xiaoling Xu, Yun Wang, Qizhao Tao, QiaoMei Hao, Hui Fang, Hongtao Cheng, Yuanwei Zhang, Qinghua Shi
{"title":"A DNAH17 missense variant causes flagella destabilization and asthenozoospermia","authors":"Beibei Zhang, Hui Ma, Teka Khan, Ao Ma, Tao Li, Huan Zhang, Jianing Gao, Jianteng Zhou, Yang Li, Changping Yu, Jianqiang Bao, Asim Ali, G. Murtaza, Hao Yin, Qian Gao, Xiaohua Jiang, Feng Zhang, Chunyu Liu, Ihsan Khan, Muhammad Zubair, H. M. Hussain, R. Khan, A. Yousaf, Limin Yuan, Yan Lu, Xiaoling Xu, Yun Wang, Qizhao Tao, QiaoMei Hao, Hui Fang, Hongtao Cheng, Yuanwei Zhang, Qinghua Shi","doi":"10.1084/jem.20182365","DOIUrl":"https://doi.org/10.1084/jem.20182365","url":null,"abstract":"Using mice modelling patients’ variant, this study demonstrates that a homozygous DNAH17 missense variant causes asthenozoospermia and specifically destabilizes microtubule doublets 4–7 in flagella, which could be largely due to the storage of sperm in epididymis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"279 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80109251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meng Deng, Haitao Guo, Jason W. Tam, Brandon M. Johnson, W. Brickey, James S. New, Austin R. Lenox, Hexin Shi, D. Golenbock, Beverly H. Koller, Karen P McKinnon, B. Beutler, Jenny P.-Y. Ting
{"title":"Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR","authors":"Meng Deng, Haitao Guo, Jason W. Tam, Brandon M. Johnson, W. Brickey, James S. New, Austin R. Lenox, Hexin Shi, D. Golenbock, Beverly H. Koller, Karen P McKinnon, B. Beutler, Jenny P.-Y. Ting","doi":"10.1084/jem.20190111","DOIUrl":"https://doi.org/10.1084/jem.20190111","url":null,"abstract":"Platelet-activating factor (PAF) can drive pathophysiological inflammation, but the mechanism remains incompletely understood. Here, Deng et al. report that PAF activates the canonical NLRP3 inflammasome independently of its receptor PAFR.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"5 1","pages":"2838 - 2853"},"PeriodicalIF":0.0,"publicationDate":"2019-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72635852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Yukawa, S. Jagannathan, Sushmitha Vallabh, A. Kartashov, Xiaoting Chen, M. Weirauch, A. Barski
{"title":"AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation","authors":"M. Yukawa, S. Jagannathan, Sushmitha Vallabh, A. Kartashov, Xiaoting Chen, M. Weirauch, A. Barski","doi":"10.1084/jem.20182009","DOIUrl":"https://doi.org/10.1084/jem.20182009","url":null,"abstract":"AP-1 transcription factor is recruited to the majority of chromatin remodeling sites during T cell activation. The activity of AP-1 is induced by co-stimulation and is required for chromatin opening. The sites of remodeling overlap with risk loci of immunological diseases.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90262831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Hosokawa, Maile Romero-Wolf, Qi Yang, Y. Motomura, D. Levanon, Y. Groner, K. Moro, Tomoaki Tanaka, E. Rothenberg
{"title":"Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells","authors":"H. Hosokawa, Maile Romero-Wolf, Qi Yang, Y. Motomura, D. Levanon, Y. Groner, K. Moro, Tomoaki Tanaka, E. Rothenberg","doi":"10.1084/jem.20190972","DOIUrl":"https://doi.org/10.1084/jem.20190972","url":null,"abstract":"Bcl11b binds to distinctive genomic regions with different partners and regulates completely different target genes in pro-T and ILC2 cells. Despite these divergences in Bcl11b function, a shared enhancer supports initial Bcl11b locus opening in both pro-T and ILC2 lineages.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82354579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mytrang H Do, Xinxin Wang, Xian Zhang, Chun Chou, Briana G. Nixon, Kristelle J. Capistrano, Min Peng, A. Efeyan, D. Sabatini, Ming O. Li
{"title":"Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance","authors":"Mytrang H Do, Xinxin Wang, Xian Zhang, Chun Chou, Briana G. Nixon, Kristelle J. Capistrano, Min Peng, A. Efeyan, D. Sabatini, Ming O. Li","doi":"10.1084/jem.20190848","DOIUrl":"https://doi.org/10.1084/jem.20190848","url":null,"abstract":"Rag GTPase–dependent nutrient mTORC1 signaling plays a critical role in control of T reg cell suppression of autoimmunity and tumor immunity. These findings establish nutrients as a novel class of signaling molecule.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"107 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77414617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xuehui Long, Le Zhang, Yang Zhang, Min Min, Bichun Lin, Jingjing Chen, Xiaojie Ma, Sulan Zhai, Zhenming Cai, Yingxia Liu, Yanlai Lu, N. Che, W. Tan, J. Qin, Xiaoming Wang
{"title":"Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation","authors":"Xuehui Long, Le Zhang, Yang Zhang, Min Min, Bichun Lin, Jingjing Chen, Xiaojie Ma, Sulan Zhai, Zhenming Cai, Yingxia Liu, Yanlai Lu, N. Che, W. Tan, J. Qin, Xiaoming Wang","doi":"10.1084/jem.20190832","DOIUrl":"https://doi.org/10.1084/jem.20190832","url":null,"abstract":"Regulation of Bcl6 expression during follicular helper T cell differentiation remains incompletely understood. Here, Long et al. show that T cell activation induces H3K36me2 methyltransferase Nsd2, in a CD28- and ICOS-dependent manner, to promote Bcl6 expression and Tfh differentiation.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86711120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GM-CSF in inflammation","authors":"J. Hamilton","doi":"10.1084/jem.20190945","DOIUrl":"https://doi.org/10.1084/jem.20190945","url":null,"abstract":"GM-CSF is a potential therapeutic target in inflammation and autoimmunity. This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78590807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}