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https://www.readbyqxmd.com/read/29719619/tp-064-a-potent-and-selective-small-molecule-inhibitor-of-prmt4-for-multiple-myeloma
#1
Kazuhide Nakayama, Magdalena M Szewczyk, Carlo Dela Sena, Hong Wu, Aiping Dong, Hong Zeng, Fengling Li, Renato Ferreira de Freitas, Mohammad S Eram, Matthieu Schapira, Yuji Baba, Mihoko Kunitomo, Douglas R Cary, Michiko Tawada, Akihiro Ohashi, Yasuhiro Imaeda, Kumar Singh Saikatendu, Charles E Grimshaw, Masoud Vedadi, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Atsushi Kiba, Daisuke Tomita, Peter J Brown
Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29681515/the-dystrophin-glycoprotein-complex-regulates-the-epigenetic-activation-of-muscle-stem-cell-commitment
#2
Natasha C Chang, Marie-Claude Sincennes, Fabien P Chevalier, Caroline E Brun, Melanie Lacaria, Jessica Segalés, Pura Muñoz-Cánoves, Hong Ming, Michael A Rudnicki
Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation...
April 19, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29659998/the-arginine-methyltransferase-carm1-represses-p300%C3%A2-act%C3%A2-crem%C3%AF-activity-and-is-required-for-spermiogenesis
#3
Jianqiang Bao, Sophie Rousseaux, Jianjun Shen, Kevin Lin, Yue Lu, Mark T Bedford
CARM1 is a protein arginine methyltransferase (PRMT) that has been firmly implicated in transcriptional regulation. However, the molecular mechanisms by which CARM1 orchestrates transcriptional regulation are not fully understood, especially in a tissue-specific context. We found that Carm1 is highly expressed in the mouse testis and localizes to the nucleus in spermatids, suggesting an important role for Carm1 in spermiogenesis. Using a germline-specific conditional Carm1 knockout mouse model, we found that it is essential for the late stages of haploid germ cell development...
April 5, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29628326/identification-of-a-novel-selective-small-molecule-inhibitor-of-protein-arginine-methyltransferase-5-prmt5-by-virtual-screening-resynthesis-and-biological-evaluations
#4
Kongkai Zhu, Chengshi Jiang, Hongrui Tao, Jingqiu Liu, Hua Zhang, Cheng Luo
As one of the most promising anticancer target in protein arginine methyltransferase (PRMT) family, PRMT5 has been drawing more and more attentions, and many efforts have been devoted to develop its inhibitors. In this study, three PRMT5 inhibitors (9, 16, and 23) with novel scaffolds were identified by performing pharmacophore- and docking-based virtual screening combined with in vitro radiometric-based scintillation proximity assay (SPA). Substructure search based on the scaffold of the most active 9 afforded 26 additional analogues, and SPA results indicated that two analogues (9-1 and 9-2) showed increased PRMT5 inhibitory activity compared with the parental compound...
March 30, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29628309/jmjd6-licenses-er%C3%AE-dependent-enhancer-and-coding-gene-activation-by-modulating-the-recruitment-of-the-carm1-med12-co-activator-complex
#5
Wei-Wei Gao, Rong-Quan Xiao, Wen-Juan Zhang, Yi-Ren Hu, Bing-Ling Peng, Wen-Juan Li, Yao-Hui He, Hai-Feng Shen, Jian-Cheng Ding, Qi-Xuan Huang, Tian-Yi Ye, Ying Li, Zhi-Ying Liu, Rong Ding, Michael G Rosenfeld, Wen Liu
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment...
April 4, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29575726/p53-mediated-regulation-of-coactivator-associated-arginine-methyltransferase-1-carm1-expression-is-critical-for-suppression-of-adipogenesis
#6
Amit K Behera, Aditya Bhattacharya, Madavan Vasudevan, Tapas K Kundu
Coactivator associated arginine methyltransferase 1 (CARM1/PRMT4) is a type I arginine methyltransferase that mediates transcriptional activation via methylation of histone H3 on R17, R26 and R42. CARM1 is also a coactivator of transcription of various transcription factors such as NF-kB, MEF2C, β-catenin, p53, PPAR-gamma etc. CARM1 has been functionally implicated in maintenance of pluripotency, cellular differentiation and tumorigenesis; where its expression status plays an important role. Although its expression has been shown to be regulated by a few miRNAs in different contexts at post-transcriptional level, transcriptional regulation of CARM1 gene is still unexplored...
March 25, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29434212/carm1-expressing-ovarian-cancer-depends-on-the-histone-methyltransferase-ezh2-activity
#7
Sergey Karakashev, Hengrui Zhu, Shuai Wu, Yuhki Yokoyama, Benjamin G Bitler, Pyoung-Hwa Park, Jeong-Heon Lee, Andrew V Kossenkov, Krutika Satish Gaonkar, Huihuang Yan, Ronny Drapkin, Jose R Conejo-Garcia, David W Speicher, Tamas Ordog, Rugang Zhang
CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in human cancers. However, clinically applicable cancer therapeutic strategies based on CARM1 expression remain to be explored. Here, we report that EZH2 inhibition is effective in CARM1-expressing epithelial ovarian cancer. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppresses the growth of CARM1-expressing, but not CARM1-deficient, ovarian tumors in two xenograft models and improves the survival of mice bearing CARM1-expressing ovarian tumors...
February 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29282318/src1-promotes-th17-differentiation-by-overriding-foxp3-suppression-to-stimulate-ror%C3%AE-t-activity-in-a-pkc-%C3%AE-dependent-manner
#8
Subha Sen, Fei Wang, Jing Zhang, Zhiheng He, Jian Ma, Yousang Gwack, Jianming Xu, Zuoming Sun
Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORγt) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORγt in vivo to promote the functional dominance of RORγt over Foxp3 and thus establishing an unopposed Th17 differentiation program...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29184174/erratum-pkm2-methylation-by-carm1-activates-aerobic-glycolysis-to-promote-tumorigenesis
#9
Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu
This corrects the article DOI: 10.1038/ncb3630.
November 29, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29183786/characterization-of-protein-methyltransferases-rkm1-rkm4-efm4-efm7-set5-and-hmt1-reveals-extensive-post-translational-modification
#10
Daniel L Winter, Gene Hart-Smith, Marc R Wilkins
Protein methylation is one of the major post-translational modifications (PTMs) in the cell. In Saccharomyces cerevisiae, over 20 protein methyltransferases (MTases) and their respective substrates have been identified. However, the way in which these MTases are modified and potentially subject to regulation remains poorly understood. Here, we investigated six overexpressed S. cerevisiae protein MTases (Rkm1, Rkm4, Efm4, Efm7, Set5 and Hmt1) to identify PTMs of potential functional relevance. We identified 48 PTM sites across the six MTases, including phosphorylation, acetylation and methylation...
January 5, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29112628/exercise-induced-protein-arginine-methyltransferase-expression-in-skeletal-muscle
#11
Tiffany L Vanlieshout, Derek W Stouth, Tania Tajik, Vladimir Ljubicic
PURPOSE: This study aimed to determine protein arginine methyltransferase 1 (PRMT1), -4 (also known as coactivator-associated arginine methyltransferase 1 [CARM1]), and -5 expression and function during acute, exercise-induced skeletal muscle remodeling in vivo. METHODS: C57BL/6 mice were assigned to one of three experimental groups: sedentary, acute bout of exercise, or acute exercise followed by 3 h of recovery. Mice in the exercise groups performed a single bout of treadmill running at 15 m·min for 90 min...
March 2018: Medicine and Science in Sports and Exercise
https://www.readbyqxmd.com/read/29058718/pkm2-methylation-by-carm1-activates-aerobic-glycolysis-to-promote-tumorigenesis
#12
Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu
Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked...
November 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28924379/the-overexpression-of-carm1-promotes-human-osteosarcoma-cell-proliferation-through-the-pgsk3%C3%AE-%C3%AE-catenin-cyclind1-signaling-pathway
#13
Shijie Li, Dongdong Cheng, Bin Zhu, Qingcheng Yang
Osteosarcoma (OS) is a kind of malignant bone tumor that occurs frequently in the region surrounding the knee joint and poses a threat to the health of teenagers. Since the application of chemotherapy to treat OS, 5-year survival rate in patients has improved from 10% to 70%, but patient survival has not changed over the past four decades. Coactivator-associated arginine methyltransferase 1 (CARM1) is a member of the PRMT protein family; it acts as an oncogene in many cancers, but its function in OS is still unknown...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28844863/structural-and-functional-impacts-of-er-coactivator-sequential-recruitment
#14
Ping Yi, Zhao Wang, Qin Feng, Chao-Kai Chou, Grigore D Pintilie, Hong Shen, Charles E Foulds, Guizhen Fan, Irina Serysheva, Steven J Ludtke, Michael F Schmid, Mien-Chie Hung, Wah Chiu, Bert W O'Malley
Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This "ordered" recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits steroid receptor coactivator-3 (SRC-3) primary coactivator and secondary coactivators, p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-electron microscopy (cryo-EM) structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early- and late-recruited coactivators...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28836411/evidence-of-oocyte-polarity-in-bovine-implications-for-intracytoplasmic-sperm-injection-and-somatic-cell-nuclear-transfer
#15
Seyed Morteza Hosseini, Fariba Moulavi, Nima TanhaieVash, Naser Shams-Esfandabadi, Mohammad Hossein Nasr-Esfahani, Abolfazl Shirazi
OBJECTIVES: We recently demonstrated spatial regionalization of maternal transcripts and proteins within unfertilized ovine oocyte. Here, we investigated the likelihood of oocyte polarity for the first time in bovine. MATERIALS AND METHODS: In this experimental study, in vitro matured bovine oocytes were used for manual bisection [into oocyte halve that were near-to (HNS) and far-from (FS) spindle] or trisection [into MII-spindle (S), the spindle-side half (NS), and the distal half unassociated with the spindle (FS)]...
October 2017: Cell Journal
https://www.readbyqxmd.com/read/28637181/crosstalk-between-histone-modifications-indicates-that-inhibition-of-arginine-methyltransferase-carm1-activity-reverses-hiv-latency
#16
Zheng Zhang, Bryan C Nikolai, Leah A Gates, Sung Yun Jung, Edward B Siwak, Bin He, Andrew P Rice, Bert W O'Malley, Qin Feng
In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28537268/global-mapping-of-carm1-substrates-defines-enzyme-specificity-and-substrate-recognition
#17
Evgenia Shishkova, Hao Zeng, Fabao Liu, Nicholas W Kwiecien, Alexander S Hebert, Joshua J Coon, Wei Xu
Protein arginine methyltransferases (PRMTs) introduce arginine methylation, a post-translational modification with the increasingly eminent role in normal physiology and disease. PRMT4 or coactivator-associated arginine methyltransferase 1 (CARM1) is a propitious target for cancer therapy; however, few CARM1 substrates are known, and its mechanism of substrate recognition is poorly understood. Here we employed a quantitative mass spectrometry approach to globally profile CARM1 substrates in breast cancer cell lines...
May 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/28455686/flightless-i-homolog-regulates-glucocorticoid-receptor-mediated-transcription-via-direct-interaction-of-the-leucine-rich-repeat-domain
#18
Hong Lan Jin, Liu Yang, Kwang Won Jeong
Flightless-I homolog (FLII) is a member of the gelsolin family of proteins, and has been identified as a coactivator of estrogen receptor-mediated transcription. Here, we investigate the role of FLII in the glucocorticoid receptor (GR) signaling pathway. Reporter gene assay and real-time quantitative PCR in A549 were performed to investigate the function of FLII in the expression of GR target genes. Co-immunoprecipitation assay and in vitro binding assay were used to identify binding domain of FLII. Chromatin immunoprecipitation assay were carried out with FLII-depleted A549 cells to determine the role of FLII at GR binding sites...
April 2017: Molecular Biology Reports
https://www.readbyqxmd.com/read/28432361/disease-biomarker-identification-from-gene-network-modules-for-metastasized-breast-cancer
#19
Pooja Sharma, Dhruba K Bhattacharyya, Jugal Kalita
Advancement in science has tended to improve treatment of fatal diseases such as cancer. A major concern in the area is the spread of cancerous cells, technically refered to as metastasis into other organs beyond the primary organ. Treatment in such a stage of cancer is extremely difficult and usually palliative only. In this study, we focus on finding gene-gene network modules which are functionally similar in nature in the case of breast cancer. These modules extracted during the disease progression stages are analyzed using p-value and their associated pathways...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28330993/transition-state-mimics-are-valuable-mechanistic-probes-for-structural-studies-with-the-arginine-methyltransferase-carm1
#20
Matthijs J van Haren, Nils Marechal, Nathalie Troffer-Charlier, Agostino Cianciulli, Gianluca Sbardella, Jean Cavarelli, Nathaniel I Martin
Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
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