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H Ü Kaniskan, M S Eram, J Liu, D Smil, M L Martini, Y Shen, V Santhakumar, P J Brown, C Arrowsmith, M Vedadi, J Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα...
September 1, 2016: MedChemComm
Fei Ye, Weiyao Zhang, Wenchao Lu, Yiqian Xie, Hao Jiang, Jia Jin, Cheng Luo
Overexpression of coactivator associated arginine methyltransferase 1 (CARM1), a protein arginine N-methyltransferase (PRMT) family enzyme, is associated with various diseases including cancers. Consequently, the development of small-molecule inhibitors targeting PRMTs has significant value for both research and therapeutic purposes. In this study, together with structure-based virtual screening with biochemical assays, two compounds DC_C11 and DC_C66 were identified as novel inhibitors of CARM1. Cellular studies revealed that the two inhibitors are cell membrane permeable and effectively blocked proliferation of cancer cells including HELA, K562, and MCF7...
2016: BioMed Research International
J F Hiken, J I McDonald, K F Decker, C Sanchez, J Hoog, N D VanderKraats, K L Jung, M Akinhanmi, L E Rois, M J Ellis, J R Edwards
Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood...
November 21, 2016: Oncogene
Ziheng Xu, Daniel J Klionsky
No abstract text is available yet for this article.
October 2016: Annals of Translational Medicine
Michal Franek, Alena Kovaříková, Eva Bártová, Stanislav Kozubek
DNA damage response (DDR) in ribosomal genes and mechanisms of DNA repair in embryonic stem cells (ESCs) are less explored nuclear events. DDR in ESCs should be unique due to their high proliferation rate, expression of pluripotency factors, and specific chromatin signature. Given short population doubling time and fast progress through G1 phase, ESCs require a sustained production of rRNA, which leads to the formation of large and prominent nucleoli. Although transcription of rRNA in the nucleolus is relatively well understood, little is known about DDR in this nuclear compartment...
November 2016: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Sara C Larsen, Kathrine B Sylvestersen, Andreas Mund, David Lyon, Meeli Mullari, Maria V Madsen, Jeremy A Daniel, Lars J Jensen, Michael L Nielsen
The posttranslational modification of proteins by arginine methylation is functionally important, yet the breadth of this modification is not well characterized. Using high-resolution mass spectrometry, we identified 8030 arginine methylation sites within 3300 human proteins in human embryonic kidney 293 cells, indicating that the occurrence of this modification is comparable to phosphorylation and ubiquitylation. A site-level conservation analysis revealed that arginine methylation sites are less evolutionarily conserved compared to arginines that were not identified as modified by methylation...
2016: Science Signaling
Fabio Marino, Geert P M Mommen, Anita Jeko, Hugo D Meiring, Jacqueline A M van Gaans-van den Brink, Richard A Scheltema, Cécile A C M van Els, Albert J R Heck
Alterations in protein post-translational modification (PTM) are recognized hallmarks of diseases. These modifications potentially provide a unique source of disease-related human leukocyte antigen (HLA) class I-presented peptides that can elicit specific immune responses. While phosphorylated HLA peptides have already received attention, arginine methylated HLA class I peptide presentation has not been characterized in detail. In a human B-cell line we detected 149 HLA class I peptides harboring mono- and/or dimethylated arginine residues by mass spectrometry...
January 6, 2017: Journal of Proteome Research
Hi-Jai R Shin, Hyunkyung Kim, Keun Il Kim, Sung Hee Baek
Macroautophagy (hereafter referred to as autophagy) is an essential self-digestion process to maintain homeostasis and promote survival in response to starvation. Although the components of autophagy in the cytoplasm have been well studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. Recently, we identified the histone arginine methyltransferase CARM1 as a new component and followed histone H3R17 dimethylation as a critical epigenetic mark in starvation-induced autophagy...
November 2016: Autophagy
Renato Ferreira de Freitas, Mohammad S Eram, David Smil, Magdalena M Szewczyk, Steven Kennedy, Peter J Brown, Vijayaratnam Santhakumar, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Masoud Vedadi, Matthieu Schapira
No abstract text is available yet for this article.
August 25, 2016: Journal of Medicinal Chemistry
Lu Wang, Zibo Zhao, Mark B Meyer, Sandeep Saha, Menggang Yu, Ailan Guo, Kari B Wisinski, Wei Huang, Weibo Cai, J Wesley Pike, Ming Yuan, Paul Ahlquist, Wei Xu
No abstract text is available yet for this article.
July 11, 2016: Cancer Cell
Renato Ferreira de Freitas, Mohammad S Eram, David Smil, Magdalena M Szewczyk, Steven Kennedy, Peter J Brown, Vijayaratnam Santhakumar, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Masoud Vedadi, Matthieu Schapira
Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods...
July 28, 2016: Journal of Medicinal Chemistry
Sitaram Gayatri, Martis W Cowles, Vidyasiri Vemulapalli, Donghang Cheng, Zu-Wen Sun, Mark T Bedford
Signal transduction in response to stimuli relies on the generation of cascades of posttranslational modifications that promote protein-protein interactions and facilitate the assembly of distinct signaling complexes. Arginine methylation is one such modification, which is catalyzed by a family of nine protein arginine methyltransferases, or PRMTs. Elucidating the substrate specificity of each PRMT will promote a better understanding of which signaling networks these enzymes contribute to. Although many PRMT substrates have been identified, and their methylation sites mapped, the optimal target motif for each of the nine PRMTs has not been systematically addressed...
2016: Scientific Reports
Marcela A Bennesch, Gregory Segala, Diana Wider, Didier Picard
The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of the transcriptional coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors and identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen...
October 14, 2016: Nucleic Acids Research
Hi-Jai R Shin, Hyunkyung Kim, Sungryong Oh, Jun-Gi Lee, Minjung Kee, Hyun-Jeong Ko, Mi-Na Kweon, Kyoung-Jae Won, Sung Hee Baek
Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well studied, the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions...
23, 2016: Nature
Ping Yu, Lexiang Ji, Kevin J Lee, Miao Yu, Chuan He, Suresh Ambati, Elizabeth C McKinney, Crystal Jackson, Clifton A Baile, Robert J Schmitz, Richard B Meagher
The reprogramming of cellular memory in specific cell types, and in visceral adipocytes in particular, appears to be a fundamental aspect of obesity and its related negative health outcomes. We explored the hypothesis that adipose tissue contains epigenetically distinct subpopulations of adipocytes that are differentially potentiated to record cellular memories of their environment. Adipocytes are large, fragile, and technically difficult to efficiently isolate and fractionate. We developed fluorescence nuclear cytometry (FNC) and fluorescence activated nuclear sorting (FANS) of cellular nuclei from visceral adipose tissue (VAT) using the levels of the pan-adipocyte protein, peroxisome proliferator-activated receptor gamma-2 (PPARg2), to distinguish classes of PPARg2-Positive (PPARg2-Pos) adipocyte nuclei from PPARg2-Negative (PPARg2-Neg) leukocyte and endothelial cell nuclei...
2016: PloS One
Ji Hye Kim, Byong Chul Yoo, Woo Seok Yang, Eunji Kim, Sungyoul Hong, Jae Youl Cho
Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I-IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required...
2016: Mediators of Inflammation
Mubeen Goolam, Antonio Scialdone, Sarah J L Graham, Iain C Macaulay, Agnieszka Jedrusik, Anna Hupalowska, Thierry Voet, John C Marioni, Magdalena Zernicka-Goetz
The major and essential objective of pre-implantation development is to establish embryonic and extra-embryonic cell fates. To address when and how this fundamental process is initiated in mammals, we characterize transcriptomes of all individual cells throughout mouse pre-implantation development. This identifies targets of master pluripotency regulators Oct4 and Sox2 as being highly heterogeneously expressed between blastomeres of the 4-cell embryo, with Sox21 showing one of the most heterogeneous expression profiles...
March 24, 2016: Cell
Maryna Panamarova, Andy Cox, Krzysztof B Wicher, Richard Butler, Natalia Bulgakova, Shin Jeon, Barry Rosen, Rho H Seong, William Skarnes, Gerald Crabtree, Magdalena Zernicka-Goetz
Dynamic control of gene expression is essential for the development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI\SNF (BAF) complex. However, the role of the BAF complex in early mouse development has remained unclear. Here, we demonstrate that BAF155, a major BAF complex subunit, regulates the assembly of the BAF complex in vivo and regulates lineage specification of the mouse blastocyst...
April 15, 2016: Development
Suzanne L Jacques, Katrina P Aquino, Jodi Gureasko, P Ann Boriack-Sjodin, Margaret Porter Scott, Robert A Copeland, Thomas V Riera
CARM1 is a type I arginine methyltransferase involved in the regulation of transcription, pre-mRNA splicing, cell cycle progression, and the DNA damage response. CARM1 overexpression has been implicated in breast, prostate, and liver cancers and therefore is an attractive target for cancer therapy. To date, little about the kinetic properties of CARM1 is known. In this study, substrate specificity and the kinetic mechanism of the human enzyme were determined. Substrate specificity was examined by testing CARM1 activity with several histone H3-based peptides in a radiometric assay...
March 22, 2016: Biochemistry
Hao Hu, Kun Qian, Meng-Chiao Ho, Y George Zheng
INTRODUCTION: Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. AREAS COVERED: The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5...
2016: Expert Opinion on Investigational Drugs
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