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https://www.readbyqxmd.com/read/28903384/a-novel-sharpin-prmt5-h3r2me1-axis-is-essential-for-lung-cancer-cell-invasion
#1
Tingxiong Fu, Xiuwei Lv, Qingzhi Kong, Changjing Yuan
SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878488/research-progress-on-the-autonomous-flowering-time-pathway-in-arabidopsis
#2
REVIEW
Jing-Zhi Cheng, Yu-Ping Zhou, Tian-Xiao Lv, Chu-Ping Xie, Chang-En Tian
The transition from vegetative to reproductive growth phase is a pivotal and complicated process in the life cycle of flowering plants which requires a comprehensive response to multiple environmental aspects and endogenous signals. In Arabidopsis, six regulatory flowering time pathways have been defined by their response to distinct cues, namely photoperiod, vernalization, gibberellin, temperature, autonomous and age pathways, respectively. Among these pathways, the autonomous flowering pathway accelerates flowering independently of day length by inhibiting the central flowering repressor FLC...
July 2017: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
https://www.readbyqxmd.com/read/28874563/epigenetic-control-via-allosteric-regulation-of-mammalian-protein-arginine-methyltransferases
#3
Kanishk Jain, Cyrus Y Jin, Steven G Clarke
Arginine methylation on histones is a central player in epigenetics and in gene activation and repression. Protein arginine methyltransferase (PRMT) activity has been implicated in stem cell pluripotency, cancer metastasis, and tumorigenesis. The expression of one of the nine mammalian PRMTs, PRMT5, affects the levels of symmetric dimethylarginine (SDMA) at Arg-3 on histone H4, leading to the repression of genes which are related to disease progression in lymphoma and leukemia. Another PRMT, PRMT7, also affects SDMA levels at the same site despite its unique monomethylating activity and the lack of any evidence for PRMT7-catalyzed histone H4 Arg-3 methylation...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28854561/sulforaphane-suppresses-prmt5-mep50-function-in-epidermal-squamous-cell-carcinoma-leading-to-reduced-tumor-formation
#4
Kamalika Saha, Matthew L Fisher, Gautam Adhikary, Daniel Grun, Richard L Eckert
Protein arginine methyltransferase 5 (PRMT5) cooperates with methylosome protein 50 (MEP50) to arginine methylate histone H3 and H4 to silence gene expression, and increased PRMT5 activity is associated with enhanced cancer cell survival. We have studied the role of PRMT5 and MEP50 in epidermal squamous cell carcinoma. We show that knockdown of PRMT5 or MEP50 results in reduced H4R3me2s formation, and reduced cell proliferation, invasion, migration and tumor formation. We further show that treatment with sulforaphane (SFN), a cancer preventive agent derived from cruciferous vegetables, reduces PRMT5 and MEP50 level and H4R3me2s formation, and this is associated with reduced cell proliferation, invasion and migration...
August 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28811300/epigenetic-regulation-by-the-menin-pathway
#5
REVIEW
Zijie Feng, Jian Ma, Xianxin Hua
There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription...
October 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28806746/selective-small-chemical-inhibitors-of-protein-arginine-methyltransferase-5-with-anti-lung-cancer-activity
#6
Gui-Mei Kong, Min Yu, Zhongping Gu, Zhi Chen, Rui-Ming Xu, Deon O'Bryant, Zhengxin Wang
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation...
2017: PloS One
https://www.readbyqxmd.com/read/28766049/usnrnp-biogenesis-mechanisms-and-regulation
#7
REVIEW
Oliver J Gruss, Rajyalakshmi Meduri, Maximilian Schilling, Utz Fischer
Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment...
August 1, 2017: Chromosoma
https://www.readbyqxmd.com/read/28757206/nitric-oxide-regulates-protein-methylation-during-stress-responses-in-plants
#8
Jiliang Hu, Huanjie Yang, Jinye Mu, Tiancong Lu, Juli Peng, Xian Deng, Zhaosheng Kong, Shilai Bao, Xiaofeng Cao, Jianru Zuo
Methylation and nitric oxide (NO)-based S-nitrosylation are highly conserved protein posttranslational modifications that regulate diverse biological processes. In higher eukaryotes, PRMT5 catalyzes Arg symmetric dimethylation, including key components of the spliceosome. The Arabidopsis prmt5 mutant shows severe developmental defects and impaired stress responses. However, little is known about the mechanisms regulating the PRMT5 activity. Here, we report that NO positively regulates the PRMT5 activity through S-nitrosylation at Cys-125 during stress responses...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28723619/a-novel-sharpin-prmt5-h3r2me1-axis-is-essential-for-lung-cancer-cell-invasion
#9
Tingxiong Fu, Xiuwei Lv, Qingzhi Kong, Changjing Yuan
SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28686580/upregulation-of-lyar-induces-neuroblastoma-cell-proliferation-and-survival
#10
Yuting Sun, Bernard Atmadibrata, Denise Yu, Matthew Wong, Bing Liu, Nicholas Ho, Dora Ling, Andrew E Tee, Jenny Wang, Imran N Mungrue, Pei Y Liu, Tao Liu
The N-Myc oncoprotein induces neuroblastoma by regulating gene transcription and consequently causing cell proliferation. Paradoxically, N-Myc is well known to induce apoptosis by upregulating pro-apoptosis genes, and it is not clear how N-Myc overexpressing neuroblastoma cells escape N-Myc-mediated apoptosis. The nuclear zinc finger protein LYAR has recently been shown to modulate gene expression by forming a protein complex with the protein arginine methyltransferase PRMT5. Here we showed that N-Myc upregulated LYAR gene expression by binding to its gene promoter...
September 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28678843/kshv-encoded-orf59-modulates-histone-arginine-methylation-of-the-viral-genome-to-promote-viral-reactivation
#11
Roxanne C Strahan, Maria McDowell-Sargent, Timsy Uppal, Pravinkumar Purushothaman, Subhash C Verma
Kaposi's sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into 'open' chromatin through the involvement of lysine demethylases and methyltransferases. Besides methylation of lysine residues of histone H3, arginine methylation of histone H4 plays an important role in controlling the compactness of the chromatin. Symmetric methylation of histone H4 at arginine 3 (H4R3me2s) negatively affects the methylation of histone H3 at lysine 4 (H3K4me3), an active epigenetic mark deposited on the viral chromatin during reactivation...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28669403/a-genetic-variant-ameliorates-%C3%AE-thalassemia-severity-by-epigenetic-mediated-elevation-of-human-fetal-hemoglobin-expression
#12
Diyu Chen, Yangjin Zuo, Xinhua Zhang, Yuhua Ye, Xiuqin Bao, Haiyan Huang, Wanicha Tepakhan, Lijuan Wang, Junyi Ju, Guangfu Chen, Mincui Zheng, Dun Liu, Shuodan Huang, Lu Zong, Changgang Li, Yajun Chen, Chenguang Zheng, Lihong Shi, Quan Zhao, Qiang Wu, Supan Fucharoen, Cunyou Zhao, Xiangmin Xu
A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks...
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28663579/genetic-deletion-or-small-molecule-inhibition-of-the-arginine-methyltransferase-prmt5-exhibit-anti-tumoral-activity-in-mouse-models-of-mll-rearranged-aml
#13
S Kaushik, F Liu, K Veazey, G Gao, P Das, L Neves, K Li, Y Zhong, Y Lu, V Giuliani, M T Bedford, S D Nimer, M A Santos
The hematological malignancies classified as Mixed Lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia (AML), here we show that genetic inactivation or small molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein driven transformation...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28662389/recent-progress-in-developing-selective-inhibitors-of-protein-methyltransferases
#14
REVIEW
H Ümit Kaniskan, Jian Jin
Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histones as well as non-histone proteins, play a crucial role in diverse biological pathways and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. There has been an increasingly growing interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases...
August 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28650658/potent-selective-and-cell-active-protein-arginine-methyltransferase-5-prmt5-inhibitor-developed-by-structure-based-virtual-screening-and-hit-optimization
#15
Ruifeng Mao, Jingwei Shao, Kongkai Zhu, Yuanyuan Zhang, Hong Ding, Chenhua Zhang, Zhe Shi, Hualiang Jiang, Dequn Sun, Wenhu Duan, Cheng Luo
PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0...
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28644004/intricate-effects-of-%C3%AE-amino-and-lysine-modifications-on-arginine-methylation-of-the-n-terminal-tail-of-histone-h4
#16
Melody D Fulton, Jing Zhang, Maomao He, Meng-Chiao Ho, Y George Zheng
Chemical modifications of the DNA and nucleosomal histones tightly control the gene transcription program in eukaryotic cells. The "histone code" hypothesis proposes that the frequency, combination, and location of post-translational modifications (PTMs) of the core histones compose a complex network of epigenetic regulation. Currently, there are at least 23 different types and >450 histone PTMs that have been discovered, and the PTMs of lysine and arginine residues account for a crucial part of the histone code...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28642865/spinal-muscular-atrophy-from-defective-chaperoning-of-snrnp-assembly-to-neuromuscular-dysfunction
#17
REVIEW
Maia Lanfranco, Neville Vassallo, Ruben J Cauchi
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28637748/impaired-spliceosomal-usnrnp-assembly-leads-to-sm-mrna-down-regulation-and-sm-protein-degradation
#18
Archana Bairavasundaram Prusty, Rajyalakshmi Meduri, Bhupesh Kumar Prusty, Jens Vanselow, Andreas Schlosser, Utz Fischer
Specialized assembly factors facilitate the formation of many macromolecular complexes in vivo. The formation of Sm core structures of spliceosomal U-rich small nuclear ribonucleoprotein particles (UsnRNPs) requires assembly factors united in protein arginine methyltransferase 5 (PRMT5) and survival motor neuron (SMN) complexes. We demonstrate that perturbations of this assembly machinery trigger complex cellular responses that prevent aggregation of unassembled Sm proteins. Inactivation of the SMN complex results in the initial tailback of Sm proteins on the PRMT5 complex, followed by down-regulation of their encoding mRNAs...
August 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28591716/adapting-alphalisa-high-throughput-screen-to-discover-a-novel-small-molecule-inhibitor-targeting-protein-arginine-methyltransferase-5-in-pancreatic-and-colorectal-cancers
#19
Lakshmi Prabhu, Han Wei, Lan Chen, Özlem Demir, George Sandusky, Emily Sun, John Wang, Jessica Mo, Lifan Zeng, Melissa Fishel, Ahmad Safa, Rommie Amaro, Murray Korc, Zhong-Yin Zhang, Tao Lu
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28588584/protein-arginine-methyltransferase-5-inhibition-upregulates-foxp3-regulatory-t-cells-frequency-and-function-during-the-ulcerative-colitis
#20
Yingxia Zheng, Liya Huang, Wensong Ge, Ming Yang, Yanhui Ma, Guohua Xie, Weiwei Wang, Bingxian Bian, Li Li, Hong Nie, Lisong Shen
Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3(+) regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence...
2017: Frontiers in Immunology
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