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https://www.readbyqxmd.com/read/29106602/prmt5-as-a-druggable-target-for-glioblastoma-therapy
#1
Yeshavanth Kumar Banasavadi-Siddegowda, Alessandra M Welker, Min An, Xiaozhi Yang, Wei Zhou, Guqin Shi, Jaime Imitola, Chenglong Li, Sigmund Hsu, Jiang Wang, Mitch Phelps, Jianying Zhang, Christine E Beattie, Robert Baiocchi, Balveen Kaur
Background: In spite of standard multi modal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy prognosis for GBM patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogenous tumor cell population. Protein arginine methyltransferase (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells...
November 2, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29099132/development-of-an-alphalisa-high-throughput-technique-to-screen-for-small-molecule-inhibitors-targeting-protein-arginine-methyltransferases
#2
Lakshmi Prabhu, Lan Chen, Han Wei, Özlem Demir, Ahmad Safa, Lifan Zeng, Rommie E Amaro, Bert H O'Neil, Zhon-Yin Zhang, Tao Lu
The protein arginine methyltransferase (PRMT) family of enzymes comprises nine family members in mammals. They catalyze arginine methylation, either monomethylation or symmetric/asymmetric dimethylation of histone and non-histone proteins. PRMT methylation of its substrate proteins modulates cellular processes such as signal transduction, transcription, and mRNA splicing. Recent studies have linked overexpression of PRMT5, a member of the PRMT superfamily, to oncogenesis, making it a potential target for cancer therapy...
November 3, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/29092819/protein-arginine-methyltransferase-expression-localization-and-activity-during-disuse-induced-skeletal-muscle-plasticity
#3
Derek W Stouth, Alexander Manta, Vladimir Ljubicic
Protein arginine methyltransferase 1 (PRMT1), PRMT4, and PRMT5 catalyze the methylation of arginine residues on target proteins. Previous work suggests that these enzymes regulate skeletal muscle plasticity. However, the function of PRMTs during disuse-induced muscle remodelling is unknown. The purpose of our study was to determine whether denervation-induced muscle disuse alters PRMT expression and activity in skeletal muscle, as well as to contextualize PRMT biology within the early disuse-evoked events that precede atrophy, which remain largely undefined...
November 1, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29076773/targeting-protein-arginine-methyltransferase-5-in-disease
#4
André Richters
PRMT5 catalyzes the mono- and symmetric dimethylation of the arginine N-guanidine group of a wide variety of target proteins including histones, transcriptional elongation factors, kinases and tumor suppressors by utilizing the essential co-factor S-adenosylmethionine as methyl source. PRMT5 overexpression has been linked to the progression of various diseases, including cancer, and is oftentimes associated with a poor prognosis. Therefore, PRMT5 is promoted as a valuable target for drug discovery approaches and was a subject matter in recent endeavors aiming for the development of specific PRMT5 inhibitors...
October 27, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29065155/prmt5-a-novel-regulator-of-hepatitis-b-virus-replication-and-an-arginine-methylase-of-hbv-core
#5
Barbora Lubyova, Jan Hodek, Ales Zabransky, Hana Prouzova, Martin Hubalek, Ivan Hirsch, Jan Weber
In mammals, protein arginine methyltransferase 5, PRMT5, is the main type II enzyme responsible for the majority of symmetric dimethylarginine formation in polypeptides. Recent study reported that PRMT5 restricts Hepatitis B virus (HBV) replication through epigenetic repression of HBV DNA transcription and interference with encapsidation of pregenomic RNA. Here we demonstrate that PRMT5 interacts with the HBV core (HBc) protein and dimethylates arginine residues within the arginine-rich domain (ARD) of the carboxyl-terminus...
2017: PloS One
https://www.readbyqxmd.com/read/29054638/the-persistent-organochlorine-pesticide-endosulfan-modulates-multiple-epigenetic-regulators-with-oncogenic-potential-in-mcf-7-cells
#6
Krishna Ghosh, Biji Chatterjee, Aparna Geetha Jayaprasad, Santosh R Kanade
Environmental cues and chemicals can potentially modulate the phenotypic expression of genome through alterations in the epigenetic mechanisms. Endosulfan is one of the extensively used organochlorine pesticides around the world which is known for its endocrine, neuro- and reproductive toxicity. This study was aimed to investigate the potential of α-endosulfan in modulation of multiple epigenetic enzymes in MCF-7 cells. The cells were treated with DMSO (control) or α-endosulfan (1 and 10μM) and the expression of various epigenetic enzymes was assayed by real-time PCR and immunoblotting, in addition to their activity assays...
October 17, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/29050343/an-integrated-multigene-expression-panel-to-predict-long-term-survival-after-curative-hepatectomy-in-patients-with-hepatocellular-carcinoma
#7
Mitsuro Kanda, Kenta Murotani, Hiroyuki Sugimoto, Takashi Miwa, Shinichi Umeda, Masaya Suenaga, Masamichi Hayashi, Norifumi Hattori, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Michitaka Fujiwara, Yasuhiro Kodera
Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1:2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29018151/correction-prmt5-selective-inhibitors-suppress-inflammatory-t-cell-responses-and-experimental-autoimmune-encephalomyelitis
#8
Lindsay M Webb, Stephanie A Amici, Kyle A Jablonski, Himanshu Savardekar, Amanda R Panfil, Linsen Li, Wei Zhou, Kevin Peine, Vrajesh Karkhanis, Eric M Bachelder, Kristy M Ainslie, Patrick L Green, Chenglong Li, Robert A Baiocchi, Mireia Guerau-de-Arellano
No abstract text is available yet for this article.
October 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29017049/exploiting-the-hidden-treasure-of-detained-introns
#9
Xiang-Dong Fu
Many mammalian genes contain poorly spliced introns, resulting in nuclear detention of partially spliced transcripts, which may be exploited to modulate gene expression. In this issue of Cancer Cell, Braun et al. report that the arginine methyltransferase PRMT5 is critical for tumor cell proliferation by regulating numerous detained introns.
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28987382/arginine-methyltransferase-inhibitor-1-inhibits-gastric-cancer-by-downregulating-eif4e-and-targeting-prmt5
#10
Baolai Zhang, Su Zhang, Lijuan Zhu, Xue Chen, Yunfeng Zhao, Li Chao, Juanping Zhou, Xing Wang, Xinyang Zhang, Nengqian Ma
Arginine methylation is carried out by protein arginine methyltransferase (PRMTs) family. Arginine methyltransferase inhibitor 1 (AMI-1) is mainly used to inhibit type I PRMT activity in vitro. However, the effects of AMI-1 on type II PRMT5 activity and gastric cancer (GC) remain unclear. In this study, we provided the first evidence that AMI-1 significantly inhibited GC cell proliferation and migration while induced GC cell apoptosis, and reduced the expression of PRMT5, eukaryotic translation initiation factor 4E (eIF4E), symmetric dimethylation of histone 3 (H3R8me2s) and histone 4 (H4R3me2s)...
October 4, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28986365/the-splicing-regulator-prmt5-is-critical-for-glioblastoma-proliferation
#11
(no author information available yet)
PRMT5 regulates the splicing of detained introns in proliferation-associated genes in GBM.
October 6, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28977470/the-prmt5-wdr77-complex-regulates-alternative-splicing-through-znf326-in-breast-cancer
#12
Madhumitha Rengasamy, Fan Zhang, Ajay Vashisht, Won-Min Song, Francesca Aguilo, Yifei Sun, SiDe Li, Weijia Zhang, Bin Zhang, James A Wohlschlegel, Martin J Walsh
We observed overexpression and increased intra-nuclear accumulation of the PRMT5/WDR77 in breast cancer cell lines relative to immortalized breast epithelial cells. Utilizing mass spectrometry and biochemistry approaches we identified the Zn-finger protein ZNF326, as a novel interaction partner and substrate of the nuclear PRMT5/WDR77 complex. ZNF326 is symmetrically dimethylated at arginine 175 (R175) and this modification is lost in a PRMT5 and WDR77-dependent manner. Loss of PRMT5 or WDR77 in MDA-MB-231 cells leads to defects in alternative splicing, including inclusion of A-T rich exons in target genes, a phenomenon that has previously been observed upon loss of ZNF326...
August 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28972166/histone-arginine-demethylase-jmjd6-is-linked-to-stress-granule-assembly-through-demethylation-of-the-stress-granule-nucleating-protein-g3bp1
#13
Wei-Chih Tsai, Lucas C Reineke, Antrix Jain, Sung Yun Jung, Richard E Lloyd
Stress granules (SG) are membrane-less organelles that are condensates of stalled translation initiation complexes and mRNAs. SG formation is a cytoprotective response to environmental stress and results from protein interactions involving regions of low amino acid complexity and poorly defined post-translational modifications of SG components. Many RNA binding proteins are methylated and we previously demonstrated that the potent SG nucleating protein G3BP1 is methylated by protein arginine methyltransferase 1 and 5 (PRMT1 and PRMT5)...
September 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28966034/coordinated-splicing-of-regulatory-detained-introns-within-oncogenic-transcripts-creates-an-exploitable-vulnerability-in-malignant-glioma
#14
Christian J Braun, Monica Stanciu, Paul L Boutz, Jesse C Patterson, David Calligaris, Fumi Higuchi, Rachit Neupane, Silvia Fenoglio, Daniel P Cahill, Hiroaki Wakimoto, Nathalie Y R Agar, Michael B Yaffe, Phillip A Sharp, Michael T Hemann, Jacqueline A Lees
Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28945229/the-paf-complex-regulation-of-prmt5-facilitates-the-progression-and-maintenance-of-mll-fusion-leukemia
#15
J Serio, J Ropa, W Chen, M Mysliwski, N Saha, L Chen, J Wang, H Miao, T Cierpicki, J Grembecka, A G Muntean
Acute myeloid leukemia (AML) is a disease associated with epigenetic dysregulation. 11q23 translocations involving the H3K4 methyltransferase MLL1 (KMT2A) generate oncogenic fusion proteins with deregulated transcriptional potential. The polymerase-associated factor complex (PAFc) is an epigenetic co-activator complex that makes direct contact with MLL fusion proteins and is involved in AML, however, its functions are not well understood. Here, we explored the transcriptional targets regulated by the PAFc that facilitate leukemia by performing RNA-sequencing after conditional loss of the PAFc subunit Cdc73...
September 25, 2017: Oncogene
https://www.readbyqxmd.com/read/28903384/a-novel-sharpin-prmt5-h3r2me1-axis-is-essential-for-lung-cancer-cell-invasion
#16
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
#17
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
#18
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 19, 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
#19
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
#20
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
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