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e3 ligase

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https://www.readbyqxmd.com/read/29053960/a-general-strategy-for-discovery-of-inhibitors-and-activators-of-ring-and-u-box-e3-ligases-with-ubiquitin-variants
#1
Mads Gabrielsen, Lori Buetow, Mark A Nakasone, Syed Feroj Ahmed, Gary J Sibbet, Brian O Smith, Wei Zhang, Sachdev S Sidhu, Danny T Huang
RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site...
October 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29051727/syvn1-an-erad-e3-ubiquitin-ligase-is-involved-in-gabaa%C3%AE-1-degradation-associated-with-methamphetamine-induced-conditioned-place-preference
#2
Dong-Liang Jiao, Yan Chen, Yao Liu, Yun-Yue Ju, Jian-Dong Long, Jiang Du, Chang-Xi Yu, Yu-Jun Wang, Min Zhao, Jing-Gen Liu
Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABAAα1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29050782/development-of-a-peptide-based-inducer-of-protein-degradation-targeting-notch1
#3
Nobumichi Ohoka, Takashi Misawa, Masaaki Kurihara, Yosuke Demizu, Mikihiko Naito
We previously developed a protein knockdown system by small-molecule hybrid compounds named SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers). Here we report a peptide-based protein knockdown system for inducing degradation of a transcriptional factor NOTCH1. The molecules designed were composed of two biologically active scaffolds: a peptide that binds to the surface of the target protein NOTCH1 and a small-molecule MV1 that binds to the E3 ubiquitin ligase inhibitor of apoptosis protein (IAP), which are expected to cross-link these proteins in cells...
October 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29050293/proapoptotic-function-of-deubiquitinase-dusp31-in-drosophila
#4
Sergey A Sinenko
Drosophila have been used to identify new components in apoptosis regulation. The Drosophila protein Dark forms an octameric apoptosome complex that induces the initiator caspase Dronc to trigger the caspase cell death pathway and, therefore, plays an important role in controlling apoptosis. Caspases and Dark are constantly expressed in cells, but their activity is blocked by DIAP1 E3 ligase-mediated ubiquitination and subsequent inactivation or proteasomal degradation. One of the regulatory mechanisms that stabilize proapoptotic factors is the removal of ubiquitin chains by deubiquitinases...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050267/reversible-regulation-of-orc2-sumoylation-by-pias4-and-senp2
#5
Ronghua Wang, Fangming Liu, Yongxu Zhao, Dan Wu, Lihan Chen, Edward T H Yeh, Chao Huang
The small ubiquitin-related modifier (SUMO) system is essential for smooth progression of cell cycle at the G2/M phase. Many centromeric proteins are reversibly SUMOylated to ensure proper chromosome segregation at the mitosis. SUMOylation of centromeric Origin Recognition Complex subunit 2 (ORC2) at the G2/M phase is essential in maintaining genome integrity. However, how ORC2 SUMOylation is regulated remains largely unclear. Here we show that ORC2 SUMOylation is reversibly controlled by SUMO E3 ligase PIAS4 and De-SUMOylase SENP2...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050245/von-hippel-lindau-regulates-interleukin-32%C3%AE-stability-in-ovarian-cancer-cells
#6
Hyo Jeong Yong, Jeong Su Park, Ae Lee Jeong, Sora Han, Sunyi Lee, Hye In Ka, Buyanravjkh Sumiyasuren, Hyun Jeong Joo, Su Jeong So, Ji Young Park, Do-Young Yoon, Jong-Seok Lim, Myeong-Seok Lee, Hee Gu Lee, Young Yang
Hypoxia-induced interleukin-32β (IL-32β) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32β stability is regulated was investigated in ovarian cancer cells. IL-32β expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32β was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32β was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050200/targeting-muc1-c-suppresses-polycomb-repressive-complex-1-in-multiple-myeloma
#7
Ashujit Tagde, Tahireh Markert, Hasan Rajabi, Masayuki Hiraki, Maroof Alam, Audrey Bouillez, David Avigan, Kenneth Anderson, Donald Kufe
The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29046370/excessive-glucocorticoids-induced-muscle-murf1-overexpression-is-independent-of-akt-foxo1-pathway
#8
Xiao Juan Wang, Jing Jing Xiao, Lei Liu, Hong Chao Jiao, Hai Lin
The ubiquitin-proteasome system (UPS)-dependent proteolysis plays a major role in the muscle catabolic action of glucocorticoids (GCs). Atrogin-1 and muscle-specific RING finger protein 1 (MuRF1), two E3 ubiquitin ligases, are uniquely expressed in muscle. It has been previously demonstrated GCs treatment induced MuRF1 and atrogin-1 over expression. However, it is yet unclear whether the higher pharmacological dose of GCs induced muscle protein catabolism through MuRF1 and atrogin-1. In the present study, the role of atrogin-1 and MuRF1 in C2C12 cells protein metabolism during excessive dexamethasone (DEX) was studied...
October 18, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#9
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29044697/atrae1-is-involved-in-degradation-of-aba-receptor-rcar1-and-negatively-regulates-aba-signaling-in-arabidopsis
#10
Dekuan Li, Liang Zhang, Xiaoyi Li, Xiangge Kong, Xiaoyu Wang, Ying Li, Zhibin Liu, Jianmei Wang, Xufeng Li, Yi Yang
The phytohormone abscisic acid (ABA) plays an important role in regulating plant growth, development and adaption to various environmental stresses. Regulatory components of ABA receptors (RCARs, also known as PYR/PYLs) sense ABA and initiate ABA signaling through inhibiting the activities of protein phosphatase 2C (PP2C) in Arabidopsis. However, the way in which ABA receptors are regulated is not well known. A DWD protein AtRAE1 (for RNA export factor 1 in Arabidopsis), which may act as a substrate receptor of CUL4-DDB1 E3 ligase, is an interacting partner of RCAR1/PYL9...
October 18, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/29043469/e3-ubiquitin-ligases-in-cancer-and-implications-for-therapies
#11
Dong Wang, Leina Ma, Bin Wang, Jia Liu, Wenyi Wei
E3 ligases are a class of enzymes that can transfer ubiquitin to substrates for their degradation, which are of importance in cellular homeostasis. Since many oncogenic or tumor-suppressive proteins are reported to be regulated by the ubiquitin-proteasome system (UPS), E3 ligases, which function as substrate interacting modules, have been attracting more and more attention as promising anticancer drug targets due to their pivotal role in conferring substrate specificity. Generally, based on their molecular structure and functional mechanism, E3 ligases can be divided into three major types: homologous to E6-associated protein C-terminus (HECT), really interesting new gene (RING), and RING-in-between-RING (RBR) E3 ligases...
October 17, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29042542/tyrosine-phosphorylation-of-the-garu-e3-ubiquitin-ligase-promotes-gibberellin-signalling-by-preventing-gid1-degradation
#12
Keiichirou Nemoto, Abdelaziz Ramadan, Gen-Ichiro Arimura, Kenichiro Imai, Kentaro Tomii, Kazuo Shinozaki, Tatsuya Sawasaki
Gibberellin (GA) is a major hormone for plant growth and development. GA response is derived from the degradation of DELLA repressor proteins after GA-dependent complex formation of the GID1 GA receptor with DELLA. Genistein is a known tyrosine (Tyr) kinase inhibitor and inhibits DELLA degradation. However, the biological role of Tyr phosphorylation on the GA response remains unclear. Here, we demonstrate that GARU (GA receptor RING E3 ubiquitin ligase) mediates ubiquitin-dependent degradation of GID1, and that the TAGK2 plant Tyr-kinase is a target of genistein and inhibits GARU-GID1A interactions by phosphorylation of GARU at Tyr321...
October 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29039560/20-hydroxyeicosatetraenoic-acid-regulates-the-expression-of-nedd4%C3%A2-2-in-kidney-and-liver-through-a-neddylation-modification-pathway
#13
Jianzhu Zhao, Bijun Zhang, Guangrui Lai, Runhong Xu, Guoming Chu, Yanyan Zhao
The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway...
October 17, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29039504/inhibitory-effects-of-ubiquitination-of-synoviolin-by-padi4
#14
Satoko Aratani, Hidetoshi Fujita, Naoko Yagishita, Yoshihisa Yamano, Yukari Okubo, Kusuki Nishioka, Toshihiro Nakajima
Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of auto‑antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl‑arginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA...
October 11, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29038616/sumo-e3-ligase-piasy-mediates-high-glucose-induced-activation-of-nf-%C3%AE%C2%BAb-inflammatory-signaling-in-rat-mesangial-cells
#15
Wei Huang, Yaling Liang, Jianhua Dong, Luping Zhou, Chenlin Gao, Chunxia Jiang, Meijuan Chen, Yang Long, Yong Xu
BACKGROUND: Sumoylation is extensively involved in the regulation of NF-κB signaling. PIASy, as a SUMO E3 ligase, has been proved to mediate sumoylation of IκB kinase γ (IKKγ) and contribute to the activation of NF-κB under genotoxic agent stimulation. However, the association of PIASy and NF-κB signaling in the pathogenesis of diabetic nephropathy (DN) has not been defined. METHODS: Rat glomerular mesangial cells (GMCs) were stimulated by high glucose; siRNA was constructed to silence the expression of PIASy; the expression of PIASy, SUMO isoforms (SUMO1, SUMO2/3), and NF-κB signaling components was analyzed by Western blot; the interaction between IKKγ and SUMO proteins was detected by coimmunoprecipitation; and the release of inflammatory cytokines MCP-1 and IL-6 was assayed by ELISA...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/29038421/stabilization-of-phosphofructokinase-1-platelet-isoform-by-akt-promotes-tumorigenesis
#16
Jong-Ho Lee, Rui Liu, Jing Li, Chuanbao Zhang, Yugang Wang, Qingsong Cai, Xu Qian, Yan Xia, Yanhua Zheng, Yuji Piao, Qianming Chen, John F de Groot, Tao Jiang, Zhimin Lu
Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29036368/proteomic-identification-of-histone-post-translational-modifications-and-proteins-enriched-at-a-dna-double-strand-break
#17
Pingping Wang, Stephanie Byrum, Faith C Fowler, Sangita Pal, Alan J Tackett, Jessica K Tyler
Here, we use ChAP-MS (chromatin affinity purification with mass spectrometry), for the affinity purification of a sequence-specific single-copy endogenous chromosomal locus containing a DNA double-strand break (DSB). We found multiple new histone post-translational modifications enriched on chromatin bearing a DSB from budding yeast. One of these, methylation of histone H3 on lysine 125, has not previously been reported. Among over 100 novel proteins enriched at a DSB were the phosphatase Sit4, the RNA pol II degradation factor Def1, the mRNA export protein Yra1 and the HECT E3 ligase Tom1...
September 26, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29035367/targeting-glioma-stem-cells-through-combined-bmi1-and-ezh2-inhibition
#18
Xun Jin, Leo J Y Kim, Qiulian Wu, Lisa C Wallace, Briana C Prager, Tanwarat Sanvoranart, Ryan C Gimple, Xiuxing Wang, Stephen C Mack, Tyler E Miller, Ping Huang, Claudia L Valentim, Qi-Gang Zhou, Jill S Barnholtz-Sloan, Shideng Bao, Andrew E Sloan, Jeremy N Rich
Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29032941/ferritin-iron-regulators-pcbp1-and-ncoa4-respond-to-cellular-iron-status-in-developing-red-cells
#19
Moon-Suhn Ryu, Kari A Duck, Caroline C Philpott
Developing red blood cells exhibit multiple, redundant systems for regulating and coordinating the uptake of iron, the synthesis of heme, and the formation of hemoglobin during terminal differentiation. We recently described the roles of poly rC-binding protein (PCBP1) and nuclear coactivator 4 (NCOA4) in mediating the flux of iron through ferritin in developing erythroid cells, with PCBP1, an iron chaperone, delivering iron to ferritin and NCOA4, an autophagic cargo receptor, directing ferritin to the lysosome for degradation and iron release...
September 28, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29030390/apc-c-fzr-1-controls-sas-5-levels-to-regulate-centrosome-duplication-in-caenorhabditis-elegans
#20
Jeffrey C Medley, Lauren E DeMeyer, Megan M Kabara, Mi Hye Song
As the primary microtubule-organizing center, centrosomes play a key role in establishing mitotic bipolar spindles that secure correct transmission of genomic content. For the fidelity of cell division, centrosome number must be strictly controlled by duplicating only once per cell cycle. Proper levels of centrosome proteins are shown to be critical for normal centrosome number and function. Overexpressing core centrosome factors leads to extra centrosomes, while depleting these factors results in centrosome duplication failure...
October 13, 2017: G3: Genes—Genomes—Genetics
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