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E1 inhibitor

Yoshitaka Wakabayashi, Yusuke Yoshino, Kazunori Seo, Ichiro Koga, Takatoshi Kitazawa, Yasuo Ota
Osteoporosis is one of the chronic complications seen in human immunodeficiency virus (HIV)-infected patients, and affects patients at high prevalence. The causes of osteoporosis in HIV-infected patients are multiple, and include chronic HIV infection, living habits such as smoking and alcohol consumption, and antiretroviral drug use. Among antiretroviral drugs, protease inhibitors have been reported to be associated with osteoporosis. However, it remains to be determined how anti-HIV drugs affect osteoblast differentiation...
December 2018: Biomedical Reports
Tetsu Kawabata, Takanobu Otsuka, Kazuhiko Fujita, Go Sakai, Woo Kim, Rie Matsushima-Nishiwaki, Gen Kuroyanagi, Osamu Kozawa, Haruhiko Tokuda
BACKGROUND: We have recently reported that epidermal growth factor (EGF) induces migration of osteoblast-like MC3T3-E1 cells through the activation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, stress-activated protein kinase/ c-Jun N-terminal kinase (SAPK/JNK) and Akt. Furthermore, we demonstrated that heat shock protein 70 (HSP70) down-regulates the transforming growth factor-β-stimulated vascular endothelial growth factor synthesis via suppression of p38 MAP kinase in osteoblast-like MC3T3-E1 cells...
December 12, 2018: Current Molecular Medicine
Hyeon-Young Min, Young Kwan Sung, Eun-Jung Kim, Won-Gu Jang
OVO homologue-like 1 (OVOL1) encodes a C2H2 zinc finger protein and is an evolutionarily conserved gene in mammals. The OVOL1 expression is required for development. However, the function of OVOL1 in bone metabolism remains unreported. Here, we show for the first time the role of OVOL1 in osteoblast differentiation. To determine the role of OVOL1 in osteogenic differentiation, we analyzed OVOL1 expression in the preosteoblastic cell line. OVOL1 messenger RNA expression was induced during osteoblast differentiation...
December 6, 2018: Journal of Cellular Physiology
Zongyang Lv, Lingmin Yuan, James H Atkison, Katelyn M Williams, Ramir Vega, E Hampton Sessions, Daniela B Divlianska, Christopher Davies, Yuan Chen, Shaun K Olsen
E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation...
December 4, 2018: Nature Communications
Rebecca Kaye, Nora Botten, Marit Lippestad, Dayu Li, Robin R Hodges, Tor P Utheim, Charles N Serhan, Darlene A Dartt
PURPOSE: To identify interactions of the epidermal growth factor receptor (EGFR) with the pro-resolving mediator receptors for RvD1 and RvE1 to stimulate an increase in intracellular [Ca2+ ] ([Ca2+ ]i ) and mucin secretion from cultured human and rat conjunctival goblet cells. METHODS: Goblet cells from human and rat conjunctiva were grown in culture using RPMI media. Cultured goblet cells were pre-incubated with inhibitors, and then stimulated with RvD1, RvE1, EGF or the cholinergic agonist carbachol (Cch)...
December 1, 2018: Experimental Eye Research
Cristina Guarducci, Martina Bonechi, Matteo Benelli, Chiara Biagioni, Giulia Boccalini, Dario Romagnoli, Roberto Verardo, Rachel Schiff, C Kent Osborne, Carmine De Angelis, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
CDK4/6 inhibitors represent a new treatment standard for hormone receptor-positive (HR+), HER2-negative advanced breast cancer (BC) patients. Although efficacious, resistance to these agents is universal. Here, we profiled a large panel of HR+ BC cell lines with conditioned resistance to the CDK4/6 inhibitor palbociclib, and analyzed cell cycle-related markers by gene expression profiles (GEP) and western blot (WB). GEP showed high molecular heterogeneity among the models, with E2F targets being significantly enriched both during treatment and at the time of resistance...
2018: NPJ Breast Cancer
Akari Nitta, Kazuya Hori, Isei Tanida, Ayumi Igarashi, Yasuyo Deyama, Takashi Ueno, Eiki Kominami, Manabu Sugai, Koji Aoki
Autophagy, a system for the bulk degradation of intracellular components, is essential for homeostasis and the healthy physiology and development of cells and tissues. Its deregulation is associated with human disease. Thus, methods to modulate autophagic activity are critical for analysis of its role in mammalian cells and tissues. Here we report a method to inhibit autophagy using a mutant variant of the protein ATG7, a ubiquitin E1-like enzyme essential for autophagosome formation. During autophagy, ATG7 activates the conjugation of LC3 (ATG8) with phosphatidylethanolamine (PE) and ATG12 with ATG5...
November 30, 2018: Biochemical and Biophysical Research Communications
Guan Shi, Pu Jia, Hao Chen, Li Bao, Fei Feng, Hai Tang
Necroptosis is a regulated cell death mechanism. However, it is unknown whether necroptosis is involved in the death of tumor necrosis factor-α (TNF-α)-treated osteoblasts. Therefore, we conducted the study with TNF-α, Nec-1 (a specific inhibitor of necroptosis), and Z-IETD-FMK (a specific inhibitor of apoptosis) to determine whether necroptosis plays a role in the death of TNF-α-treated osteoblast cell line MC3T3-E1. Cell viability, cell death, and lactate dehydrogenase (LDH) release were assayed to evaluate cytotoxicity...
November 23, 2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Tetsu Kawabata, Haruhiko Tokuda, Go Sakai, Kazuhiko Fujita, Rie Matsushima-Nishiwaki, Gen Kuroyanagi, Takanobu Otsuka, Osamu Kozawa
Heat shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone in a variety of cells including osteoblasts. We previously showed that insulin-like growth factor-I (IGF-I) elicits migration of osteoblast-like MC3T3-E1 cells through the activation of phosphatidylinositol 3-kinase/Akt and p44/p42 mitogen-activated protein (MAP) kinase. In the present study, we investigated the effects of HSP70 inhibitors on the IGF-I-elicited migration of these cells and the mechanism involved. The IGF-I-stimulated osteoblast migration evaluated by a wound-healing assay and by a transwell cell migration was significantly reduced by VER-155008 and YM-08, which are both HSP70 inhibitors...
November 21, 2018: Biomedicines
Shikui Zhang, Yaqiong Ma, Xiaoyan Hu, Yonghua Zheng, Xiaoke Chen
The emerging evidence reveals that protein arginine methyltransferase 5 (PRMT5) is involved in regulation of tumour cell proliferation and cancer development. Nevertheless, the exact role of PRMT5 in human lung cancer cell proliferation and the underlying molecular mechanism remains largely obscure. Here, we showed that PRMT5 was highly expressed in human lung cancer cells and lung cancer tissues. Furthermore, we generated PRMT5 stable knockdown cell lines (A549 and H1299 cells) and explored the functions of PRMT5 in lung cancer cell proliferation...
November 20, 2018: Journal of Cellular and Molecular Medicine
Peng Zhang, Xiao-Bing Chen, Bing-Qian Ding, Hong-Lin Liu, Tao He
The ATP binding cassette E1 (ABCE1), a member of the ABC family, was originally described as the RNase L inhibitor. Through forming a heterodimer with RNase L, ABCE1 participates in the negative regulation of the 2-5A/RNase L system and thus mediates a wide range of biological functions. Recent evidence has shown the new roles of ABCE1 in tumorigenesis. However, there have been no investigations on the specific effect of ABCE1 on glioma. In this study, we examined the expression pattern and possible role of ABCE1 in glioma...
November 19, 2018: Bioscience Reports
Yin-Gi Jang, Kyung-A Hwang, Kyung-Chul Choi
Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti-inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis...
November 16, 2018: Nutrients
Xin Li, Ekinci Elmira, Sagar Rohondia, Jicang Wang, Jinbao Liu, Q Ping Dou
Ubiquitin-Proteasome System (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step, and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs...
November 19, 2018: Expert Opinion on Therapeutic Patents
Xiao Liang, Baoshan Li, Qian Huang, Dan Liu, Houxun Ma
Dexamethasone (DEX) is a commonly used anti-inflammatory drug and an immunosuppressive drug used in clinical practice to treat a variety of diseases. Glucocorticoid-induced osteoporosis (GIOP) is a consequence of high dose, or a long-term low dose use of glucocorticoids (GCs). These treatment regimens can cause a variety of bone-related adverse effects, leading to increased osteoblast and bone cell apoptosis. Evidence suggests that klotho (KL) can inhibit GIOP. It is unknown whether KL attenuates DEX-induced apoptosis in MC3T3-E1 cells or the underlying mechanisms involved...
December 9, 2018: Biochemical and Biophysical Research Communications
Ioannis Manolaridis, Scott M Jackson, Nicholas M I Taylor, Julia Kowal, Henning Stahlberg, Kaspar P Locher
ABCG2 is a transporter protein of the ATP-binding-cassette (ABC) family that is expressed in the plasma membrane in cells of various tissues and tissue barriers, including the blood-brain, blood-testis and maternal-fetal barriers1-4 . Powered by ATP, it translocates endogenous substrates, affects the pharmacokinetics of many drugs and protects against a wide array of xenobiotics, including anti-cancer drugs5-12 . Previous studies have revealed the architecture of ABCG2 and the structural basis of its inhibition by small molecules and antibodies13,14 ...
November 2018: Nature
Liu Gao, Shi-Lun Li, Yu-Kun Li
Diabetes is a worldwide health problem with increasing prevalence. Some reports indicate the interplay between bone and glucose metabolism. The imbalance between bone resorption and formation resulted in the structural integrity and strength of bone. Glucagon-like peptide-1 (GLP-1) and its agonists (Liraglutide) have an anabolic action on bone remodeling by stimulating osteoblast differentiation as well as increasing osteoblast longevity. However, the underlying mechanisms remain elusive. We detected the presence of GLP-1 receptor (GLP-1R) in MC3T3-E1 cells via immunocytochemistry assay...
November 7, 2018: DNA and Cell Biology
Yoshimasa Takafuji, Kohei Tatsumi, Masayoshi Ishida, Naoyuki Kawao, Kiyotaka Okada, Osamu Matsuo, Hiroshi Kaji
Plasminogen activator inhibitor-1 (PAI-1) is known as an inhibitor of fibrinolytic system. Previous studies suggest that PAI-1 is involved in the pathogenesis of osteoporosis induced by ovariectomy, diabetes, and glucocorticoid excess in mice. However, the roles of PAI-1 in early-stage osteogenic differentiation have remained unknown. In the current study, we investigated the roles of PAI-1 in osteoblastic differentiation of mesenchymal stem cells (MSCs) using wild-type (WT) and PAI-1-deficient (PAI-1 KO) mice...
November 1, 2018: Journal of Cellular Physiology
Aiko Itoh, Yasuhiro Nonaka, Takashi Ogawa, Takanori Nakamura, Nozomu Nishi
Galectin-9 is the most potent inducer of cell death in lymphomas and other malignant cell types among the members of the galectin family. We investigated the mechanism of galectin-9-induced cell death in PC-3 prostate cancer cells in comparison with in Jurkat T cells. Galectin-9 induced apoptotic cell death in Jurkat cells, as typically revealed by DNA ladder formation. On the other hand, DNA ladder formation and other features of apoptosis were not apparent in PC-3 cells undergoing galectin-9-induced death...
October 24, 2018: Glycobiology
Han-Liang He, Chao Liu, Bing-Xue Li, Chen-Qiu Wang, Hai-Tao Li, Lin Gu
Background: Estrogen, as an important hormone in human physiological process, is closely related to bone metabolism. The aim of this study was to investigate the mechanism of estrogen on osteoblasts metabolism in MC3T3-E1 cells. Methods: We treated the MC3T3-E1 cells with different concentrations of β-estradiol (0.01, 0.1, 1, and 10 nmol/L), observed the morphological changes of the cells, and detected the cell's proliferation and apoptosis of MC3T3-E1 cells. Two transcriptome libraries were constructed and sequenced...
November 5, 2018: Chinese Medical Journal
Qingfeng Wang, Guoqiang Wang, Bin Wang, Huilin Yang
Impairment of normal osteoblast differentiation has been associated with bone loss-related disorders, such as osteoporosis. Takeda G-protein coupled receptor 5 (TGR5) has been identified as an important modulator of bile acid and energy homeostasis. Little information regarding the effects of TGR5 on osteoblastic bone formation and matrix mineralization has been reported before. In the current study, we found that TGR5 was expressed in osteoblast-like cell line MC3T3-E1 cells. Osteogenic medium (OM) stimulation promoted the expression of TGR5 in a dose-dependent manner...
December 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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