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Benxu Cheng, Pinki Anand, Anxiu Kuang, Feroz Akhtar, Virginia L Scofield
Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells...
2016: Parkinson's Disease
Yan Xu, Yawei Xing, Yanjie Xu, Chahua Huang, Huihui Bao, Kui Hong, Xiaoshu Cheng
We know that silencing Bim, a pro-apoptosis protein, significantly attenuates glucose and oxygen-deprived induced apoptosis in cardiomyocytes. However, the mechanisms underlying the regulation of the Bim activation in the heart have remained unknown. Pim-2 is one of three Pim serine/threonine kinase family members thought to be involved in cell survival and proliferation. H9c2 cardiomyocytes were subjected to a hypoxia/reoxygenation (H/R) condition in vitro, mimicking ischemic/reperfusion injury in vivo. H/R augmented the expression of Bim, Cyt C, and Pim-2 and induced H9c2 cell apoptosis...
October 17, 2016: Environmental Toxicology and Pharmacology
Alfredo Lagunas-Martínez, Enrique García-Villa, Magaly Arellano-Gaytán, Carla O Contreras-Ochoa, Jisela Dimas-González, María E López-Arellano, Vicente Madrid-Marina, Patricio Gariglio
The E6 oncoprotein can interfere with the ability of infected cells to undergo programmed cell death through the proteolytic degradation of proapoptotic proteins such as p53, employing the proteasome pathway. Therefore, inactivation of the proteasome through MG132 should restore the activity of several proapoptotic proteins. We investigated whether in HPV16 E6-expressing keratinocytes (KE6 cells), the restoration of p53 levels mediated by MG132 and/or activation of the CD95 pathway through apoptosis antigen-1 (APO-1) antibody are responsible for the induction of apoptosis...
October 20, 2016: Apoptosis: An International Journal on Programmed Cell Death
Takehito Kondo, Ichiro Hisatome, Shouichi Yoshimura, Endang Mahati, Tomomi Notsu, Peili Li, Kazuhiko Iitsuka, Masaru Kato, Kazuyoshi Ogura, Junichiro Miake, Takeshi Aiba, Wataru Shimizu, Yasutaka Kurata, Shinji Sakata, Naoe Nakasone, Haruaki Ninomiya, Akira Nakai, Katsumi Higaki, Yasushi Kawata, Yasuaki Shirayoshi, Akio Yoshida, Kazuhiro Yamamoto
BACKGROUND: The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). METHODS: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein...
October 2016: Journal of Arrhythmia
Cody S Shirriff, John J Heikkila
Endoplasmic reticulum (ER) stress can result in the accumulation of unfolded/misfolded protein in the ER lumen, which can trigger the unfolded protein response (UPR) resulting in the activation of various genes including immunoglobulin-binding protein (BiP; also known as glucose-regulated protein 78 or HSPA5). BiP, an ER heat shock protein 70 (HSP70) family member, binds to unfolded protein, inhibits their aggregation and re-folds them in an ATP-dependent manner. While cadmium, an environmental contaminant, was shown to induce the accumulation of HSP70 in vertebrate cells, less information is available regarding the effect of this metal on BiP accumulation or function...
October 13, 2016: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Mi Suk Lee, Hyo-Jung Choi, Eui-Jung Park, Hye-Jeong Park, Tae-Hwan Kwon
Carboxyl-terminus of AQP2 (AQP2c) undergoes post-translational modifications, including phosphorylation and ubiquitination, for the regulation of aquaporin-2 (AQP2) translocation and protein abundance. We aimed to identify novel proteins interacting with AQP2c. Recombinant AQP2c protein was made in E. coli BL21 (DE3) by exploiting the pET32 TrxA fusion system. Lysates of rat kidney inner medullary collecting duct (IMCD) tubule suspensions interacted with rat AQP2c bound to Ni(2+)-resin were subjected to LC-MS/MS proteomic analysis...
October 12, 2016: American Journal of Physiology. Renal Physiology
Chandni V Jain, Philip Jessmon, Brian A Kilburn, Meritxell Jodar, Edward Sendler, Stephen A Krawetz, D Randall Armant
INTRODUCTION: The growth factor HBEGF is upregulated post-transcriptionally in the low O2 environment of the human placenta during the first 10 weeks of pregnancy. We have examined the possible roles of HBEGF turnover and micro-RNA (miRNA) in its regulation by O2 in human first trimester trophoblast. METHODS: HTR-8/SVneo trophoblast cells were cultured at 2% or 20% O2. The cells were transfected with a dual luciferase reporter construct (psiCHECK-2) containing no insert (control), the HBEGF 3' untranslated region (3'UTR), or sub-regions of the 3'UTR, as well as with siRNA for DGCR8...
2016: PloS One
Momoko Isogai, Hidefumi Suzuki, Ryo Maeda, Taka-Aki Tamura
Although the majority of gene expression is driven by TATA-binding protein (TBP)-based transcription machinery, it has been reported that TBP-related factors (TRFs) are also involved in the regulation of gene expression. TBP-like protein (TLP), which is one of the TRFs and exhibits the highest affinity to TFIIA among known proteins, has recently been showed to have significant roles in gene regulation. However, how the level of TLP is maintained in vivo has remained unknown. In this study, we explored the mechanism by which TLP protein is turned over in vivo and the factor that maintains the amount of TLP...
October 3, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Ming-Ming Ji, Jae Man Lee, Hiroaki Mon, Jian Xu, Tsuneyuki Tatsuke, Takahiro Kusakabe
MG132 has been used as a proteasome inhibitor on Bombyx cells, but its physiological effects on autophagy still have not been elucidated. In this study, we find that the lipidated BmAtg8, BmAtg8-PE as an autophagosomal marker protein, is only localized to membranes. Then we established systems to monitor autophagic flux in Bombyx cells: Induction of autophagy reduces exogenous BmAtg8 and exogenous BmAtg8-PE, facilitates formation of autophagosomes indicated by green EGFP-BmAtg8 puncta after cotreatment by Rapamycin and Bafilomycin A1, and causes accumulation of free EGFP from EGFP-BmAtg8 cleavage in autolysosomes...
October 28, 2016: Biochemical and Biophysical Research Communications
Stephanie T Chan, Jiyoung Lee, Mansi Narula, J-H James Ou
: Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an important adapter molecule that mediates the TNFR family and interleukin-1/Toll-like receptor (IL-1/TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a post-translational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes...
September 28, 2016: Journal of Virology
Fangfang Song, Hualing Sun, Yake Wang, Hongye Yang, Liyuan Huang, Dongjie Fu, Jing Gan, Cui Huang
Human dental pulp cells (HDPCs) play a crucial role in dental pulp inflammation. Pannexin 3 (Panx3), a member of Panxs (Pannexins), has been recently found to be involved in inflammation. However, the mechanism of Panx3 in human dental pulp inflammation remains unclear. In this study, the role of Panx3 in inflammatory response was firstly explored, and its potential mechanism was proposed. Immunohistochemical staining showed that Panx3 levels were diminished in inflamed human and rat dental pulp tissues. In vitro, Panx3 expression was significantly down-regulated in HDPCs following a TNF-α challenge in a concentration-dependent way, which reached the lowest level at 10 ng/ml of TNF-α...
September 29, 2016: Journal of Cellular and Molecular Medicine
Katsunori Murota, Hanako Shimura, Minoru Takeshita, Chikara Masuta
Cucumber mosaic virus (CMV) can induce a specific necrosis on Arabidopsis through the interaction between the CMV 2b protein and host catalase, in which the ubiquitin-proteasome pathway may be involved. We previously reported that the CMV 2b protein, the viral RNA silencing suppressor, interacted with the H2O2 scavenger catalase (CAT3), leading to necrosis on CMV-inoculated Arabidopsis leaves. We here confirmed that CMV could more abundantly accumulate in the CAT3-knockout mutant (cat3), and that CAT3 makes host plants a little more tolerant to CMV...
September 22, 2016: Plant Cell Reports
Sara Ortega-Atienza, Blazej Rubis, Caitlin McCarthy, Anatoly Zhitkovich
Endogenous and exogenous formaldehyde (FA) has been linked to cancer, neurotoxicity, and other pathophysiologic effects. Molecular and cellular mechanisms that underlie FA-induced damage are poorly understood. In this study, we investigated whether proteotoxicity is an important, unrecognized factor in cell injury caused by FA. We found that irrespective of their cell cycle phases, all FA-treated human cells rapidly accumulated large amounts of proteins with proteasome-targeting K48-linked polyubiquitin, which was comparable with levels of polyubiquitination in proteasome-inhibited MG132 controls...
September 14, 2016: American Journal of Pathology
Hang Nguyen, Bruce D Uhal
Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the pro-apoptotic cathepsin D and reducing anti-apoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system...
September 16, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Matthias Kroiss, Silviu Sbiera, Sabine Kendl, Max Kurlbaum, Martin Fassnacht
Mitotane is the only drug approved for treatment of the orphan disease adrenocortical carcinoma (ACC) and was recently shown to be the first clinically used drug acting through endoplasmic reticulum (ER)-stress induced by toxic lipids. Since mitotane has limited clinical activity as monotherapy, we here study the potential of activating ER-stress through alternative pathways. The single reliable NCI-H295 cell culture model for ACC was used to study the impact MG132, bortezomib (BTZ) and carfilzomib (CFZ) on mRNA and protein expression of ER-stress markers, cell viability and steroid hormone secretion...
September 8, 2016: Hormones & Cancer
Jian-Zhen Shan, Yan-Yan Xuan, Qi Zhang, Jian-Jin Huang
OBJECTIVE: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. METHODS: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting...
September 2016: Journal of Zhejiang University. Science. B
Kaisheng Liu, Xiaohu Zhang, Jie Ting Zhang, Lai Ling Tsang, Xiaohua Jiang, Hsiao Chang Chan
While inflammation with aberrant activation of NF-κB pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-κB-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-κB activation in ΔF508cftr-/- mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-κB/COX-2/PGE2 pathway is activated whereas the β-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells...
August 31, 2016: Oncotarget
Shaobo Wang, Haibin Liu, Xiangyang Zu, Yang Liu, Liman Chen, Xueqin Zhu, Leike Zhang, Zheng Zhou, Gengfu Xiao, Wei Wang
The host-virus interaction during the cellular entry of Japanese encephalitis virus (JEV) is poorly characterized. The ubiquitin-proteasome system (UPS), the major intracellular proteolytic pathway, mediates diverse cellular processes, including endocytosis and signal transduction, which may be involved in the entry of virus. Here, we showed that the proteasome inhibitors, MG132 and lactacystin, impaired the productive entry of JEV by effectively interfering with viral intracellular trafficking at the stage between crossing cell membrane and the initial translation of the viral genome after uncoating...
November 2016: Virology
Sajjad Molavi Pordanjani, Seyed Jalal Hosseinimehr
It is well documented that ionizing radiation (IR) activates the transcription factor (NF-κB) which is a trigger for resistance cancer cells to treatment. It is involved in activation of pro-survival signaling pathways and resulting in cancer development and progression. In unstimulated condition, NF-κB is sequestered in cytoplasm but after the cell exposure to IR, proteasomal degradation of IκB flowing phosphorylation via IKK, leads to aberrantly NF-κB activation and nuclear translocation. Therefore, interruption in IκB degradation, proteasome action, IKK phosphorylation and NF-κB nuclear translocation provide robust strategies for inhibiting adverse effect of IR induced NF-κB...
August 24, 2016: Current Medicinal Chemistry
Won-Hee Song, Young-Joo Yi, Miriam Sutovsky, Stuart Meyers, Peter Sutovsky
Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
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