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Roi Isaac, Ido Goldstein, Noa Furth, Neta Zilber, Sarina Streim, Sigalit Boura-Halfon, Eytan Elhanany, Varda Rotter, Moshe Oren, Yehiel Zick
Earlier reported small interfering RNA (siRNA) high-throughput screens, identified seven-transmembrane superfamily member 3 (TM7SF3) as a novel inhibitor of pancreatic β-cell death. Here we show that TM7SF3 maintains protein homeostasis and promotes cell survival through attenuation of ER stress. Overexpression of TM7SF3 inhibits caspase 3/7 activation. In contrast, siRNA-mediated silencing of TM7SF3 accelerates ER stress and activation of the unfolded protein response (UPR). This involves inhibitory phosphorylation of eukaryotic translation initiation factor 2α activity and increased expression of activating transcription factor-3 (ATF3), ATF4 and C/EBP homologous protein, followed by induction of apoptosis...
October 14, 2016: Cell Death and Differentiation
Huimin Gao, Zhaoyu Chen, Yongmei Fu, Xiaoyan Yang, Ruihui Weng, Rui Wang, Jianjun Lu, Mengqiu Pan, Kunlin Jin, Chris McElroy, Beisha Tang, Ying Xia, Qing Wang
The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77...
September 29, 2016: Scientific Reports
Jair Bar, Mohamed S Hasim, Tabassom Baghai, Nima Niknejad, Theodore J Perkins, David J Stewart, Harmanjatinder S Sekhon, Patrick J Villeneuve, Jim Dimitroulakos
Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6)...
September 2016: Neoplasia: An International Journal for Oncology Research
Christine Altmann, Stefanie Hardt, Caroline Fischer, Juliana Heidler, Hee-Young Lim, Annett Häussler, Boris Albuquerque, Béla Zimmer, Christine Möser, Christian Behrends, Frank Koentgen, Ilka Wittig, Mirko H H Schmidt, Albrecht M Clement, Thomas Deller, Irmgard Tegeder
Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis...
September 11, 2016: Neurobiology of Disease
Sophie E van der Krieken, Herman E Popeijus, Maurice Konings, Stefan P J Dullens, Ronald P Mensink, Jogchum Plat
Increasing apolipoproteinA-I (apoA-I) production may be anti-atherogenic. Thus, there is a need to identify regulatory factors involved. Transcription of apoA-I involves peroxisome-proliferator-activated-receptor-alpha (PPARα) activation, but endoplasmic reticulum (ER) -stress and inflammation also influence apoA-I production. To unravel why PPARα agonist GW7647 increased apoA-I production compared to PPARα agonist fenofibric acid (FeAc) in human hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (CaCo-2) cells, gene expression profiles were compared...
September 12, 2016: Journal of Cellular Biochemistry
Jian Li, Zishan Yang, Zhiuguo Chen, Yonghua Bao, Huijuan Zhang, Xinhui Fang, Wancai Yang
Esophageal cancer is one of the most prevalent forms of cancer and has a particularly high mortality rate due to early metastasis; however, the underlying mechanisms of its formation and progression remain unclear. The present study performed immunohistochemical analysis and observed that the expression of activating transcription factor 3 (ATF3) was reduced in esophageal squamous cell carcinoma (ESCC) in comparison with non-tumor adjacent tissues. By contrast, inhibitor of DNA binding 1 (ID1) was overexpressed in ESCC tissues, demonstrating an inverse correlation with ATF3 (P<0...
September 2016: Oncology Letters
Nancy Lévesque, Karen E Christensen, Lauren Van Der Kraak, Ana F Best, Liyuan Deng, Don Caldwell, Amanda J MacFarlane, Nicole Beauchemin, Rima Rozen
The common R653Q variant (∼20% homozygosity in Caucasians) in the synthetase domain of the folate-metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1-synthetase deficiency (Mthfd1S(+/-) ) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S(+/-) mice...
September 6, 2016: Molecular Carcinogenesis
Marc Clément, Gemma Basatemur, Leanne Masters, Lauren Baker, Patrick Bruneval, Takao Iwawaki, Manfred Kneilling, Sho Yamasaki, Jane Goodall, Ziad Mallat
BACKGROUND: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation...
October 4, 2016: Circulation
Manuel Gey, Renate Wanner, Corinna Schilling, Maria T Pedro, Daniela Sinske, Bernd Knöll
Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce 'effector' RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased...
August 2016: Open Biology
Yu-Feng Liu, Jian-Yang Wei, Mao-Hua Shi, Hua Jiang, Jie Zhou
: Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GCs-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cell (MDSC) in the liver of animals, the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3) / S100A9 signaling plays an important role...
August 29, 2016: Journal of Biological Chemistry
Chen Li, Yu Zhou, Anastacia Loberg, Stanley M Tahara, Punam Malik, Vijay K Kalra
Previous studies showed higher levels of placenta growth factor (PlGF) correlated with increased plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor, in sickle cell disease (SCD). PlGF mediated transcription of ET-1 occurred by activation of HIF-1α, and post-transcriptionally by miR-199a2, which targets the 3' -UTR of HIF-1α mRNA. However, relatively less is known how PlGF represses the expression of miR-199a2 located in the DNM3os transcription unit. Here we show PlGF induces the expression of ATF3, which in association with accessory proteins (JDP2, ATF2 and HDAC6), as determined by proteomic analysis, bind to the DNM3os promoter...
August 29, 2016: Molecular and Cellular Biology
Yuzhi Jia, Hsiang-Chun Chang, Matthew J Schipma, Jing Liu, Varsha Shete, Ning Liu, Tatsuya Sato, Edward B Thorp, Philip M Barger, Yi-Jun Zhu, Navin Viswakarma, Yashpal S Kanwar, Hossein Ardehali, Bayar Thimmapaya, Janardan K Reddy
Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure...
2016: PloS One
Shuichi Miyamoto, Junichi Nakamura, Seiji Ohtori, Sumihisa Orita, Takayuki Nakajima, Takanori Omae, Shigeo Hagiwara, Makoto Takazawa, Miyako Suzuki, Takane Suzuki, Kazuhisa Takahashi
This principal aim of this study was to clarify the time course of pain-related behavior and pain-related sensory innervation in a rat model of hip osteoarthritis (OA) induced by intra-articular injection of mono-iodoacetate (MIA). Using sixty six-week-old male Sprague Dawley rats, 25 μl of sterile saline of 1% Fluoro-Gold solution (FG) (control group; n = 30) and 25 μl of sterile saline of 1% FG with 2 mg of MIA (MIA group; n = 30) was injected into the right hip joints. Gait function was evaluated using a CatWalk system after 7, 14, 28, 42, and 56 days (n = 5, respectively)...
August 20, 2016: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Carolyne K Smith, Nickie L Seto, Anuradha Vivekanandan-Giri, Wenmin Yuan, Martin P Playford, Zerai Manna, Sarfaraz A Hasni, Rui Kuai, Nehal N Mehta, Anna Schwendeman, Subramaniam Pennathur, Mariana J Kaplan
OBJECTIVES: Recent evidence indicates that high-density lipoprotein (HDL) exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to downregulation of toll-like receptor (TLR)-induced inflammatory responses. Systemic lupus erythematosus (SLE) is associated with increased cardiovascular disease risk not explained by the Framingham risk score. Recent studies have indicated oxidised HDL as a possible contributor. We investigated the potential mechanisms by which lupus HDL may lose its anti-inflammatory effects and promote immune dysregulation...
August 19, 2016: Annals of the Rheumatic Diseases
Zixuan Liu, Qiong Shi, Xiufang Song, Yuxin Wang, Yawen Wang, Erqun Song, Yang Song
Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ...
September 19, 2016: Chemical Research in Toxicology
(no author information available yet)
No abstract text is available yet for this article.
August 1, 2016: Cancer Research
Kazuya Fukasawa, Gyujin Park, Takashi Iezaki, Tetsuhiro Horie, Takashi Kanayama, Kakeru Ozaki, Yuki Onishi, Yoshifumi Takahata, Yukio Yoneda, Takeshi Takarada, Shigetaka Kitajima, Jean Vacher, Eiichi Hinoi
Bone homeostasis is maintained by the sophisticated coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-κB (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition...
2016: Scientific Reports
Silke Leiting, Sebastian Seidl, Adoracion Martinez-Palacian, Lars Muhl, Sandip M Kanse
Deletion of the Habp2 gene encoding Factor VII-activating protease (FSAP) increases liver fibrosis in mice. A single nucleotide polymorphism (G534E) in HABP2 leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. Liver fibrosis is associated with a decrease in FSAP expression but, to date, nothing is known about how this might be regulated. Primary mouse hepatocytes or the hepatocyte cell line, AML12, were treated with different factors, and expression of FSAP was determined...
September 30, 2016: Journal of Biological Chemistry
Qing Zhao, Xiaoyan Yang, Dingfang Cai, Ling Ye, Yuqing Hou, Lijun Zhang, Jiwei Cheng, Yuan Shen, Kaizhe Wang, Yu Bai
Echinacoside (ECH) is protective in a mouse model of Parkinson's disease (PD) induced by 1-methyl-4-phenylpyridinium ion (MPP(+)). To investigate the mechanisms involved, SH-SY5Y neuroblastoma cells were treated with MPP(+) or a combination of MPP(+) and ECH, and the expression of ATF3 (activating transcription factor 3), CHOP (C/EBP-homologous protein), SCNA (synuclein alpha), and GDNF (glial cell line-derived neurotrophic factor) was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP(+)-induced reactive oxygen species (ROS)...
August 2016: Neuroscience Bulletin
M Jargosch, S Kröger, E Gralinska, U Klotz, Z Fang, W Chen, U Leser, J Selbig, D Groth, R Baumgrass
Data integration has become a useful strategy for uncovering new insights into complex biological networks. We studied whether this approach can help to delineate the signal transducer and activator of transcription 6 (STAT6)-mediated transcriptional network driving T helper (Th) 2 cell fate decisions. To this end, we performed an integrative analysis of publicly available RNA-seq data of Stat6-knockout mouse studies together with STAT6 ChIP-seq data and our own gene expression time series data during Th2 cell differentiation...
2016: Genetics and Molecular Research: GMR
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