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Ramya Ganesan, Karen M Henkels, Lucile E Wrenshall, Yasunori Kanaho, Gilbert Di Paolo, Michael A Frohman, Julian Gomez-Cambronero
The uptake of cholesterol carried by low-density lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into "foam cells," an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow-derived macrophages from genetically PLD deficient mice, we demonstrate that PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg-Ox-LDL), which was phenocopied with a PLD2-selective inhibitor...
April 14, 2018: Journal of Leukocyte Biology
Yulin Tian, Qing Lin
Three γ-heteroatom-substituted N-methylpyrroletetrazole-lysines (mPyTXKs) were synthesized and subsequently incorporated into proteins site-specifically via genetic code expansion. The γ-seleno-substituted derivative, mPyTSeK, showed excellent incorporation efficiency in Escherichia coli and allowed site-selective photo-cross-linking of the GST dimer. Furthermore, the mPyTSeK-cross-linked GST dimer can be cleaved under mild oxidative conditions. The incorporation of mPyTXKs into proteins in mammalian cells was also demonstrated...
April 13, 2018: Chemical Communications: Chem Comm
Fang Yang, Meng Wang, Baoyun Zhang, Wei Xiang, Ke Zhang, Mingxin Chu, Pingqing Wang
BACKGROUND: Progesterone plays an essential role in mammalian ovulation. Although much is known about this process, the gene networks involved in ovulation have yet to be established. When analyze the mechanisms of ovulation, we often need to determine key genes or pathways to investigate the reproduction features. However, traditional experimental methods have a number of limitations. RESULTS: Data, in this study, were acquired from GSE41836 and GSE54584 which provided different samples...
April 3, 2018: BMC Systems Biology
Lan Yang, Xiliang Wang, Juan Xu, Ya Wen, Manqiao Zhang, Jingxiao Lu, Rongfu Wang, Xiaojuan Sun
Hepatocellular carcinoma is the most frequent primary liver cancer worldwide. The use of antioxidants as cancer prevention and treatment agents has become a focus of research in recent years due to their limited adverse effects. Alpha lipoic acid (ɑ-LA) is synthesized in the liver and is considered a naturally occurring antioxidant. In this study, a total of 4446 differentially expressed genes (2097 down-regulated and 2349 up-regulated) were identified via RNA-Seq in HepG2 cells after exposure to α-LA for 24 hrs...
March 25, 2018: Journal of Cellular and Molecular Medicine
Malak Haidar, Zineb Rchiad, Hifzur Rahman Ansari, Fathia Ben-Rached, Shahin Tajeri, Perle Latre De Late, Gordon Langsley, Arnab Pain
Theileria annulata is an apicomplexan parasite that infects and transforms bovine macrophages that disseminate throughout the animal causing a leukaemia-like disease called tropical theileriosis. Using deep RNAseq of T. annulata-infected B cells and macrophages we identify a set of microRNAs induced by infection, whose expression diminishes upon loss of the hyper-disseminating phenotype of virulent transformed macrophages. We describe how infection-induced upregulation of miR-126-5p ablates JIP-2 expression to release cytosolic JNK to translocate to the nucleus and trans-activate AP-1-driven transcription of mmp9 to promote tumour dissemination...
March 23, 2018: PLoS Pathogens
Jingjiang Pi, Jie Liu, Tao Zhuang, Lin Zhang, Huimin Sun, Xiaoli Chen, Qian Zhao, Yashu Kuang, Sheng Peng, Xiaohui Zhou, Zuoren Yu, Ting Tao, Brian Tomlinson, Paul Chan, Ying Tian, Huimin Fan, Zhongmin Liu, Xiangjian Zheng, Edward Morrisey, Yuzhen Zhang
Rationale: Angiogenesis is critical for embryonic development and microRNAs fine-tune this process, but the underlying mechanisms remain incompletely understood. Methods: Endothelial cell (EC) specific miR302-367 line was used as gain-of-function and anti-miRs as loss-of-function models to investigate the effects of miR302-367 on developmental angiogenesis with embryonic hindbrain vasculature as an in vivo model and fibrin gel beads and tube formation assay as in vitro models. Cell migration was evaluated by Boyden chamber and scratch wound healing assay and cell proliferation by cell count, MTT assay, Ki67 immunostaining and PI cell cycle analysis...
2018: Theranostics
Xavier Thomas, Etienne Paubelle
No abstract text is available yet for this article.
April 2018: Lancet Haematology
Maro Ohanian, Ana Tari Ashizawa, Guillermo Garcia-Manero, Naveen Pemmaraju, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gautam Borthakur, Michael Andreeff, Marina Konopleva, Miranda Lim, Sherry Pierce, Susan O'Brien, Yesid Alvarado, Srdan Verstovsek, William Wierda, Hagop Kantarjian, Jorge Cortes
BACKGROUND: Activating mutations of tyrosine kinases are common in leukaemias. Oncogenic tyrosine kinases use the growth factor receptor-bound protein 2 (Grb2) for signal transduction, leading to activation of mitogen-activated protein kinase (MAPK) 1 and MAPK3 (ERK2 and ERK1). We hypothesised that inhibition of Grb2 would suppress ERK1 and ERK2 activation and inhibit leukaemia progression. To inhibit Grb2, a liposome-incorporated antisense oligodeoxynucleotide that blocks Grb2 protein expression, BP1001, was developed...
April 2018: Lancet Haematology
Fumihiko Hakuno, Shin-Ichiro Takahashi
Insulin-like growth factors (IGFs) bind specifically to the IGF-I receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src-homology collagen (Shc). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain containing signaling molecules...
March 13, 2018: Journal of Molecular Endocrinology
Hector R Mendez-Gomez, Jasbir Singh, Craig Meyers, Weijun Chen, Oleg S Gorbatyuk, Nicholas Muzyczka
Phospholipase D2 (PLD2), an enzyme involved in vesicle trafficking and membrane signaling, interacts with α-synuclein, a protein known to contribute in the development of Parkinson disease. We previously reported that PLD2 overexpression in rat substantia nigra pars compacta (SNc) causes a rapid neurodegeneration of dopamine neurons, and that α-synuclein suppresses PLD2-induced nigral degeneration (Gorbatyuk et al., 2010). Here, we report that PLD2 toxicity is due to its lipase activity. Overexpression of a catalytically inactive mutant (K758R) of PLD2 prevents the loss of dopaminergic neurons in the SNc and does not show signs of toxicity after 10 weeks of overexpression...
March 8, 2018: Neuroscience
Kanika Vanshylla, Caren Bartsch, Christoffer Hitzing, Laura Krümpelmann, Jürgen Wienands, Niklas Engels
The B cell antigen receptor (BCR) employs enzymatically inactive adaptor proteins to facilitate activation of intracellular signaling pathways. In animal model systems, adaptor proteins of the growth factor receptor-bound 2 (Grb2) family have been shown to serve critical functions in lymphocytes. However, the roles of Grb2 and the Grb2-related adaptor protein (GRAP) in human B lymphocytes remain unclear. Using TALEN-mediated gene targeting, we show that in human B cells Grb2 and GRAP amplify signaling by the immunoglobulin tail tyrosine (ITT) motif of mIgE-containing BCRs and furthermore connect immunoreceptor tyrosine-based activation motif (ITAM) signaling to activation of the Ras-controlled Erk MAP kinase pathway...
March 9, 2018: Scientific Reports
Michio Hiroshima, Chan-Gi Pack, Kazunari Kaizu, Koichi Takahashi, Masahiro Ueda, Yasushi Sako
Cell signaling depends on spatiotemporally regulated molecular interactions. Although the movements of signaling proteins have been analyzed with various technologies, how spatial dynamics influence the molecular interactions that transduce signals is unclear. Here, we developed a single-molecule method to analyze the spatiotemporal coupling between motility, clustering, and signaling. The analysis was performed with the epidermal growth factor receptor (EGFR), which triggers signaling through its dimerization and phosphorylation after association with EGF...
March 2, 2018: Journal of Molecular Biology
Min Cheng, Yuqiang Niu, Jingjing Fan, Xiaojing Chi, Xiuying Liu, Wei Yang
Induction of interferons (IFNs) is a central event of antiviral innate immunity. As crucial post-transcriptional regulators, microRNAs (miRNAs) are important for IFN-mediated host defense. Although screening has indicated a substantial number of miRNAs to be differentially expressed after IFN stimulation, the detailed mechanisms of these miRNAs in the antiviral response is underexplored and of great significance. Here, we show that hsa-miR-1225-3p is specifically downregulated by type I IFN through IFN/JAK/STAT signaling pathway...
March 1, 2018: Journal of Biological Chemistry
Jeonghee Cho, Sujin Kim, Jinyan Du, Matthew Meyerson
Aberrant activation of cancer-derived mutants of the epidermal growth factor receptor (EGFR) is closely associated with cancer pathogenesis and is thought to be mediated through multiple tyrosine phosphorylations within the C-terminal domain. Here, we examined the consequences of the loss of these C-terminal phosphorylation sites on cellular transformation in the context of lung-cancer derived L858R, exon 19 deletion and exon 20 insertion mutant EGFR. Oncogenic EGFR mutants with substitution of the 10 potential C-terminal tyrosine autophosphorylation sites for phenylalanine (CYF10) were still able to promote anchorage-independent growth in soft agar at levels comparable to the parental L858R or exon19 deletion or exon 20 insertion mutants with intact autophosphorylation sites...
February 21, 2018: International Journal of Cancer. Journal International du Cancer
Jacqueline R Ha, Ryuhjin Ahn, Harvey W Smith, Valerie Sabourin, Steven Hėbert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia Kleinman, William J Muller, Josie Ursini-Siegel
The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA (SHC1) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTKs), such as ErbB2, engage the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling...
February 16, 2018: Molecular Cancer Research: MCR
Jennifer E Howes, Denis T Akan, Michael C Burns, Olivia W Rossanese, Alex G Waterson, Stephen W Fesik
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms...
February 13, 2018: Molecular Cancer Therapeutics
Huan Wang, Hui He, Hongmei Meng, Yang Cui, Wenbo Wang
To investigate the association between the expression of growth factor receptor binding protein 2-associated binding protein 2 (Gab2) in human osteosarcoma as well as the effects of Gab2 on invasion and metastasis, human MG-63 osteosarcoma cells were transfected with small interfering (si)RNA plasmid. Gab2 protein and mRNA expression levels were detected using western blotting and reverse transcription-polymerase chain reaction, respectively. The cell migration and invasion abilities were detected using in vitro chemotaxis and invasion assays, respectively, following siRNA vector expression...
January 2018: Oncology Letters
Danni Chen, Wengong Si, Jiaying Shen, Chengyong Du, Weiyang Lou, Chang Bao, Huilin Zheng, Jie Pan, Guansheng Zhong, Liang Xu, Peifen Fu, Weimin Fan
Drug resistance remains a major problem in the treatment of conventional chemotherapeutic agents in breast cancers. Owing to heterogeneity and complexity of chemoresistance mechanisms, most efforts that focus on a single pathway were unsuccessful, and exploring novel personalized therapeutics becomes urgent. By a system approach, we identified that microRNA-27b-3p (miR-27b), a miRNA deleted in breast cancer tissues and cell lines, has a master role in sensitizing breast cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo...
February 7, 2018: Cell Death & Disease
Tamica N Collins, Yingyu Mao, Hongge Li, Michael Bouaziz, Angela Hong, Gen-Sheng Feng, Fen Wang, Lawrence A Quilliam, Lin Chen, Taeju Park, Tom Curran, Xin Zhang
Specific cell shapes are fundamental to the organization and function of multicellular organisms. Fibroblast Growth Factor (FGF) signaling induces the elongation of lens fiber cells during vertebrate lens development. Nonetheless, exactly how this extracellular FGF signal is transmitted to the cytoskeletal network has previously not been determined. Here, we show that the Crk family of adaptor proteins, Crk and Crkl, are required for mouse lens morphogenesis but not differentiation. Genetic ablation and epistasis experiments demonstrated that Crk and Crkl play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation...
January 23, 2018: ELife
Ismini Lasithiotaki, Eliza Tsitoura, Anastasios Koutsopoulos, Eleni Lagoudaki, Chara Koutoulaki, George Pitsidianakis, Demetrios A Spandidos, Nikolaos M Siafakas, George Sourvinos, Katerina M Antoniou
Merkel Cell Polyoma Virus (MCPyV) infection has been associated with non-small cell lung cancer (NSCLC). Viruses can manipulate cellular miRNAs or have a profound impact on cellular miRNA expression to control host regulatory pathways. In this study, we evaluated the expression profiles of cancer-associated and virally affected host microRNAs miR-21, miR-145, miR-146a, miR-155, miR-302c, miR-367 and miR-376c in a series of NSCLC tissue samples as well as in samples from "healthy" sites, distant from the tumour region that were either positive or negative for MCPyV DNA...
December 22, 2017: Oncotarget
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