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https://www.readbyqxmd.com/read/28436422/rational-design-of-non-resistant-targeted-cancer-therapies
#1
Francisco Martínez-Jiménez, John P Overington, Bissan Al-Lazikani, Marc A Marti-Renom
Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28420753/the-kinase-tpl2-activates-erk-and-p38-signaling-to-promote-neutrophilic-inflammation
#2
Kate Senger, Victoria C Pham, Eugene Varfolomeev, Jason A Hackney, Cesar A Corzo, Jenna Collier, Vivian W C Lau, Zhiyu Huang, Kajal Hamidzhadeh, Patrick Caplazi, Ivan Peng, A Francesca Setiadi, Ross Francis, Andres Paler-Martinez, Youngsu C Kwon, Vladimir Ramirez-Carrozzi, Yonglian Sun, Patricia W Grigg, Merone Roose-Girma, Surinder Jeet, Kai H Barck, Anna Pham, Naruhisa Ota, Connie Ha, Jeremy Stinson, Joseph Guillory, Lucinda Tam, Zora Modrusan, Claire Emson, Brent S McKenzie, Michael J Townsend, Richard A D Carano, Søren Warming, Domagoj Vucic, Jason DeVoss, Wyne P Lee, Jennie R Lill, Ali A Zarrin
Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal-regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in macrophages stimulated through the interleukin-1 receptor (IL-1R), Toll-like receptors (TLRs), or the tumor necrosis factor receptor (TNFR). We describe a conserved and critical role for TPL2 in mediating the effector functions of neutrophils through the activation of the p38 MAPK signaling pathway...
April 18, 2017: Science Signaling
https://www.readbyqxmd.com/read/28418405/adenosine-a2a-receptor-and-erk-driven-impulsivity-potentiates-hippocampal-neuroblast-proliferation
#3
A Oliveros, C H Cho, A Cui, S Choi, D Lindberg, D Hinton, M-H Jang, D-S Choi
Dampened adenosine A2A receptor (A2AR) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A2AR to the control of impulsive reward seeking remains unknown. Using mice that were exposed to differential reward of low rate (DRL) schedules during Pavlovian-conditioning, second-order schedule discrimination, and the 5-choice serial reaction time task (5-CSRTT), we demonstrate that deficits of A2AR function promote impulsive responses. Antagonism of the A2AR lowered ERK1 and ERK2 phosphorylation in the dorsal hippocampus (dHip) and potentiated impulsivity during Pavlovian-conditioning and the 5-CSRTT...
April 18, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28413458/mir-9-functions-as-a-tumor-inhibitor-of-cell-proliferation-in-epithelial-ovarian-cancer-through-targeting-the-sdf-1-cxcr4-pathway
#4
Lin He, Li Zhang, Mengfei Wang, Wenrong Wang
The current study aimed to investigate the potential role of miR-9 in the inhibition of ovarian cancer progression through the stromal cell-derived factor-1 (SDF-1)/ C-X-C chemokine receptor type 4 (CXCR4) pathway and to provide a theoretical basis for the diagnosis and treatment of ovarian cancer. Human ovarian cancer OVCAR-3 cells were transfected with miR-9 short hairpin RNA (shRNA). The effect of miR-9 on the mRNA expression levels of CXCR4 were analyzed using reverse transcription-quantitative polymerase chain reaction...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28406179/genetic-visualization-of-protein-interactions-harnessing-liquid-phase-transitions
#5
Taku Watanabe, Tatsuya Seki, Takashi Fukano, Asako Sakaue-Sawano, Satoshi Karasawa, Misaki Kubota, Hiroshi Kurokawa, Ken Inoue, Junichi Akatsuka, Atsushi Miyawaki
Protein-protein interactions (PPIs) are essential components of cellular function. Current fluorescence-based technologies to measure PPIs have limited dynamic range and quantitative reproducibility. Here, we describe a genetically-encoded PPI visualization system that harnesses the dynamics of condensed liquid-phase transitions to analyze protein interactions in living cells. The fluorescent protein Azami-Green and p62-PB1 domain when fused to PPI partners triggered a rapid concatenation/oligomerization process that drove the condensation of liquid-phase droplets for real-time analysis of the interaction with unlimited dynamic range in the fluorescence signal...
April 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28400509/oncogene-kras-activates-fatty-acid-synthase-resulting-in-specific-erk-and-lipid-signatures-associated-with-lung-adenocarcinoma
#6
Arvin M Gouw, Livia S Eberlin, Katherine Margulis, Delaney K Sullivan, Georgia G Toal, Ling Tong, Richard N Zare, Dean W Felsher
KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28396345/the-ww-domain-of-the-scaffolding-protein-iqgap1-is-neither-necessary-nor-sufficient-for-binding-to-the-mapks-erk1-and-erk2
#7
A Jane Bardwell, Leonila Lagunes, Ronak Zebarjedi, Lee Bardwell
Mitogen-activated protein kinase (MAPK) scaffold proteins, such as IQ motif containing GTPase activating protein 1 (IQGAP1), are promising targets for novel therapies against cancer and other diseases. Such approaches require accurate information about which domains on the scaffold protein bind to the kinases in the MAPK cascade. Results from previous studies have suggested that the WW domain of IQGAP1 binds to the cancer-associated MAPKs ERK1 and ERK2, and that this domain might thus offer a new tool to selectively inhibit MAPK activation in cancer cells...
April 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28393304/lanthanum-chloride-precipitation-based-toxicoproteomic-analysis-of-3-monochloropropane-1-2-diol-toxicity-in-rat-kidney-reveals-involvement-of-extracellular-signal-regulated-kinase-2
#8
Axel Oberemm, Monique Braun, Stefanie Sawada, Mario Pink, Falko Frenzel, Christel Rozycki, Christine Meckert, Elke Zabinsky, Albert Braeuning, Alfonso Lampen
The heat-induced food contaminant 3-monochloropropane-1,2-diol (3-MCPD) and its fatty acid esters exert nephrotoxicity in rodents. Previous studies including a non-targeted toxicoproteomics approach using samples from a 28-day oral toxicity study in rats with 10 mg/kg body weight (b.w.) of 3-MCPD, an equimolar dose of 53 mg/kg b.w. 3-MCPD dipalmitate and a lower dose of 13.3 mg/kg b.w. of 3-MCPD dipalmitate, revealed substance-induced alterations in metabolic pathways, especially for glycolysis and energy metabolism...
April 9, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28380434/inos-derived-nitric-oxide-promotes-glycolysis-by-inducing-pyruvate-kinase-m2-nuclear-translocation-in-ovarian-cancer
#9
Linlin Li, Lingqun Zhu, Bingtao Hao, Wenwen Gao, Qianli Wang, Keyi Li, Meng Wang, Mengqiu Huang, Zhengjun Liu, Qiaohong Yang, Xiqing Li, Zhuo Zhong, Wenhua Huang, Guanghui Xiao, Yang Xu, Kaitai Yao, Qiuzhen Liu
Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (≤ 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (≥ 500 nM) inhibits it...
March 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28359799/paxillin-and-embryonic-polyadenylation-binding-protein-epabp-engage-to-regulate-androgen-dependent-xenopus-laevis-oocyte-maturation-a-model-of-kinase-dependent-regulation-of-protein-expression
#10
Susanne U Miedlich, Manisha Taya, Melissa Rasar Young, Stephen R Hammes
Steroid-triggered Xenopus laevis oocyte maturation is an elegant physiologic model of nongenomic steroid signaling, as it proceeds completely independent of transcription. We previously demonstrated that androgens are the main physiologic stimulator of oocyte maturation in Xenopus oocytes, and that the adaptor protein paxillin plays a crucial role in mediating this process through a positive feedback loop in which paxillin first enhances Mos protein translation, ensued by Erk2 activation and Erk-dependent phosphorylation of paxillin on serine residues...
March 28, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28359774/trpv4-regulates-insulin-mrna-expression-and-ins-1e-cell-death-via-erk1-2-and-no-dependent-mechanisms
#11
M Billert, M Skrzypski, M Sassek, D Szczepankiewicz, T Wojciechowicz, S Mergler, M Z Strowski, K W Nowak
TRPV4 is a Ca(2+)-permeable, nonselective cation channel. Recently, TRPV4 was implicated in controlling peripheral insulin sensitivity, insulin secretion and apoptosis of pancreatic beta cells. Here, we characterize the role and potential mechanisms of TRPV4 in regulating insulin mRNA expression and cell death in insulin producing INS-1E cells and rat pancreatic islets. TRPV4 protein production was downregulated by siRNA. Intracellular calcium level was measured using Fluo-3 AM. Gene expression was studied by real-time PCR...
March 27, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28333195/genome-wide-genetic-analyses-highlight-mitogen-activated-protein-kinase-mapk-signaling-in-the-pathogenesis-of-endometriosis
#12
Outi Uimari, Nilufer Rahmioglu, Dale R Nyholt, Katy Vincent, Stacey A Missmer, Christian Becker, Andrew P Morris, Grant W Montgomery, Krina T Zondervan
STUDY QUESTION: Do genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis? SUMMARY ANSWER: GWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways...
April 1, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28331335/microrna-543-suppresses-breast-cancer-cell-proliferation-blocks-cell-cycle-and-induces-cell-apoptosis-via-direct-targeting-of-erk-mapk
#13
Po Chen, Wentao Xu, Yi Luo, Yi Zhang, Yi He, Shuo Yang, Zhijun Yuan
BACKGROUND: Breast cancer affects millions of people with a high mortality rate throughout the world; microRNA 543 (miR-543) has been reported to suppress progression in some kinds of cancers, but has not been reported in breast cancer. Thus, the purpose of this study is to investigate the function of miR-543 in breast cancer cells. METHODS: Two cell lines, MCF-7 and MDA-MB-231, were selected to be the research objects; the miR-543 overexpression and knockdown models were established in the study by transforming miR-543 mimics and miR-543 inhibitor...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28322346/resveratrol-mitigates-lipopolysaccharide-mediated-acute-inflammation-in-rats-by-inhibiting-the-tlr4-nf-%C3%AE%C2%BAbp65-mapks-signaling-cascade
#14
Guangxi Wang, Zhiqiang Hu, Qiuting Fu, Xu Song, Qiankun Cui, Renyong Jia, Yuanfeng Zou, Changliang He, Lixia Li, Zhongqiong Yin
Resveratrol (RSV) is a natural compound exhibiting anti-inflammatory effect, but the anti-inflammatory mechanism has not been fully understood. This study is aimed to evaluate the anti-inflammatory activity and mechanism of RSV in lipopolysaccharides-induced rats' model. The visceral wet/dry weight ratios and the changes of hematologic and biochemical indices indicated that LPS- stimulation mainly caused damages to liver and lung, while pretreatment with RSV could alleviate the lesions. The cytokine assays showed that RSV could markedly decrease the production of proinflammatory mediators and cytokines (IL-1, IL-1β, IL-6, NO, iNOS and COX-2), and increase the expression of anti-inflammatory mediator (IL-10)...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302472/erk1-and-erk2-activation-modulates-diet-induced-obesity-in-mice
#15
Amira Sayed Khan, Selvakumar Subramaniam, Gado Dramane, Douadi Khelifi, Naim Akhtar Khan
Obesity is a worldwide problem, and dietary lipids play an important role in its pathogenesis. Recently, Erk1 knock-out (ERK1(-/-)) mice have been shown to exhibit low preference for dietary fatty acids. Hence, we maintained Erk1(-/-) mice on a high-fat diet (HFD) to assess the implication of this mitogen-activated protein (MAP) kinase in obesity. The Erk1(-/-) mice, fed the HFD, were more obese than wild-type (WT) animals, fed the same diet. Erk1(-/-) obese mice gained more fat and liver mass than WT obese animals...
March 13, 2017: Biochimie
https://www.readbyqxmd.com/read/28274314/-inhibitory-effect-of-magnesium-cantharidate-on-human-hepatoma-smmc-7721-cell-proliferation-by-blocking-mapk-signaling-pathway
#16
Yun Liu, Xiaofei Li, Qianqian Zou, Liu Liu, Xinting Zhu, Qi Jia, Lingjun Wang, Rong Yan
Objective To investigate the anticancer mechanism of magnesium cantharidate by observing its effect on the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma SMMC-7721 cells. Methods The protein phosphatase 2A (PP2A) activity detection kit was used to detect the effects of magnesium cantharidate and okadaic acid (OA) on PP2A activity. After the treatment of SMMC-7721 cells with magnesium cantharidate and/or OA, mRNA levels of extracellular signal-regulated kinase 1 (ERK1), ERK2, p38MAPK, c-Jun N-terminal kinase 1 (JNK1) and JNK2 were detected by real-time quantitative PCR, and the protein expression levels and protein phosphorylation of ERK1, ERK2, p38 MAPK and JNK were determined by Western blotting...
March 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28274095/sphingosylphosphorylcholine-induces-thrombospondin-1-secretion-in-mcf10a-cells-via-erk2
#17
June Hee Kang, Hyun Ji Kim, Mi Kyung Park, Chang Hoon Lee
Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and Ca²⁺ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia...
March 10, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28262736/knockdown-of-the-mapk-p38-pathway-increases-the-susceptibility-of-chilo-suppressalis-larvae-to-bacillus-thuringiensis-cry1ca-toxin
#18
Lin Qiu, Jinxing Fan, Lang Liu, Boyao Zhang, Xiaoping Wang, Chaoliang Lei, Yongjun Lin, Weihua Ma
The bacterium Bacillus thuringiensis (Bt) produces a wide range of toxins that are effective against a number of insect pests. Identifying the mechanisms responsible for resistance to Bt toxin will improve both our ability to control important insect pests and our understanding of bacterial toxicology. In this study, we investigated the role of MAPK pathways in resistance against Cry1Ca toxin in Chilo suppressalis, an important lepidopteran pest of rice crops. We first cloned the full-length of C. suppressalis mitogen-activated protein kinase (MAPK) p38, ERK1, and ERK2, and a partial sequence of JNK (hereafter Csp38, CsERK1, CsERK2 and CsJNK)...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28260027/pstat5-and-erk-exhibit-different-expression-in-myeloproliferative-neoplasms
#19
Ewa Wiśniewska-Chudy, Łukasz Szylberg, Grzegorz Dworacki, Ewa Mizera-Nyczak, Andrzej Marszałek
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic progenitor cell disorders characterized by the proliferation of one or more hematopoietic lineages. The classical MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) entities. These disorders are characterized by bone marrow morphology typical for each disease, and by the presence of JAK2V617F mutation in the marrow and blood. However, JAK2V617F cannot account for the phenotypic heterogeneity of MPNs because approximately half of all cases of ET and PMF show no evidence of this molecular marker...
April 2017: Oncology Reports
https://www.readbyqxmd.com/read/28230313/crosstalk-between-smad2-3-and-specific-isoforms-of-erk-in-tgf-%C3%AE-1-induced-timp-3-expression-in-rat-chondrocytes
#20
Yanhui Zhu, Jianhua Gu, Tong Zhu, Chen Jin, Xiaopeng Hu, Xiang Wang
This study investigated the roles of ERK1 and ERK2 in transforming growth factor-β1 (TGF-β1)-induced tissue inhibitor of metalloproteinases-3 (TIMP-3) expression in rat chondrocytes, and the specific roles of ERK1 and ERK2 in crosstalk with Smad2/3 were investigated to demonstrate the molecular mechanism of ERK1/2 regulation of TGF-β1 signalling. To examine the interaction of specific isoforms of ERK and the Smad2/3 signalling pathway, chondrocytes were infected with LV expressing either ERK1 or ERK2 siRNA and stimulated with or without TGF-β1...
February 23, 2017: Journal of Cellular and Molecular Medicine
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