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https://www.readbyqxmd.com/read/28346426/mrl-proteins-cooperate-with-activated-ras-in-glia-to-drive-distinct-oncogenic-outcomes
#1
E Taylor, N Alqadri, L Dodgson, D Mason, E Lyulcheva, G Messina, D Bennett
The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of Ras(V12)-induced cell tumours in the brain...
March 27, 2017: Oncogene
https://www.readbyqxmd.com/read/28343148/de-novo-mutations-in-cbl-causing-early-onset-paediatric-moyamoya-angiopathy
#2
Stéphanie Guey, Lou Grangeon, Francis Brunelle, Françoise Bergametti, Jeanne Amiel, Stanislas Lyonnet, Audrey Delaforge, Minh Arnould, Béatrice Desnous, Céline Bellesme, Dominique Hervé, Jan C Schwitalla, Markus Kraemer, Elisabeth Tournier-Lasserve, Manoelle Kossorotoff
BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome...
March 25, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28341660/the-noncoding-rna-linc-adamts5-cooperates-with-rreb1-to-protect-from-intervertebral-disc-degeneration-through-inhibiting-adamts5-expression
#3
Kun Wang, Yu Song, Wei Liu, Xinghuo Wu, Yukun Zhang, Shuai Li, Liang Kang, Ji Tu, Kangcheng Zhao, Wenbin Hua, Cao Yang
Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration. However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, that was transcribed in the opposite direction of ADAMTS5. In this study, through mining computational algorithm programs, and public available data sets, we identified Ras responsive element binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells...
March 24, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28338001/renin-angiotensin-system-acting-on-reactive-oxygen-species-in-paraventricular-nucleus-induces-sympathetic-activation-via-at1r-pkc%C3%AE-rac1-pathway-in-salt-induced-hypertension
#4
Qing Su, Chan-Juan Huo, Hong-Bao Li, Kai-Li Liu, Xiang Li, Qing Yang, Xin-Ai Song, Wen-Sheng Chen, Wei Cui, Guo-Qing Zhu, Xiao-Lian Shi, Jin-Jun Liu, Yu-Ming Kang
Brain renin-angiotensin system (RAS) could regulate oxidative stress in the paraventricular nucleus (PVN) in the development of hypertension. This study was designed to explore the precise mechanisms of RAS acting on reactive oxygen species (ROS) in salt-induced hypertension. Male Wistar rats were administered with a high-salt diet (HS, 8.0% NaCl) for 8 weeks to induced hypertension. Those rats were received PVN infusion of AT1R antagonist losartan (LOS, 10 μg/h) or microinjection of small interfering RNAs for protein kinase C γ (PKCγ siRNA) once a day for 2 weeks...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28335584/atrap-expression-in-brown-adipose-tissue-does-not-influence-the-development-of-diet-induced-metabolic-disorders-in-mice
#5
Kohji Ohki, Hiromichi Wakui, Kengo Azushima, Kazushi Uneda, Sona Haku, Ryu Kobayashi, Kotaro Haruhara, Sho Kinguchi, Miyuki Matsuda, Masato Ohsawa, Akinobu Maeda, Shintaro Minegishi, Tomoaki Ishigami, Yoshiyuki Toya, Akio Yamashita, Satoshi Umemura, Kouichi Tamura
Activation of tissue renin-angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAP(fl/fl)) mice and adipose tissue-specific ATRAP downregulated (ATRAP(adipoq)) mice by the Cre/loxP system using Adipoq-Cre...
March 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28333924/csl-encodes-a-leucine-rich-repeat-protein-implicated-in-red-violet-light-signaling-to-the-circadian-clock-in-chlamydomonas
#6
Ayumi Kinoshita, Yoshimi Niwa, Kiyoshi Onai, Takashi Yamano, Hideya Fukuzawa, Masahiro Ishiura, Takuya Matsuo
The green alga Chlamydomonas reinhardtii shows various light responses in behavior and physiology. One such photoresponse is the circadian clock, which can be reset by external light signals to entrain its oscillation to daily environmental cycles. In a previous report, we suggested that a light-induced degradation of the clock protein ROC15 is a trigger to reset the circadian clock in Chlamydomonas. However, light signaling pathways of this process remained unclear. Here, we screened for mutants that show abnormal ROC15 diurnal rhythms, including the light-induced protein degradation at dawn, using a luciferase fusion reporter...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28333549/ksr-as-a-therapeutic-target-for-ras-dependent-cancers
#7
Beth K Neilsen, Danielle E Frodyma, Robert E Lewis, Kurt W Fisher
Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered: Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins...
March 23, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28328117/noonan-syndrome-ptpn11-mutations-and-brain-tumors-a-clinical-report-and-review-of-the-literature
#8
Aurore Siegfried, Claude Cances, Marie Denuelle, Najat Loukh, Maïté Tauber, Hélène Cavé, Marie-Bernadette Delisle
Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28327932/integrated-safety-analysis-of-rolapitant-with-coadministered-drugs-from-phase-ii-iii-trials-an-assessment-of-cyp2d6-or-bcrp-inhibition-by-rolapitant
#9
S Barbour, T Smit, X Wang, D Powers, S Arora, V Kansra, M Aapro, J Herrstedt
Background: Rolapitant, a long-acting neurokinin (NK) 1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK 1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events by use versus non-use of drug substrates of CYP2D6 or BCRP...
February 23, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28327630/rassf-proteins-as-modulators-of-mst1-kinase-activity
#10
Aruna Bitra, Srinivas Sistla, Jessy Mariam, Harshada Malvi, Ruchi Anand
Rassf1A/5 tumor suppressors serve as adaptor proteins possessing a modular architecture with the C-terminal consisting of a coiled-coil SARAH (Salvador-Rassf-Hippo) domain and the central portion being composed of Ras associated (RA) domain. Here, we investigate the effect of Rassf effectors on Mst1 function by mapping the interaction of various domains of Rassf1A/5 and Mst1 kinase using surface plasmon resonance (SPR). The results revealed that apart from the C-terminal SARAH domain of Mst1 which interacts to form heterodimers with Rassf1A/5, the N-terminal kinase domain of Mst1 plays a crucial role in the stabilization of this complex...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28325292/sirna-encapsulated-hybrid-nanoparticles-target-mutant-k-ras-and-inhibit-metastatic-tumor-burden-in-a-mouse-model-of-lung-cancer
#11
Maryna Perepelyuk, Olubunmi Shoyele, Ruth Birbe, Chellappagounder Thangavel, Yi Liu, Robert B Den, Adam E Snook, Bo Lu, Sunday A Shoyele
There is an unmet need in the development of an effective therapy for mutant K-ras-expressing non-small-cell lung cancer (NSCLC). Although various small molecules have been evaluated, an effective therapy remains a dream. siRNAs have the potential to downregulate mutant K-ras both at the protein and mRNA levels. However, a safe and effective delivery of siRNAs to tumors remains a limitation to their translational application in the treatment of this highly debilitating disease. Here we developed a novel hybrid nanoparticle carrier for effective delivery of anti-mutant K-ras to NSCLC (AKSLHN)...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28322443/all-trans-retinoic-acid-ameliorates-hepatic-stellate-cell-activation-via-suppression-of-thioredoxin-interacting-protein-expression
#12
Hiroki Shimizu, Toshiaki Tsubota, Keita Kanki, Goshi Shiota
Activation of hepatic stellate cells (HSCs) is the effector factor of hepatic fibrosis and hepatocellular carcinoma (HCC) development. Accumulating evidence suggests that retinoic acids (RAs), derivatives of vitamin A, contribute to prevention of liver fibrosis and carcinogenesis, however, regulatory mechanisms of RAs still remain exclusive. To elucidate RA signaling pathway, we previously performed a genome-wide screening of RA-responsive genes by in silico analysis of RA-response elements, and identified 26 RA-responsive genes...
March 21, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28322341/angiotensin-ii-induces-kidney-inflammatory-injury-and-fibrosis-through-binding-to-myeloid-differentiation-protein-2-md2
#13
Zheng Xu, Weixin Li, Jibo Han, Chunpeng Zou, Weijian Huang, Weihui Yu, Xiaoou Shan, Hazel Lum, Xiaokun Li, Guang Liang
Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2(-/-) mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322269/a-ras-gtpase-associated-protein-is-involved-in-the-phototropic-and-circadian-photobiology-responses-in-fungi
#14
Silvia Polaino, José M Villalobos-Escobedo, Viplendra P S Shakya, Alejandro Miralles-Durán, Suman Chaudhary, Catalina Sanz, Mahdi Shahriari, Eva M Luque, Arturo P Eslava, Luis M Corrochano, Alfredo Herrera-Estrella, Alexander Idnurm
Light is an environmental signal perceived by most eukaryotic organisms and that can have major impacts on their growth and development. The MadC protein in the fungus Phycomyces blakesleeanus (Mucoromycotina) has been postulated to form part of the photosensory input for phototropism of the fruiting body sporangiophores, but the madC gene has remained unidentified since the 1960s when madC mutants were first isolated. In this study the madC gene was identified by positional cloning. All madC mutant strains contain loss-of-function point mutations within a gene predicted to encode a GTPase activating protein (GAP) for Ras...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#15
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#16
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28316325/silencing-of-the-small-gtpase-diras3-induces-cellular-senescence-in-human-white-adipose-stromal-progenitor-cells
#17
Asim Ejaz, Monika Mattesich, Werner Zwerschke
Inhibition of Akt-mTOR signaling protects from obesity and extends life span in animals. In the present study, we analyse the impact of the small GTPase, GTP-binding RAS-like 3 (DIRAS3), a recently identified weight-loss target gene, on cellular senescence in adipose stromal/progenitor cells (ASCs) derived from human subcutaneous white adipose tissue (sWAT). We demonstrate that DIRAS3 knock-down (KD) in ASCs induces activation of Akt-mTOR signaling and proliferation arrest. DIRAS3 KD ASCs lose the potential to form colonies and are negative for Ki-67...
March 17, 2017: Aging
https://www.readbyqxmd.com/read/28316063/endothelial-long-non-coding-rnas-regulated-by-oxidized-ldl
#18
Krishna K Singh, Pratiek N Matkar, Yi Pan, Adrian Quan, Vijay Gupta, Hwee Teoh, Mohammed Al-Omran, Subodh Verma
Oxidized low-density lipoprotein (oxLDL) plays a central role in the pathogenesis of atherosclerosis, in part via an effect to promote endothelial dysfunction. In the present study, we evaluated the expression profiles of long non-coding RNAs (lncRNAs) and protein-coding mRNAs in endothelial cells following oxLDL stimulation. LncRNAs and mRNAs from human umbilical vein endothelial cells (HUVECs) were profiled with the Arraystar Human lncRNA Expression Microarray V3.0 following 24 h of oxLDL treatment (100 µg/mL)...
March 18, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28314843/quantitative-proteome-heterogeneity-in-myeloproliferative-neoplasm-subtypes-and-association-with-jak2-mutation-status
#19
Nuria Socoro-Yuste, Cokic Vladan P, Julie Mondet, Isabelle Plo, Pascal Mossuz
Apart from well-known genetic abnormalities, several studies have reported variations in protein expression in Philadelphia negative (Ph-) Myeloproliferative Neoplasm (MPN) patients that could contribute towards their clinical phenotype. In this context, a quantitative mass spectrometry proteomics protocol was used to identify differences in the granulocyte proteome with the goal to characterize the pathogenic role of aberrant protein expression in MPNs. LC MS/MS (LTQ Orbitrap) coupled to iTRAQ labeling showed significant and quantitative differences in protein content among various MPN subtypes [polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)], and according to the genetic status of JAK2 (JAK2V617F presence and JAK2V617F allele burden)...
March 17, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28306189/map4k4-is-a-novel-mapk-erk-pathway-regulator-required-for-lung-adenocarcinoma-maintenance
#20
Xuan Gao, Guangming Chen, Chenxi Gao, Dennis Han Zhang, Shih-Fan Kuan, Laura P Stabile, Guoxiang Liu, Jing Hu
About 76% of lung adenocarcinoma patients harbor activating mutations in the receptor tyrosine kinase (RTK)/RAS/RAF pathways, leading to aberrant activation of the MAPK pathways particularly the MAPK/ERK pathway. However, many lung adenocarcinomas lacking these genomic mutations also display significant MAPK pathway activation, suggesting that additional MAPK pathway alterations remain undetected. This study has identified serine/threonine kinase mitogen-activated protein 4 kinase 4 (MAP4K4) as a novel positive regulator of MAPK/ERK signaling in lung adenocarcinoma...
March 17, 2017: Molecular Oncology
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