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https://www.readbyqxmd.com/read/28087344/up-regulation-of-the-active-form-of-small-gtpase-rab13-promotes-macroautophagy-in-vascular-endothelial-cells
#1
Lu Zhang, Fang Dai, LiuQing Cui, Bo Zhou, YuQi Guo
The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray...
January 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28078757/lamellar-events-related-to-insulin-like-growth-factor-1-receptor-signaling-in-two-models-relevant-to-endocrinopathic-laminitis
#2
H E Lane, T A Burns, O C Hegedus, M R Watts, P S Weber, K A Woltman, R J Geor, L J McCutcheon, S C Eades, L E Mathes, J K Belknap
BACKGROUND: Insulin dysregulation, obesity, and exposure to high-non structural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome (EMS)-associated laminitis (EMSAL); high systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the IGF-1 receptor. OBJECTIVES: To use a dietary challenge model (DCM) and a euglycemic hyperinsulinemic clamp (EHC) model to assess lamellar growth factor-related signaling...
January 11, 2017: Equine Veterinary Journal
https://www.readbyqxmd.com/read/28077873/translation-from-unconventional-5-start-sites-drives-tumour-initiation
#3
Ataman Sendoel, Joshua G Dunn, Edwin H Rodriguez, Shruti Naik, Nicholas C Gomez, Brian Hurwitz, John Levorse, Brian D Dill, Daniel Schramek, Henrik Molina, Jonathan S Weissman, Elaine Fuchs
We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs...
January 11, 2017: Nature
https://www.readbyqxmd.com/read/28077300/pharmacological-strategies-to-target-oncogenic-kras-signaling-in-pancreatic-cancer
#4
REVIEW
Hsiao-Ching Chuang, Po-Hsien Huang, Samuel K Kulp, Ching-Shih Chen
The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents...
January 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28077299/anaplastic-lymphoma-kinase-alk-inhibitors-in-the-treatment-of-alk-driven-lung-cancers
#5
REVIEW
Robert Roskoski
Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors...
January 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28076404/combined-inhibition-of-the-renin-angiotensin-system-and-neprilysin-positively-influences-complex-mitochondrial-adaptations-in-progressive-experimental-heart-failure
#6
Laura Grois, Julian Hupf, Jörg Reinders, Josef Schröder, Alexander Dietl, Peter M Schmid, Carsten Jungbauer, Markus Resch, Lars S Maier, Andreas Luchner, Christoph Birner
BACKGROUND: Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF). METHODS AND RESULTS: By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL)...
2017: PloS One
https://www.readbyqxmd.com/read/28075478/high-expression-of-rab43-predicts-poor-prognosis-and-is-associated-with-epithelial-mesenchymal-transition-in-gliomas
#7
Ming-Zhi Han, Bin Huang, An-Jing Chen, Xin Zhang, Ran Xu, Jian Wang, Xin-Gang Li
The Ras-related GTP-binding protein (RAB) family plays an important role in regulating signal transduction and cellular processes including vesicle transport, cytoskeleton formation and membrane trafficking. More recently, several RAB members have been reported to promote tumorigenesis in many types of cancers. However, the clinical significance and potential function of RAB43 in gliomas remain unclear. Herein, we found that RAB43 was upregulated and positively correlated with the grade of progression in glioma patients by in silico analysis and immunohistochemistry (IHC)...
January 3, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28073589/mechanisms-of-oncogene-induced-genomic-instability
#8
Simona Graziano, Susana Gonzalo
Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means...
November 24, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/28073348/wild-carrot-pentane-based-fractions-suppress-proliferation-of-human-hacat-keratinocytes-and-protect-against-chemically-induced-skin-cancer
#9
Wassim N Shebaby, Mohamad A Mroueh, Petra Boukamp, Robin I Taleb Ri, Kikki Bodman-Smith, Mirvat El-Sibai, Costantine F Daher
BACKGROUND: Previous studies in our laboratory showed that the Lebanese Daucus carota ssp. carota (wild carrot) oil extract possesses in vitro and in vivo anticancer activities. The present study aims to examine the cytotoxic effect of Daucus carota oil fractions on human epidermal keratinocytes and evaluate the chemopreventive activity of the pentane diethyl ether fraction on DMBA/TPA induced skin carcinogenesis in mice. METHODS: Wild carrot oil extract was chromatographed to yield four fractions (F1, 100% pentane; F2, 50:50 pentane:diethyl ether; F3, 100% diethyl ether; F4 93:7 chloroform:methanol)...
January 10, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28073102/cancer-resistance-to-therapies-against-the-egfr-ras-raf-pathway-the-role-of-mek
#10
REVIEW
Erika Martinelli, Floriana Morgillo, Teresa Troiani, Fortunato Ciardiello
The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC)...
December 30, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28070119/ocd-like-behavior-is-caused-by-dysfunction-of-thalamo-amygdala-circuits-and-upregulated-trkb-erk-mapk-signaling-as-a-result-of-spred2-deficiency
#11
M Ullrich, M Weber, A M Post, S Popp, J Grein, M Zechner, H Guerrero González, A Kreis, A G Schmitt, N Üçeyler, K-P Lesch, K Schuh
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling...
January 10, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28069069/arresting-kinase-suppressor-of-ras-in-an-inactive-state
#12
EDITORIAL
Syed Lal Badshah, Yahia Mabkhot
Ras protein signaling pathways are important in controlling the plight of different types of cancer. Here we discussed the paper entitled "Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling" published in Nature journal on inactivating the kinase suppressor of Ras (KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state...
January 9, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28068326/klf4-is-regulated-by-ras-raf-mek-erk-signaling-through-e2f1-and-promotes-melanoma-cell-growth
#13
M Riverso, V Montagnani, B Stecca
Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors show only temporary benefit due the occurrence of resistance and immunotherapy is effective only in a subset of patients. To improve patient survival, there is a need to better understand molecular mechanisms that drive melanoma growth and operate downstream of the mitogen activated protein kinase (MAPK) signaling. The Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a critical role in embryonic development, stemness and cancer, where it can act either as oncogene or tumor suppressor...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067895/the-nf1-gene-in-tumor-syndromes-and-melanoma
#14
Maija Kiuru, Klaus J Busam
Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28067632/hcv-genotype-1-subtypes-and-resistance-associated-substitutions-in-drug-naive-and-in-direct-acting-antiviral-treatment-failure-patients
#15
Yael Gozlan, Ziv Ben-Ari, Roy Moscona, Rachel Shirazi, Avia Rakovsky, Arij Kabat, Ella Veizman, Tania Berdichevski, Peretz Weiss, Oranit Cohen-Ezra, Yoav Lurie, Inna Gafanovich, Marius Braun, Michal Cohen-Naftaly, Amir Shlomai, Oren Shibolet, Ehud Zigmond, Eli Zuckerman, Michal Carmiel-Haggai, Assy Nimer, Rawi Hazzan, Yaakov Maor, Yona Kitay-Cohen, Yonat Shemer, Zipi Kra-Oz, Lisita Schreiber, Ofer Peleg, Ella Mendelson, Orna Mor
BACKGROUND: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with hepatitis C virus (HCV) genotype 1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. METHODS: In a multicenter cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes...
January 9, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/28067274/computational-and-biochemical-characterization-of-two-partially-overlapping-interfaces-and-multiple-weak-affinity-k-ras-dimers
#16
Priyanka Prakash, Abdallah Sayyed-Ahmad, Kwang-Jin Cho, Drew M Dolino, Wei Chen, Hongyang Li, Barry J Grant, John F Hancock, Alemayehu A Gorfe
Recent studies found that membrane-bound K-Ras dimers are important for biological function. However, the structure and thermodynamic stability of these complexes remained unknown because they are hard to probe by conventional approaches. Combining data from a wide range of computational and experimental approaches, here we describe the structure, dynamics, energetics and mechanism of assembly of multiple K-Ras dimers. Utilizing a range of techniques for the detection of reactive surfaces, protein-protein docking and molecular simulations, we found that two largely polar and partially overlapping surfaces underlie the formation of multiple K-Ras dimers...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28065675/altered-expression-of-irs2-and-grb2-in-demyelination-of-peripheral-neurons-implications-in-diabetic-neuropathy
#17
Mallahalli S Manu, Kuruvanthe S Rachana, Gopal M Advirao
Demyelination of the peripheral nerves and dysfunction of Schwann cells (SCs) are the chronic complications involved in the development of peripheral neuropathy among diabetic patients. Insulin signaling plays an important role in restoring the myelin proteins in diabetic peripheral neuropathy (DPN). Since insulin levels are altered in diabetes, it becomes of great interest to appreciate the role and regulation of docking and adaptor protein, how these proteins respond to variations in the levels of insulin as experienced in juvenile diabetes...
December 29, 2016: Neuropeptides
https://www.readbyqxmd.com/read/28064406/up-regulation-of-vps4a-promotes-neuronal-apoptosis-after-intracerebral-hemorrhage-in-adult-rats
#18
Jianbing Ren, Debin Yuan, Lili Xie, Xuelei Tao, Chenwei Duan, Yifeng Bao, Yunfeng He, Jianbin Ge, Hongjian Lu
Vps4, vacuolar protein sorting 4, belongs to ATPases Associated with diverse cellular Activities (AAA) protein family which is made up of Vps4A and Vps4B. Previous studies demonstrated that Vps4A plays vital roles in diverse aspects such as virus budding, the efficient transport of H-Ras to the PM (plasma membrane) and the involvement in the MVB (multivesiculate bodies) pathway. Interestingly, Vps4A is also expressed in the brain. However, the distribution and function of Vps4A in ICH diseases remain unclear...
January 7, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28062402/the-ras-effector-interaction-as-a-drug-target
#19
REVIEW
Adam B Keeton, E Alan Salter, Gary A Piazza
About a third of all human cancers harbor mutations in one of the K-, N-, or HRAS genes that encode an abnormal RAS protein locked in a constitutively activated state to drive malignant transformation and tumor growth. Despite more than three decades of intensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs that are broadly effective against RAS-driven cancers. Although RAS proteins are often said to be "undruggable," there is mounting evidence suggesting it may be feasible to develop direct inhibitors of RAS proteins...
January 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/28062358/alterations-in-transcription-and-protein-expressions-of-hcc-related-genes-in-hepg2-cells-caused-by-microcystin-lr
#20
Xiaoyu Li, Xiangyang Zhang, Wenjie Xie, Chune Zhou, Yao Li, Xiuhua Zhang
Microcystin-LR (MC-LR) is the most common and toxic hepatotoxin and it could induce human hepatitis and hepatocellular carcinoma (HCC) via the route of drinking water. The aim of the present study was to determine the expressions of oncogenes c-fos, c-jun, c-myc, c-met, and N-ras and tumor suppressor gene PTEN in HepG2 cells following MC-LR-exposure to understand the possible mechanism of MC-LR-related human primary liver cancer. The results of qPCR and Western blotting showed that MC-LR-exposure at non- or sub-cytotoxic concentrations promoted the expressions of oncogenes c-fos, c-jun, c-myc, c-met, and N-ras while suppressed tumor-suppressor gene PTEN in HepG2 cells at both transcription and protein levels...
January 3, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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