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https://www.readbyqxmd.com/read/29239724/sirt2-and-lysine-fatty-acylation-regulate-the-transforming-activity-of-k-ras4a
#1
Hui Jing, Xiaoyu Zhang, Stephanie A Wisner, Xiao Chen, Nicole A Spiegelman, Maurine E Linder, Hening Lin
Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a...
December 14, 2017: ELife
https://www.readbyqxmd.com/read/29238356/arbuscular-mycorrhizal-fungus-enhances-lateral-root-formation-in-poncirus-trifoliata-l-as-revealed-by-rna-seq-analysis
#2
Weili Chen, Juan Li, Honghui Zhu, Pengyang Xu, Jiezhong Chen, Qing Yao
Arbuscular mycorrhizal fungi (AMF) establish symbiosis with most terrestrial plants, and greatly regulate lateral root (LR) formation. Phosphorus (P), sugar, and plant hormones are proposed being involved in this regulation, however, no global evidence regarding these factors is available so far, especially in woody plants. In this study, we inoculated trifoliate orange seedlings (Poncirus trifoliata L. Raf) with an AMF isolate, Rhizophagus irregularis BGC JX04B. After 4 months of growth, LR formation was characterized, and sugar contents in roots were determined...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29236326/knockdown-of-ski-decreased-the-reactive-astrocytes-proliferation-in-vitro-induced-by-oxygen-glucose-deprivation-reoxygenation
#3
Xin Zhao, Kai-Sheng Zhou, Zhong-Hao Li, Wei Nan, Jing Wang, Ya-Yi Xia, Hai-Hong Zhang
Glia scar is a pathological marker in late phase of brain ischemia disease, which constitutes a major physical biochemical barrier to impede axonal regrowth. Astrocytes are known to be critically involved in the formation of glial scar. However, their response to ischemia and their role in neuroprotection after central nervous system (CNS) injury are not completely clear. Recently, we have demonstrated for the first time that Ski was up-regulated in reactive astrocytes after spinal cord injury in vivo and in vitro, which indicates Ski may be a new molecule that control astrocytes biologic properties after CNS injury...
December 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29235861/kras-switch-mutants-d33e-and-a59g-crystallize-in-the-state-1-conformation
#4
Jia Lu, Asim Bera, Sudershan R Gondi, Kenneth Dale Westover
KRAS switch loop movements play a crucial role in regulating RAS signaling and alteration in these sensitive dynamics are a principal mechanism through which disease-associated RAS mutations lead to aberrant RAS activation. Prior studies suggest that despite high sequence similarity, the switches in KRAS are more dynamic than HRAS. We solved x-ray crystal structures of the rare tumorigenic KRAS mutants KRASD33E, in switch 1 (SW1), and KRASA59G, in switch 2 (SW2), bound to GDP and found these adopt nearly identical, open SW1 conformations as well as altered SW2 conformations...
December 13, 2017: Biochemistry
https://www.readbyqxmd.com/read/29235562/targeting-the-raf-kinases-in-human-cancer-the-raf-dimer-dilemma
#5
David E Durrant, Deborah K Morrison
The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29234285/a-microarray-study-of-carpet-shell-clam-ruditapes-decussatus-shows-common-and-organ-specific-growth-related-gene-expression-differences-in-gills-and-digestive-gland
#6
Carlos Saavedra, Massimo Milan, Ricardo B Leite, David Cordero, Tomaso Patarnello, M Leonor Cancela, Luca Bargelloni
Growth rate is one of the most important traits from the point of view of individual fitness and commercial production in mollusks, but its molecular and physiological basis is poorly known. We have studied differential gene expression related to differences in growth rate in adult individuals of the commercial marine clam Ruditapes decussatus. Gene expression in the gills and the digestive gland was analyzed in 5 fast-growing and five slow-growing animals by means of an oligonucleotide microarray containing 14,003 probes...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29232553/synthetic-lethality-of-combined-bcl-2-inhibition-and-p53-activation-in-aml-mechanisms-and-superior-antileukemic-efficacy
#7
Rongqing Pan, Vivian Ruvolo, Hong Mu, Joel D Leverson, Gwen Nichols, John C Reed, Marina Konopleva, Michael Andreeff
Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition...
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29232129/the-effect-of-structural-modifications-to-glyoxalbis-thiosemicarbazanoto-copper-ii-complexes-on-cellular-copper-uptake-copper-mediated-atp7a-trafficking-and-p-glycoprotein-mediated-efflux
#8
Karla M Acevedo, David J Hayne, Lachlan E McInnes, Asif Noor, Clare Duncan, Diane Moujalled, Irene Volitakis, Angela Rigopoulos, Kevin Jeffrey Barnham, Victor L Villemagne, Anthony R White, Paul S Donnelly
Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups, Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293 and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway...
December 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29227119/-molecular-pathology-of-lung-cancer-in-routine-diagnostic-practice-2017-update
#9
Radoslav Matěj, Zdeněk Rohan, Kristýna Němejcová, Pavel Dundr
The group of non-small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Analysis of EGFR gene mutations and ALK rearrangement in lung adenocarcinomas are already routinely performed and are closely related to the indication for the administration of tyrosinkinase inhibitors...
2017: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/29225069/stimulation-of-b-raf-increases-c-jun-and-c-fos-expression-and-upregulates-ap-1-regulated-gene-transcription-in-insulinoma-cells
#10
Daniel S Langfermann, Oliver G Rössler, Gerald Thiel
Stimulation of pancreatic β-cells with glucose activates the protein kinases B-Raf and extracellular signal-regulated protein kinase that participate in glucose sensing. Inhibition of both kinases results in impairment of glucose-regulated gene transcription. To analyze the signaling pathway controlled by B-Raf, we expressed a conditionally active form of B-Raf in INS-1 insulinoma cells. Here, we show that stimulation of B-Raf strongly activated the transcription factor AP-1 which is accompanied by increased c-Jun and c-Fos promoter activities, an upregulation of c-Jun and c-Fos biosynthesis, and elevated transcriptional activation potentials of c-Jun and c-Fos...
December 7, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29220330/early-recurrence-and-major-bleeding-in-patients-with-acute-ischemic-stroke-and-atrial-fibrillation-treated-with-non-vitamin-k-oral-anticoagulants-raf-noacs-study
#11
Maurizio Paciaroni, Giancarlo Agnelli, Nicola Falocci, Georgios Tsivgoulis, Kostantinos Vadikolias, Chrysoula Liantinioti, Maria Chondrogianni, Paolo Bovi, Monica Carletti, Manuel Cappellari, Marialuisa Zedde, George Ntaios, Efstathia Karagkiozi, George Athanasakis, Kostantinos Makaritsis, Giorgio Silvestrelli, Alessia Lanari, Alfonso Ciccone, Jukka Putaala, Liisa Tomppo, Turgut Tatlisumak, Azmil H Abdul-Rahim, Kennedy R Lees, Andrea Alberti, Michele Venti, Monica Acciarresi, Cataldo D'Amore, Cecilia Becattini, Maria Giulia Mosconi, Ludovica Anna Cimini, Rossana Soloperto, Luca Masotti, Vieri Vannucchi, Gianni Lorenzini, Rossana Tassi, Francesca Guideri, Maurizio Acampa, Giuseppe Martini, Sung-Il Sohn, Simona Marcheselli, Nicola Mumoli, Maria Luisa De Lodovici, Giorgio Bono, Karen L Furie, Prasanna Tadi, Shadi Yaghi, Danilo Toni, Federica Letteri, Tiziana Tassinari, Odysseas Kargiotis, Enrico Maria Lotti, Yuriy Flomin, Michelangelo Mancuso, Miriam Maccarrone, Nicola Giannini, Fabio Bandini, Alessandro Pezzini, Loris Poli, Alessandro Padovani, Umberto Scoditti, Licia Denti, Domenico Consoli, Franco Galati, Simona Sacco, Antonio Carolei, Cindy Tiseo, Vanessa Gourbali, Giovanni Orlandi, Martina Giuntini, Alberto Chiti, Elisa Giorli, Gino Gialdini, Francesco Corea, Walter Ageno, Marta Bellesini, Giovanna Colombo, Serena Monaco, Mario Maimone Baronello, Theodore Karapanayiotides, Valeria Caso
BACKGROUND: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. METHODS AND RESULTS: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding...
November 29, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29219946/c1206-a-novel-curcumin-derivative-potently-inhibits-hsp90-and-human-chronic-myeloid-leukemia-cells-in-vitro
#12
Ying-Juan Fan, Yi-Xiang Zhou, Lian-Ru Zhang, Qiao-Fa Lin, Ping-Zhang Gao, Fang Cai, Li-Ping Zhu, Bi Liu, Jian-Hua Xu
4-(4-Pyridinyl methylene) curcumin (C1206) is a new derivative of curcumin that is more active than curcumin in inhibition of heat shock protein 90 (Hsp90) and antitumor action. In this study we investigated the relationship between C1206-induced inhibition of Hsp90 and its anti-leukemic effects. The fluorescence quenching experiments showed that C1206 seemed to bind the middle dimerization domain of Hsp90. The interaction between C1206 and Hsp90 was driven mainly by electrostatic interaction. In in vitro enzyme activity assay, C1206 dose-dependently inhibited Hsp90 ATPase activity with an IC50 value of 4...
December 7, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29216010/calcitonin-gene-related-peptide-cgrp-role-in-peripheral-nerve-regeneration
#13
REVIEW
Albert M Chung
Calcitonin gene-related peptide (CGRP) is a neuropeptide that has an important anti-inflammatory role in the immune system. Research has shown that CGRP is an integral part in peripheral nerve regeneration by (1) suppressing tumor necrosis factor-α, (2) forming an initial nerve bridge by increasing fibroblast motility and extracellular matrix synthesis, (3) vascularizing the spinal cord injury site, and (4) inducing Schwann cell (SC) proliferation. In this treatise, the following hypotheses will be explored: (1) CGRP is induced by c-Jun to regulate SC dedifferentiation, (2) CGRP promotes the chemotaxic migration of SCs along the nerve bridge, and (3) CGRP induces myelinophagy by activating various signaling pathways, such as p38 mitogen-activated protein kinase and Raf/extracellular signal-regulated kinase...
December 7, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29215709/the-potential-role-of-aquaporin-1-on-aristolochic-acid-i-induced-epithelial-mesenchymal-transition-on-hk-2-cells
#14
Ji Li, Mincheng Zhang, Yong Mao, Yimao Li, Xiaoxia Zhang, Xuehan Peng, Feng Yu
Aristolochic acid I (AA-I), one of the main active components in Aristolochaia herbs, may induce aristolochic acid nephropathy (AAN). Renal interstitial fibrosis is one of the most typical features of AAN. To investigate the mechanism of Aristolochic acid I (AA-I) -induced renal epithelial-mesenchymal transition (EMT) and determine the role of aquaporin-1 (AQP1) in this process, we established an AA-I-induced EMT model in human proximal tubular epithelial cells (HK-2 cells). Morphological examination, MTT assay, and Western blot analysis were performed...
December 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29214525/treatment-of-melanoma-with-selected-inhibitors-of-signaling-kinases-effectively-reduces-proliferation-and-induces-expression-of-cell-cycle-inhibitors
#15
Dorota Ciołczyk-Wierzbicka, Dorota Gil, Piotr Laidler
Cancer treatment often tends to involve direct targeting enzymes essential for the growth and proliferation of cancer cells. The aim of this study was the recognition of the possible role of selected protein kinases: PI3K, ERK1/2, and mTOR in cell proliferation and cell cycle in malignant melanoma. We investigated the role of protein kinase inhibitors: U0126 (ERK1/2), LY294002 (PI3K), rapamycin (mTOR), everolimus (mTOR), GDC-0879 (B-RAF), and CHIR-99021 (GSK3beta) in cell proliferation and expression of crucial regulatory cell cycle proteins in human melanoma cells: WM793 (VGP) and Lu1205 (metastatic)...
December 6, 2017: Medical Oncology
https://www.readbyqxmd.com/read/29209643/nras-driven-melanoma-a-raf-can-hide-another
#16
Sabine Druillennec, Celio Pouponnot, Alain Eychène
Using mouse genetics, we recently showed that BRAF has a critical role in initiation of NRAS-driven melanoma that cannot be compensated by CRAF. In contrast, RAF proteins display compensatory functions in fully established tumors and ARAF can sustain proliferation in the absence of BRAF and CRAF, highlighting an addiction to RAF signaling in NRAS-driven melanoma.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29208709/conserved-salt-bridge-competition-triggered-by-phosphorylation-regulates-the-protein-interactome
#17
John J Skinner, Sheng Wang, Jiyoung Lee, Colin Ong, Ruth Sommese, Sivaraj Sivaramakrishnan, Wolfgang Koelmel, Maria Hirschbeck, Hermann Schindelin, Caroline Kisker, Kristina Lorenz, Tobin R Sosnick, Marsha Rich Rosner
Phosphorylation is a major regulator of protein interactions; however, the mechanisms by which regulation occurs are not well understood. Here we identify a salt-bridge competition or "theft" mechanism that enables a phospho-triggered swap of protein partners by Raf Kinase Inhibitory Protein (RKIP). RKIP transitions from inhibiting Raf-1 to inhibiting G-protein-coupled receptor kinase 2 upon phosphorylation, thereby bridging MAP kinase and G-Protein-Coupled Receptor signaling. NMR and crystallography indicate that a phosphoserine, but not a phosphomimetic, competes for a lysine from a preexisting salt bridge, initiating a partial unfolding event and promoting new protein interactions...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29207655/egr-1-regulates-rta-transcription-through-a-cooperative-involvement-of-transcriptional-regulators
#18
Roni Sarkar, Subhash C Verma
Kaposi's sarcoma associated herpesvirus (KSHV) regulates the host cellular environment to establish life-long persistent infection by manipulating cellular signaling pathways, with approximately 1- 5% of cells undergoing lytic reactivation during the course of infection. Egr-1 (Early Growth Response Factor-1) is one such cellular transcription factor, which gets phosphorylated during the lytic phase of viral life cycle to perpetrate its function. This study demonstrates the mechanism of how Egr-1 mediates transcription of the immediate early gene, RTA (Replication and transcription activator), which is the lytic switch gene of KSHV...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207285/heat-and-health-in-antwerp-under-climate-change-projected-impacts-and-implications-for-prevention
#19
Gerardo Sanchez Martinez, Julio Diaz, Hans Hooyberghs, Dirk Lauwaet, Koen De Ridder, Cristina Linares, Rocio Carmona, Cristina Ortiz, Vladimir Kendrovski, Raf Aerts, An Van Nieuwenhuyse, Maria Bekker-Nielsen Dunbar
BACKGROUND: Excessive summer heat is a serious environmental health problem in several European cities. Heat-related mortality and morbidity is likely to increase under climate change scenarios without adequate prevention based on locally relevant evidence. METHODS: We modelled the urban climate of Antwerp for the summer season during the period 1986-2015, and projected summer daily temperatures for two periods, one in the near (2026-2045) and one in the far future (2081-2100), under the Representative Concentration Pathway (RCP) 8...
December 2, 2017: Environment International
https://www.readbyqxmd.com/read/29207185/novel-multi%C3%A2-kinase-inhibitor-t03-inhibits-taxol%C3%A2-resistant-breast-cancer
#20
Yan Li, Chunxia Liu, Ke Tang, Yan Chen, Kang Tian, Zhiqiang Feng, Jindong Chen
Activation of kinase-associated signaling pathways is one of the leading causes of various malignant phenotypes in breast tumors. Strategies of drug discovery and development have investigated approaches to target the inhibition of protein kinase signaling. In the current study, the anti‑tumor activities of a novel multi‑kinase inhibitor, T03 were evaluated in breast cancer. T03 inhibited Taxol‑resistant breast cancer cell proliferation and induced cell cycle arrest and apoptosis in vitro and in vivo...
November 28, 2017: Molecular Medicine Reports
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