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RAS/RAF/ERK

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https://www.readbyqxmd.com/read/28188228/time-resolved-phosphoproteome-analysis-of-paradoxical-raf-activation-reveals-novel-targets-of-erk
#1
Peter Kubiniok, Hugo Lavoie, Marc Therrien, Pierre Thibault
Small molecules targeting aberrant RAF activity, like Vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation, and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS-mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream paradoxical ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to Vemurafenib...
February 10, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28180061/kinase-suppressor-of-ras-2-ksr2-expression-in-the-brain-regulates-energy-balance-and-glucose-homeostasis
#2
Lili Guo, Diane L Costanzo-Garvey, Deandra R Smith, Beth K Neilsen, Richard G MacDonald, Robert E Lewis
OBJECTIVE: Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance. METHODS: Mice bearing floxed alleles of KSR2 (KSR2(fl/fl)) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2(fl/fl) mice...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28174173/the-apc-c-e3-ligase-complex-activator-fzr1-restricts-braf-oncogenic-function
#3
Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai, Qing Yin, Jinfang Zhang, Su-Jung Song, Ying Lu, Jing Liu, Hiroyuki Inuzuka, Jesse M Katon, Kelsey Berry, Jacqueline Fung, Christopher Ng, Pengda Liu, Min Sup Song, Lian Xue, Roderick T Bronson, Marc W Kirschner, Rutao Cui, Pier Paolo Pandolfi, Wenyi Wei
BRAF drives tumorigenesis by coordinating the activation of RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathway(s) governing BRAF kinase activity and protein stability remains undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, while in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis...
February 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28161506/mathematical-modelling-unveils-the-essential-role-of-cellular-phosphatases-in-the-inhibition-of-raf-mek-erk-signalling-by-sorafenib-in-hepatocellular-carcinoma-cells
#4
Zuzana Saidak, Anne-Sophie Giacobbi, Christophe Louandre, Chloé Sauzay, Youcef Mammeri, Antoine Galmiche
The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. We analysed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib...
February 2, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28131904/potential-therapeutic-targets-of-epithelial-mesenchymal-transition-in-melanoma
#5
Ross L Pearlman, Mary Katherine Montes de Oca, Harish Chandra Pal, Farrukh Afaq
Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others...
January 25, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28100485/quantification-of-growth-factor-signaling-and-pathway-crosstalk-by-live-cell-imaging
#6
Sean M Gross, Peter Rotwein
Peptide growth factors stimulate cellular responses through activation of their trans-membrane receptors. Multiple intracellular signaling cascades are engaged following growth factor - receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation, but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor-stimulated pathways, Ras - Raf - Mek - Erk and PI3-kinase - Akt...
January 18, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#7
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28069929/genomic-alterations-of-adamantinomatous-and-papillary-craniopharyngioma
#8
Tobias Goschzik, Marco Gessi, Verena Dreschmann, Ursel Gebhardt, Linghua Wang, Shigeru Yamaguchi, David A Wheeler, Libero Lauriola, Ching C Lau, Hermann L Müller, Torsten Pietsch
Craniopharyngiomas are rare histologically benign but clinically challenging neoplasms. To obtain further information on the molecular genetics and biology of craniopharyngiomas, we analyzed a cohort of 121 adamantinomatous and 16 papillary craniopharyngiomas (ACP, PCP). We extracted DNA from formalin-fixed paraffin-embedded tissue and determined mutational status of CTNNB1, BRAF, and DDX3X by Sanger sequencing, next generation panel sequencing, and pyrosequencing. Sixteen craniopharyngiomas were further analyzed by molecular inversion profiling (MIP); 76...
January 9, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28068326/klf4-is-regulated-by-ras-raf-mek-erk-signaling-through-e2f1-and-promotes-melanoma-cell-growth
#9
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/28067893/vemurafenib-and-trametinib-reduce-expression-of-ctgf-and-il-8-in-v600e-braf-melanoma-cells
#10
Mariusz L Hartman, Michal Rozanski, Marta Osrodek, Izabela Zalesna, Malgorzata Czyz
Clinical evidence has revealed that while RAS/RAF/MEK/ERK pathway is a crucial component of melanomagenesis, other signaling pathways can also contribute to the malignant growth and development of resistance to targeted therapies. We explored the response of (V600E)BRAF melanoma cells derived from surgical specimens and grown in stem cell medium to vemurafenib and trametinib, drugs targeting the activity of (V600E)BRAF and MEK1/2, respectively. Cell growth and apoptosis were monitored by real-time imaging system, immunophenotype and cell cycle by flow cytometry, gene expression by quantitative real-time PCR, immunoblotting and enzyme-linked immunosorbent assay...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28059052/gastrin-enhances-autophagy-and-promotes-gastric-carcinoma-proliferation-via-inducing-ampk%C3%AE
#11
Zhuang Kun, Guo Hanqing, Tang Hailing, Yan Yuan, Zhang Jun, Zhang Lingxia, Han Kun, Zhang Xin
Gastric cancer (GC) is one of the most frequent epithelial malignancies worldwide. The gastrointestinal (GI) peptide gastrin is an important regulator of the secretion and release of gastric acid from stomach parietal cells and it also plays a vital role in the development and progression of gastric cancer. The aim of the current study was to investigate the role and underlying mechanism of gastrin and autophagy in regulating gastric cancer tumorigenesis. Gastrin-17 amide (G-17) was applied in the gastric cancer cell lines SGC7901 and MGC-803...
January 5, 2017: Oncology Research
https://www.readbyqxmd.com/read/28051352/antisense-oligonucleotides-targeting-raf-1-block-japanese-encephalitis-virus-in-vitro-and-in-vivo
#12
Li Zhang, Qingjun Li, Xiaoran Ding, Bo Zhang, Qiling Zhang, Xinyan Qu, Yujia Huo, Jing Yang, Shengqi Wang
Japanese encephalitis virus (JEV) infections represent a major health concern in Southeast Asia since no effective treatments are available. Recently, several reports have demonstrated that inhibition of certain host cell proteins prevents viral infection. Raf-1 kinase is a central component of many signaling pathways involved in normal cell growth and oncogenic transformation, and Ras/Raf/ERK signaling activation has been observed during viral infections (including JEV infection). In this study, Raf-1 was confirmed to be upregulated by JEV infection, which suggested that Raf-1 might be important for JEV infection and might be a target for novel anti-JEV drugs...
January 4, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28045041/relaxation-oscillations-and-hierarchy-of-feedbacks-in-mapk-signaling
#13
Marek Kochańczyk, Paweł Kocieniewski, Emilia Kozłowska, Joanna Jaruszewicz-Błońska, Breanne Sparta, Michael Pargett, John G Albeck, William S Hlavacek, Tomasz Lipniacki
We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28030835/co-targeting-translation-and-proteasome-rapidly-kills-colon-cancer-cells-with-mutant-ras-raf-via-er-stress
#14
Xiangyun Li, Mei Li, Hang Ruan, Wei Qiu, Xiang Xu, Lin Zhang, Jian Yu
Colorectal cancers with mutant RAS/RAF are therapy refractory. Deregulated mRNA translation has become an emerging target in cancer treatment. We recently reported that mTOR inhibitors induce apoptosis via ER stress and the extrinsic pathway upon acute inhibition of the eIF4F complex in colon cancer cells and xenografts, while mutant BRAF600E leads to therapeutic resistance via ERK-mediated Mcl-1 stabilization. In this study, we demonstrated that several other translation inhibitors also activate ER stress and the extrinsic apoptotic pathway...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28003362/phosphorylation-of-rap1-by-camp-dependent-protein-kinase-pka-creates-a-binding-site-for-ksr-to-sustain-erk-activation-by-camp
#15
Maho Takahashi, Yanping Li, Tara J Dillon, Philip J S Stork
Cyclic adenosine monophosphate (cAMP) is an important mediator of hormonal stimulation of cell growth and differentiation through its activation of the extracellular signal-regulated kinase (ERK) cascade. Two small G proteins, Ras and Rap1 have been proposed to mediate this activation. Using HEK293 cells as a model system, we have recently shown that both Ras and Rap1 are required for cAMP signaling to ERKs. However, cAMP-dependent Ras signaling to ERKs is transient and rapidly terminated by PKA phosphorylation of the Raf isoforms C-Raf and B-Raf...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27999210/ly3009120-a-panraf-inhibitor-has-significant-anti-tumor-activity-in-braf-and-kras-mutant-preclinical-models-of-colorectal-cancer
#16
Eliza Vakana, Susan Pratt, Wayne Blosser, Michele Dowless, Nicholas Simpson, Xiu-Juan Yuan, Susan Jaken, Jason Manro, Jennifer Stephens, Youyan Zhang, Lysiane Huber, Sheng-Bin Peng, Louis F Stancato
Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27999207/roles-of-gsk-3-and-micrornas-on-epithelial-mesenchymal-transition-and-cancer-stem-cells
#17
REVIEW
James A McCubrey, Timothy L Fitzgerald, Li V Yang, Kvin Lertpiriyapong, Linda S Steelman, Stephen L Abrams, Giuseppe Montalto, Melchiorre Cervello, Luca M Neri, Lucio Cocco, Alberto M Martelli, Piotr Laidler, Joanna DuliÅ Ska-Litewka, Dariusz Rakus, Agnieszka Gizak, Ferdinando Nicoletti, Luca Falzone, Saverio Candido, Massimo Libra
Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27979926/crebbp-knockdown-enhances-ras-raf-mek-erk-signalling-in-ras-pathway-mutated-acute-lymphoblastic-leukaemia-but-does-not-modulate-chemotherapeutic-response
#18
Zach A Dixon, Lindsay Nicholson, Martin Zeppetzauer, Elizabeth Matheson, Paul Sinclair, Christine J Harrison, Julie A E Irving
Relapsed acute lymphoblastic leukaemia is the most common cause of cancer related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukaemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukaemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukaemia cell lines and various primagraft acute lymphoblastic leukaemia cells...
December 15, 2016: Haematologica
https://www.readbyqxmd.com/read/27974551/apicobasal-polarity-and-ras-raf-mek-erk-signalling-in-cancer
#19
Juan Peng, Ama Gassama-Diagne
No abstract text is available yet for this article.
December 14, 2016: Gut
https://www.readbyqxmd.com/read/27956260/allosteric-mek1-2-inhibitors-including-cobimetanib-and-trametinib-in-the-treatment-of-cutaneous-melanomas
#20
REVIEW
Robert Roskoski
The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer...
December 9, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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