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RAS/RAF/ERK

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https://www.readbyqxmd.com/read/29341215/microrna181c-inhibits-prostate-cancer-cell-growth-and-invasion-by-targeting-multiple-erk-signaling-pathway-components
#1
Zhengzheng Su, Mengni Zhang, Miao Xu, Xinglan Li, Junya Tan, Yunyi Xu, Xiuyi Pan, Ni Chen, Xueqin Chen, Qiao Zhou
BACKGROUND: The ERK signaling pathway is frequently deregulated in tumorigenesis, mostly by classical mechanisms such as gene mutation of its components (eg, RAS and RAF). However, whether and how multiple key components of ERK pathway are regulated by microRNAs are not clear. METHODS: We firstly predicted post-transcriptional regulation of multiple key components of the ERK signaling pathway by miR181c through bioinformatics analysis, and then confirmed the post-transcriptional regulation by dual luciferase reporter gene assays and Western blot analysis...
January 16, 2018: Prostate
https://www.readbyqxmd.com/read/29331658/sulforaphene-enhances-the-efficacy-of-photodynamic-therapy-in-anaplastic-thyroid-cancer-through-ras-raf-mek-erk-pathway-suppression
#2
Saswata Chatterjee, Yunhee Rhee, Phil-Sang Chung, Rui-Feng Ge, Jin-Chul Ahn
Sulforaphene (SFE), a natural isothiocyanate from cruciferous vegetables has shown a potential anticancer effect against cervical and lung cancer. Palliative treatments like photodynamic therapy (PDT) are being implemented for a long time however, the results are still not promising in case of aggressive cancers like anaplastic thyroid cancer. The objective of this work is to establish an alternative method with the combination of photofrin-PDT and sulforaphene, a natural isothiocyanate from cruciferous vegetables, against human anaplastic thyroid cancer to enhance the efficacy of PDT...
December 11, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/29330773/mechanistic-regulation-of-epithelial-to-mesenchymal-transition-through-ras-signaling-pathway-and-therapeutic-implications-in-human-cancer
#3
REVIEW
Kiran Tripathi, Minal Garg
RAS effector signaling instead of being simple, unidirectional and linear cascade, is actually recognized as highly complex and dynamic signaling network. RAF-MEK-ERK cascade, being at the center of complex signaling network, links to multiple scaffold proteins through feed forward and feedback mechanisms and dynamically regulate tumor initiation and progression. Three isoforms of Ras harbor mutations in a cell and tissue specific manner. Besides mutations, their epigenetic silencing also attributes them to exhibit oncogenic activities...
January 12, 2018: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/29328495/fucoidan-downregulates-insulin-like-growth-factor-i-receptor-levels-in-ht-29-human-colon-cancer-cells
#4
In-Hye Kim, Taek-Jeong Nam
Fucoidan, a sulfated polysaccharide present in brown seaweed, has demonstrated anticancer activity in lung, breast, liver and colon cells. The insulin-like growth factor (IGF) signaling pathway regulates growth in HT-29 cells through the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Ras/Raf/extracellular signal-regulated kinase (ERK) pathways. The aim of the present study was to investigate whether fucoidan downregulates the IGF-IR signaling pathway in HT-29 human colon cancer cells...
January 4, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#5
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29317674/spred2-deficiency-exacerbates-d-galactosamine-lipopolysaccharide-induced-acute-liver-injury-in-mice-via-increased-production-of-tnf%C3%AE
#6
Xu Yang, Masayoshi Fujisawa, Teizo Yoshimura, Toshiaki Ohara, Miwa Sato, Megumi Mino, Thar Htet San, Tong Gao, Steven L Kunkel, Akihiro Matsukawa
Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2-/- mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2-/--livers, and the MEK/ERK inhibitor U0126 ameliorated ALI...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29312576/matrine-inhibits-bcr-abl-mediated-erk-mapk-pathway-in-human-leukemia-cells
#7
Lingdi Ma, Zhenyu Xu, Jian Wang, Zhichao Zhu, Guibin Lin, Lijia Jiang, Xuzhang Lu, Chang Zou
The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML). Our previous study showed that matrine, an alkaloid extracted from a Chinese herb radix sophorae, significantly inhibited the proliferation of human CML K562cells, induced cell cycle arrest in G0/G1, and promoted cell apoptosis. In the present study, we investigated the molecular mechanism of matrine in the growth inhibition of leukemia cells using K562 and HL-60 cell lines...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311130/mras-a-close-but-understudied-member-of-the-ras-family
#8
Lucy C Young, Pablo Rodriguez-Viciana
MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and transformation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29309927/glycogen-synthase-kinases-moonlighting-proteins-with-theranostic-potential-in-cancer
#9
REVIEW
Siddavaram Nagini, Josephraj Sophia, Rajakishore Mishra
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase is an archetypal multifunctional moonlighting protein involved in diverse cellular processes including metabolism, insulin signaling, proliferation, differentiation, apoptosis, neuronal function and embryonic development. The two known isoforms, GSK-3α and GSK-3β that undergo activation/inactivation by post-translational, site-specific phosphorylation incorporate a vast number of substrates in their repertoire. Dysregulation of GSK-3 has been linked to diverse disease entities including cancer...
January 5, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29307569/is-nanoclustering-essential-for-all-oncogenic-kras-pathways-can-it-explain-why-wild-type-kras-can-inhibit-its-oncogenic-variant
#10
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Membrane-anchored oncogenic KRas can dimerize, form nanoclusters, and signal through the MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. Both pathways are needed in KRAS-driven proliferation. Here we ask: Is oncogenic KRas nanoclustering (or dimerization) essential for all KRas signaling pathways? Raf kinase domain dimerization, thus MAPK activation, requires KRas nanoclusters. By contrast, the PI3Kα heterodimer acts as a monomeric unit; thus, does PI3Kα activation and PI3Kα/Akt/mTOR signaling require nanoclustering? Further, calmodulin binds only to oncogenic KRas4B...
January 5, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29298734/ailanthone-promotes-human-vestibular-schwannoma-cells-apoptosis-and-autophagy-by-down-regulation-of-mir-21
#11
Peizhen Yang, Dechong Sun, Fei Jiang
Ailanthone (AIL) is a quassinoid isolated from the traditional Chinese medicinal herb Ailanthus altissima. The anti-tumor activities of AIL have been reported in several cancers. The purpose of the present study was to explore the effect of AIL on vestibular schwannomas (VSs). Various concentration of AIL (0~1 μM) was used to treat human primary VS cells, and then cell viability, proliferation, apoptosis, and autophagy were assessed, respectively. Expression of miR-21 in VS cells was altered by miRNA transfection...
January 3, 2018: Oncology Research
https://www.readbyqxmd.com/read/29296238/the-implication-from-ras-raf-erk-signaling-pathway-increased-activation-in-epirubicin-treated-triple-negative-breast-cancer
#12
Jianbo Huang, Qingqing Luo, Yun Xiao, Hongyuan Li, Lingquan Kong, Guosheng Ren
Background: Triple negative breast cancer (TNBC) is not sensitive to RAS/RAF/ERK signaling pathway (ERK pathway) targeting therapy, due to the absence of excessive activation of ERK pathway. However, the kinase cascades might be activated after chemotherapy in TNBC. Here we aimed to predict whether ERK pathway targeting therapy could be used as an adjuvant therapy in TNBC. Methods: Within online GEO datasets (GSE43816 and GSE54326), gene set enrichment analysis (GSEA) was performed to detect molecular changes in epirubicin treated TNBC samples and cells, ERK pathway components and regulation genes changes were included...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29275358/wild-type-kirsten-rat-sarcoma-is-a-novel-microrna-622-regulated-therapeutic-target-for-hepatocellular-carcinoma-and-contributes-to-sorafenib-resistance
#13
Peter Dietrich, Andreas Koch, Valerie Fritz, Arndt Hartmann, Anja Katrin Bosserhoff, Claus Hellerbrand
OBJECTIVE: Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC...
December 23, 2017: Gut
https://www.readbyqxmd.com/read/29273632/oncogenic-ras-isoforms-signaling-specificity-at-the-membrane
#14
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity...
December 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/29261154/the-role-of-par2-in-tgf-%C3%AE-1-induced-erk-activation-and-cell-motility
#15
Hendrik Ungefroren, David Witte, Christian Fiedler, Thomas Gädeken, Roland Kaufmann, Hendrik Lehnert, Frank Gieseler, Bernhard H Rauch
BACKGROUND: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. METHODS: RNA interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation to detect a PAR2-ALK5 physical interaction...
December 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29259156/dual-blockade-of-the-lipid-kinase-pip4ks-and-mitotic-pathways-leads-to-cancer-selective-lethality
#16
Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, See Cheng Shang, Noriaki Minami, Oltea Sampetrean, Hideyuki Saya, Dai Lingyun, Nayana Prabhu, Go Ka Diam, Radoslaw Sobota, Andreas Larsson, Pär Nordlund, Frank McCormick, Sujoy Ghosh, David M Epstein, Brian W Dymock, Sang Hyun Lee
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29235562/targeting-the-raf-kinases-in-human-cancer-the-raf-dimer-dilemma
#17
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/29232553/synthetic-lethality-of-combined-bcl-2-inhibition-and-p53-activation-in-aml-mechanisms-and-superior-antileukemic-efficacy
#18
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
#19
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/29203859/interleukin-13-receptor-alpha-2-cooperates-with-egfrviii-signaling-to-promote-glioblastoma-multiforme
#20
Jennifer P Newman, Grace Y Wang, Kazuhiko Arima, Shou P Guan, Michael R Waters, Webster K Cavenee, Edward Pan, Edita Aliwarga, Siao T Chong, Catherine Y L Kok, Berwini B Endaya, Amyn A Habib, Tomohisa Horibe, Wai H Ng, Ivy A W Ho, Kam M Hui, Tomasz Kordula, Paula Y P Lam
The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo...
December 4, 2017: Nature Communications
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