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https://www.readbyqxmd.com/read/28921051/fine-particle-matters-induce-dna-damage-and-g2-m-cell-cycle-arrest-in-human-bronchial-epithelial-beas-2b-cells
#1
Jing Wu, Yanfeng Shi, Collins Otieno Asweto, Lin Feng, Xiaozhe Yang, Yannan Zhang, Hejing Hu, Junchao Duan, Zhiwei Sun
There is compelling evidence that exposure to particulate matter (PM) is linked to lung tumorigenesis. However, there is not enough experimental evidence to support the specific mechanisms of PM2.5-induced DNA damage and cell cycle arrest in lung tumorigenesis. In this study, we investigated the toxic effects and molecular mechanisms of PM2.5 on bronchial epithelial (BEAS-2B) cells. PM2.5 exposure reduced cell viability and enhanced LDH activity. The cell growth curves of BEAS-2B cells decreased gradually with the increase in PM2...
September 18, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28915623/inhibition-of-the-pi3k-akt-mtor-pathway-activates-autophagy-and-compensatory-ras-raf-mek-erk-signalling-in-prostate-cancer
#2
Dominika E Butler, Christopher Marlein, Hannah F Walker, Fiona M Frame, Vincent M Mann, Matthew S Simms, Barry R Davies, Anne T Collins, Norman J Maitland
The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901503/high-glucose-and-high-insulin-conditions-promote-mcf%C3%A2-7-cell-proliferation-and-invasion-by-upregulating-irs1-and-activating-the-ras-raf-erk-pathway
#3
Mei-Lin Wei, Peng Duan, Zhi-Ming Wang, Miao Ding, Ping Tu
Diabetes mellitus is associated with an increased risk of breast cancer, but the molecular mechanism underlying this association remains unclear. The aim of the present study was to investigate the effect of high glucose and high insulin conditions on MCF‑7 breast cancer cells and to elucidate the molecular mechanisms underlying these effects. High glucose and high insulin conditions resulted in increased viability, proliferation, and invasion in MCF‑7 cells compared with normal glucose and low insulin conditions...
August 31, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28888848/prevention-of-oxytosis-induced-c-raf-down-regulation-by-arylthio-cyclopentenone-prostaglandins-is-neuroprotective
#4
Shoko Shibata, Kyoji Furuta, Kentaro Oh-Hashi, Hiroshi Ueda, Kazutoshi Kiuchi, Yoko Hirata
Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca(2+) influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line...
September 6, 2017: Toxicology
https://www.readbyqxmd.com/read/28874847/a-guanine-derivative-as-a-new-mek-inhibitor-produced-by-streptomyces-sp-mk63-43f2
#5
Masatomi Iijima, Yuji Kubota, Ryuichi Sawa, Yumiko Kubota, Masaki Hatano, Masayuki Igarashi, Manabu Kawada, Isao Momose, Mutsuhiro Takekawa, Masakatsu Shibasaki
Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK...
September 6, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28868020/erdheim-chester-disease-the-importance-of-information-integration
#6
Anna Nikonova, Khashayar Esfahani, Guillaume Chausse, Stephan Probst, Tina Petrogiannis-Haliotis, Hans Knecht, Genevieve Gyger
BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis disorder that utilizes the RAS-RAF-MEK-ERK pathway. It has a highly variable clinical presentation, where virtually any organ can be involved, thus having the potential of posing a great diagnostic challenge. Over half of the reported cases have the BRAF V600E mutation and have shown a remarkable response to vemurafenib. CASE PRESENTATION: We describe herein a patient with a history of stroke-like symptoms and retroperitoneal fibrosis that on initial pathology raised the possibility of IgG4-related disease...
May 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28855298/spinal-bdnf-induced-phrenic-motor-facilitation-requires-pkc%C3%AE-activity
#7
Ibis M Agosto-Marlin, Gordon S Mitchell
Spinal brain derived neurotrophic factor (BDNF) is necessary and sufficient to elicit certain forms of long-lasting phrenic motor facilitation (pMF). BDNF elicits pMF by binding to its high affinity receptor tropomyosin receptor kinase B (TrkB), potentially activating multiple downstream signaling cascades. Canonical BDNF/TrkB signaling includes three pathways: 1) the Ras/RAF/MEK/ERK MAP Kinase pathway; 2) the phosphatidylinositol 3-kinase/Akt pathway; and 3) the PLCγ/PKC pathway. Here, we demonstrate that spinal BDNF-induced pMF requires PLCγ/PKCθ in normal rats, but not MEK/ERK or PI3K/Akt signaling...
August 30, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28844715/manumycin-a-suppresses-exosome-biogenesis-and-secretion-via-targeted-inhibition-of-ras-raf-erk1-2-signaling-and-hnrnp-h1-in-castration-resistant-prostate-cancer-cells
#8
Amrita Datta, Hogyoung Kim, Madhu Lal, Lauren McGee, Adedoyin Johnson, Ahmed A Moustafa, Jennifer C Jones, Debasis Mondal, Marc Ferrer, Asim B Abdel-Mageed
Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds...
August 24, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28819643/membrane-localization-of-acetylated-cnk1-mediates-a-positive-feedback-on-raf-erk-signaling
#9
Adrian Fischer, Wignand W D Mühlhäuser, Bettina Warscheid, Gerald Radziwill
Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)-binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28781955/erbb2-signaling-epigenetically-suppresses-microrna-205-transcription-via-ras-raf-mek-erk-pathway-in-breast-cancer
#10
Takuya Hasegawa, Ryohei Adachi, Hitoshi Iwakata, Takayoshi Takeno, Koji Sato, Toshiyuki Sakamaki
We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect...
August 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28744398/kinase-inhibitors-of-her2-akt-pathway-induce-erk-phosphorylation-via-a-foxo-dependent-feedback-loop
#11
Smita Matkar, Chiying An, Xianxin Hua
Inhibitors of the HER2/PI3K/AKT pathway are being developed, and shown promise in clinical trials for various types of cancers. However, development of drug resistance is a challenging problem for therapy. Elucidating various adaptive pathways leading to resistance or reduced sensitivity to drugs targeting the HER2/PI3K/AKT pathway may provide new insights into countering the resistance. Epidermal growth factor receptor (EGFR, aka HER1), which can dimerize with HER2, can activate a cascade consisting of Ras/RAF/MEK/ERK, promoting tumorigenesis...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28740606/structure-guided-strategy-for-the-development-of-potent-bivalent-erk-inhibitors
#12
Bernhard C Lechtenberg, Peter D Mace, E Hampton Sessions, Robert Williamson, Romain Stalder, Yann Wallez, Gregory P Roth, Stefan J Riedl, Elena B Pasquale
ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28732393/microrna-30a-suppresses-tumor-progression-by-blocking-ras-raf-mek-erk-signaling-pathway-in-hepatocellular-carcinoma
#13
Kun Zhou, Xiaoyu Luo, Yu Wang, Dachun Cao, Gang Sun
Emerging reports suggest microRNAs (miRNAs) play a vital role in the progression of malignant tumors. MiR-30a is downregulated in a variety of cancers and acts as a tumor suppressing gene. However, the molecular mechanisms of miRNA-30a in hepatocellular carcinoma (HCC) are still unclear. Hereby, in this study, we detected that miR-30a expression was significantly down-regulated in both HCC tissues compared with adjacent non-cancerous liver tissues, and we also observed that miR-30a expression was lower in HCC cell lines than that of normal controls...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28724936/an-engineered-protein-antagonist-of-k-ras-b-raf-interaction
#14
Monique J Kauke, Michael W Traxlmayr, Jillian A Parker, Jonathan D Kiefer, Ryan Knihtila, John McGee, Greg Verdine, Carla Mattos, K Dane Wittrup
Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724426/high-expression-of-ets2-predicts-poor-prognosis-in-acute-myeloid-leukemia-and-may-guide-treatment-decisions
#15
Lin Fu, Huaping Fu, Qingyun Wu, Yifan Pang, Keman Xu, Lei Zhou, Jianlin Qiao, Xiaoyan Ke, Kailin Xu, Jinlong Shi
BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 (low)), high expression of ETS2 (ETS2 (high)) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100)...
July 19, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28724377/combination-therapy-for-melanoma-with-braf-mek-inhibitor-and-immune-checkpoint-inhibitor-a-mathematical-model
#16
Xiulan Lai, Avner Friedman
BACKGROUND: The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years...
July 19, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28718440/selective-targeting-of-rsk-isoforms-in-cancer
#17
REVIEW
Kimberly A Casalvieri, Christopher J Matheson, Donald S Backos, Philip Reigan
The p90 ribosomal S6 kinase family (RSK1-4) is a group of highly conserved Ser/Thr kinases that act as downstream effectors of the Ras/Raf/MEK/ERK signaling pathway. The RSKs phosphorylate a range of substrates involved in transcription, translation, cell cycle regulation, and cell survival. Although the RSKs have a high degree of sequence homology, their functional differences in cancer are of great interest. Current RSK inhibitors target more than one RSK isoform, and this may limit their efficacy as anticancer agents...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28694330/phosphorylation-of-the-c-raf-n-region-promotes-raf-dimerization
#18
Maho Takahashi, Yanping Li, Tara J Dillon, Yumi Kariya, Philip J S Stork
Activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop and the other lies within the N-terminal acidic region (N-region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341), and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylation of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization...
July 10, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28693259/rktg-overexpression-inhibits-proliferation-and-induces-apoptosis-of-human-leukemia-cells-via-suppression-of-the-erk-and-pi3k-akt-signaling-pathways
#19
Yingdong Xu, Na Deng, Xiaoou Wang, Yinghui Chen, Guiji Li, Hua Fan
Raf kinase trapping to Golgi (RKTG) is reported to be a tumor suppressor in a number of solid tumors due to its negative modulation of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. However, the role of RKTG in the progression of leukemia remains unknown. In the present study, a human leukemia U937 cell line overexpressing RKTG was established, and the effect of RKTG on proliferation, cell cycle and apoptosis of human leukemia cells was analyzed. The results of the present study demonstrated that exogenous overexpression of RKTG significantly inhibited cell proliferation, which was accompanied by cell cycle arrest...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28693200/sorafenib-induced-alteration-of-protein-glycosylation-in-hepatocellular-carcinoma-cells
#20
Tianhua Liu, Riqiang Liu, Shu Zhang, Kun Guo, Qinle Zhang, Wei Li, Yinkun Liu
Sorafenib is a multikinase inhibitor and is effective in treating hepatocellular carcinoma (HCC). However, it remains unknown whether sorafenib induces the alteration of protein glycosylation. The present study treated HCC MHCC97L and MHCC97H cells with a 50% inhibitory concentration of sorafenib. Following this treatment, alteration of protein glycosylation was detected using a lectin microarray. Compared with the controls, the binding capacity of glycoproteins extracted from sorafenib-treated HCC cells to the lectins Bauhinia purpurea lectin, Dolichos biflorus agglutinin, Euonymus europaeus lectin, Helix aspersa lectin, Helix pomatia lectin, Jacalin, Maclura pomifera lectin and Vicia villosa lectin were enhanced; while, the binding capacities to the lectins Caragana arborescens lectin, Lycopersicon esculentum lectin, Limulus polyphemus lectin, Maackia amurensis lecin I, Phaseolus vulgaris leucoagglutinin, Ricinus communis agglutinin 60, Sambucus nigra lectin and Solanum tuberosum lectin were reduced (spot intensity median/background intensity median ≥2, P<0...
July 2017: Oncology Letters
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