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RAS/RAF/ERK

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https://www.readbyqxmd.com/read/27926503/foxd3-is-a-tumor-suppressor-of-colon-cancer-by-inhibiting-egfr-ras-raf-mek-erk-signal-pathway
#1
Kun Li, Qunfeng Guo, Jun Yang, Hui Chen, Kewen Hu, Juan Zhao, Shunxin Zheng, Xiufeng Pang, Sufang Zhou, Yongyan Dang, Lei Li
Forkhead box D3 (FOXD3), as a transcriptional repressor, is well known to be involved in the regulation of development. Although FoxD3 is associated with several cancers, its role in colon cancer and the underlying mechanism are still unclear. Here, we first showed that FOXD3 knockdown dramatically increased the proliferation of human colon cancer cells, enhanced cell invasive ability and inhibited cell apoptosis. In vivo xenograft studies confirmed that the FOXD3-knockdown cells were more tumorigenic than the controls...
December 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27924574/genetic-validation-of-cell-proliferation-via-ras-independent-activation-of-the-raf-mek-erk-pathway
#2
Carmen G Lechuga, Lucía Simón-Carrasco, Harrys K C Jacob, Matthias Drosten
Signaling transmitted by the Ras family of small GTPases (H-, N-, and K-Ras) is essential for proliferation of mouse embryonic fibroblasts (MEFs). However, constitutive activation of the downstream Raf/Mek/Erk pathway can bypass the requirement for Ras proteins and allow cells to proliferate in the absence of the three Ras isoforms. Here we describe a protocol for a colony formation assay that permits evaluating the role of candidate proteins that are positive or negative regulators of cell proliferation mediated via Ras-independent Raf/Mek/Erk pathway activation...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924565/analysis-of-ras-erk-compartmentalization-by-subcellular-fractionation
#3
Lorena Agudo-Ibañez, Piero Crespo, Berta Casar
A vast number of stimuli use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their cognate receptors, in order to regulate multiple cellular functions, including key processes such as proliferation, cell cycle progression, differentiation, and survival. The duration, intensity and specificity of the responses are, in part, controlled by the compartmentalization/subcellular localization of the signaling intermediaries. Ras proteins are found in different plasma membrane microdomains and endomembranes...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924558/structural-studies-of-erk2-protein-complexes
#4
Johannes F Weijman, Stefan J Riedl, Peter D Mace
ERK1 and ERK2 (ERK1/2) are the primary effector kinases of the RAS-RAF-MEK-ERK signaling pathway. A variety of substrates and regulatory partners associate with ERK1/2 through distinct D-peptide- and DEF-docking sites on their kinase domains. While understanding of D-peptides that bind to ERK1/2 has become increasingly clear over the last decade, only more recently have structures of proteins interacting with other binding sites on ERK1/2 become available. PEA-15 is a 130-residue ERK1/2 regulator that engages both the D-peptide- and DEF-docking sites of ERK kinases, and directly sequesters the ERK2 activation loop in various different phosphorylation states...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924064/toward-the-use-of-precision-medicine-for-the-treatment-of-head-and-neck-squamous-cell-carcinoma
#5
REVIEW
Wang Gong, Yandi Xiao, Zihao Wei, Yao Yuan, Min Qiu, Chongkui Sun, Xin Zeng, Xinhua Liang, Mingye Feng, Qianming Chen
Precision medicine is a new strategy that aims at preventing and treating human diseases by focusing on individual variations in people's genes, environment and lifestyle. Precision medicine has been used for cancer diagnosis and treatment and shows evident clinical efficacy. Rapid developments in molecular biology, genetics and sequencing technologies, as well as computational technology, has enabled the establishment of "big data", such as the Human Genome Project, which provides a basis for precision medicine...
December 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27910068/endometrial-carcinoma-specific-targeted-pathways
#6
Nuria Eritja, Andree Yeramian, Bo-Juen Chen, David Llobet-Navas, Eugenia Ortega, Eva Colas, Miguel Abal, Xavier Dolcet, Jaume Reventos, Xavier Matias-Guiu
Endometrial cancer (EC) is the most common gynecologic malignancy in the western world with more than 280,000 cases per year worldwide. Prognosis for EC at early stages, when primary surgical resection is the most common initial treatment, is excellent. Five-year survival rate is around 70 %.Several molecular alterations have been described in the different types of EC. They occur in genes involved in important signaling pathways. In this chapter, we will review the most relevant altered pathways in EC, including PI3K/AKT/mTOR, RAS-RAF-MEK-ERK, Tyrosine kinase, WNT/β-Catenin, cell cycle, and TGF-β signaling pathways...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27902699/modeling-cellular-noise-underlying-heterogeneous-cell-responses-in-the-epidermal-growth-factor-signaling-pathway
#7
Kazunari Iwamoto, Yuki Shindo, Koichi Takahashi
Cellular heterogeneity, which plays an essential role in biological phenomena, such as drug resistance and migration, is considered to arise from intrinsic (i.e., reaction kinetics) and extrinsic (i.e., protein variability) noise in the cell. However, the mechanistic effects of these types of noise to determine the heterogeneity of signal responses have not been elucidated. Here, we report that the output of epidermal growth factor (EGF) signaling activity is modulated by cellular noise, particularly by extrinsic noise of particular signaling components in the pathway...
November 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27900042/antitumor-activity-of-7rh-a-discoidin-domain-receptor-1-inhibitor-alone-or-in-combination-with-dasatinib-exhibits-antitumor-effects-in-nasopharyngeal-carcinoma-cells
#8
Qiu-Ping Lu, Wen-Dan Chen, Jie-Ren Peng, Yao-Dong Xu, Qian Cai, Gong-Kan Feng, Ke Ding, Xiao-Feng Zhu, Zhong Guan
Dysregulation of the discoidin domain receptors (DDRs) has been implicated in the development of numerous types of tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas. Furthermore, agents that inhibit DDR1 activity are hypothesized to be useful for the treatment of nasopharyngeal carcinoma (NPC). The aim of the present study was to evaluate the effect of the DDR1 inhibitory (3-(2-(pyrazolo(1,5-a)pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH, in NPC cells both in vitro and in vivo, and its effect when used in combination with dasatinib, a SRC family kinase (SFK) inhibitor...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899961/the-ras-raf-mek-erk-signaling-pathway-and-its-role-in-the-occurrence-and-development-of-hcc
#9
Lei Li, Guo-Dong Zhao, Zhe Shi, Li-Li Qi, Li-Yuan Zhou, Ze-Xian Fu
Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide and has a very poor prognosis. Its occurrence has been on the increase in recent years. Surgical resection and liver transplantation are the primary methods of treatment for HCC patients, but can only be applied to 15% of patients. The median survival time of unresectable or metastasizing HCC patients is only a few months. Existing systemic treatment methods are not effective for advanced HCC patients and a new method of treatment is needed for these patients...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27889448/inhibition-of-ras-raf-mek-erk-pathway-signaling-by-a-stress-induced-phospho-regulatory-circuit
#10
Daniel A Ritt, María T Abreu-Blanco, Lakshman Bindu, David E Durrant, Ming Zhou, Suzanne I Specht, Andrew G Stephen, Matthew Holderfield, Deborah K Morrison
Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27883322/molecular-biology-and-genetic-mechanisms-in-the-progression-of-the-malignant-skin-melanoma
#11
Sofija Pejkova, Gjorgje Dzokic, Smilja Tudzarova-Gjorgova, Sasho Panov
Malignant skin melanoma is a tumor deriving from transformed skin melanocytes as a result of complex interactions between genetic and environmental factors. This melanoma has a potential to metastasize early and very often it is resistant to the existing modalities of the systemic therapy. As in any other neoplasms, certain types of melanoma may skip certain stages of progression. The progression from one stage to another is accompanied by specific biological changes. Several key changes in the melanoma tumorogenesis influence the regulation of the cell proliferation and vitality, including the RAS-RAF-ERK, PI3K-AKT, and p16INK4/CDK4/RB pathways...
November 1, 2016: Prilozi (Makedonska Akademija Na Naukite i Umetnostite. Oddelenie za Medicinski Nauki)
https://www.readbyqxmd.com/read/27872195/estrogen-receptors-and-signaling-in-fibroids-role-in-pathobiology-and-therapeutic-implications
#12
Mostafa A Borahay, Mehmet R Asoglu, Aymara Mas, Sarah Adam, Gokhan S Kilic, Ayman Al-Hendy
Uterine fibroids are the most common gynecologic tumors with a significant medical and financial burden. Several genetic, hormonal, and biological factors have been shown to contribute to the development and growth of fibroid tumors. Of these factors, estrogen is particularly critical since fibroids are considered estrogen dependent because no prepubertal cases have been described in the literature and tumors tend to regress after menopause. Understanding the role of estrogen in fibroids is not only important for understanding the pathobiology of fibroids but also for the development of successful therapeutics...
November 20, 2016: Reproductive Sciences
https://www.readbyqxmd.com/read/27870838/a-computationally-engineered-ras-rheostat-reveals-ras-erk-signaling-dynamics
#13
John C Rose, Po-Ssu Huang, Nathan D Camp, Jordan Ye, Andrew M Leidal, Inna Goreshnik, Bridget M Trevillian, Miles S Dickinson, Daniel Cunningham-Bryant, Jayanta Debnath, David Baker, Alejandro Wolf-Yadlin, Dustin J Maly
Synthetic protein switches controlled with user-defined inputs are powerful tools for studying and controlling dynamic cellular processes. To date, these approaches have relied primarily on intermolecular regulation. Here we report a computationally guided framework for engineering intramolecular regulation of protein function. We utilize this framework to develop chemically inducible activator of RAS (CIAR), a single-component RAS rheostat that directly activates endogenous RAS in response to a small molecule...
November 21, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27869219/a-novel-role-of-spred2-in-the-colonic-epithelial-cell-homeostasis-and-inflammation
#14
Sakuma Takahashi, Teizo Yoshimura, Takahiro Ohkura, Masayoshi Fujisawa, Soichiro Fushimi, Toshihiro Ito, Junya Itakura, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto, Akihiro Matsukawa
Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naïve Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index...
November 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27822414/differences-in-mek-inhibitor-efficacy-in-molecularly-characterized-low-grade-serous-ovarian-cancer-cell-lines
#15
Marta Llauradó Fernández, Gabriel E DiMattia, Amy Dawson, Sylvia Bamford, Shawn Anderson, Bryan T Hennessy, Michael S Anglesio, Trevor G Shepherd, Clara Salamanca, Josh Hoenisch, Anna Tinker, David G Huntsman, Mark S Carey
Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations in RAS or RAF, leading to several clinical trials evaluating MEK inhibitors (MEKi). As LGSC cell lines and xenografts have been difficult to establish, little is known about the efficacy and on-target activity of MEKi treatment in this disease. We compared four different MEKi (trametinib, selumetinib, binimetinib and refametinib) in novel LGSC patient-derived cell lines. Molecular characterization of these cells included copy-number variation and hotspot mutational analysis...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27816338/-adult-langerhans-cell-histiocytosis
#16
Mathilde de Menthon, Véronique Meignin, Alfred Mahr, Abdellatif Tazi
Langerhans cell histiocytosis (LCH) is a rare disease affecting both genders and can occur at any age. It often evolves through successive flares, and its severity varies from benign forms that don't require treatment to life threatening disease. Some patients have important functional impairment with psychological and social consequences and prolonged disability. LCH may affect only one organ, with uni- or multifocal involvement or be multisystem disease involving multiple organs. The organs most frequently involved are bones, lung, skin and the endocrinal system...
November 2, 2016: La Presse Médicale
https://www.readbyqxmd.com/read/27760319/phenotypic-characterization-of-a-comprehensive-set-of-mapk1-erk2-missense-mutants
#17
Lisa Brenan, Aleksandr Andreev, Ofir Cohen, Sasha Pantel, Atanas Kamburov, Davide Cacchiarelli, Nicole S Persky, Cong Zhu, Mukta Bagul, Eva M Goetz, Alex B Burgin, Levi A Garraway, Gad Getz, Tarjei S Mikkelsen, Federica Piccioni, David E Root, Cory M Johannessen
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27748799/growth-arrest-by-activated-braf-and-mek-inhibition-in-human-anaplastic-thyroid-cancer-cells
#18
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27741509/mek1-is-required-for-the-development-of-nras-driven-leukemia
#19
Joanna D Nowacka, Christian Baumgartner, Cristiana Pelorosso, Mareike Roth, Johannes Zuber, Manuela Baccarini
The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context...
October 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27733477/clinically-viable-gene-expression-assays-with-potential-for-predicting-benefit-from-mek-inhibitors
#20
Roz G Brant, Alan Sharpe, Tom Liptrot, Jonathan Dry, Elizabeth A Harrington, J Carl Barrett, Nicky Whalley, Chris Womack, Paul D Smith, Darren Hodgson
PURPOSE: To develop a clinically viable gene expression assay to measure RAS/RAF/MEK/ERK (RAS-ERK) pathway output suitable for hypothesis testing in non-small cell lung cancer (NSCLC) clinical studies. EXPERIMENTAL DESIGN: A published MEK-functional-activation signature (MEK signature) that measures RAS-ERK functional output was optimized for NSCLC in silico. NanoString assays were developed for the NSCLC optimized MEK signature and the 147-gene RAS signature. First, platform transfer from Affymetrix to NanoString, and signature modulation following treatment with KRAS siRNA and MEK inhibitor, were investigated in cell lines...
October 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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