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https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#1
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
November 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27913220/mapk-erk-activity-is-required-for-the-successful-progression-of-mitosis-in-sea-urchin-embryos
#2
Mulner-Lorillon Odile, Chassé Héloïse, Morales Julia, Bellé Robert, Cormier Patrick
Using sea urchin embryos, we demonstrate that the MEK/MAPK/ERK cascade is essential for the proper progression of the cell cycle. Activation of a limited fraction of MAPK/ERK is required between S-phase and M-phase. Neither DNA replication nor CDK1 activation are impacted by the inhibition of this small active MAPK/ERK fraction. Nonetheless, the chromatin and spindle organisations are profoundly altered. Early morphological disorders induced by the absence of MAPK/ERK activation are correlated with an important inhibition of global protein synthesis and modification in the cyclin B accumulation profile...
November 29, 2016: Developmental Biology
https://www.readbyqxmd.com/read/27910068/endometrial-carcinoma-specific-targeted-pathways
#3
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/27905182/optimizing-combination-dabrafenib-and-trametinib-therapy-in-braf-mutation-positive-advanced-melanoma-patients-guidelines-from-australian-melanoma-medical-oncologists
#4
Victoria Atkinson, Georgina V Long, Alexander M Menzies, Grant McArthur, Matteo S Carlino, Michael Millward, Rachel Roberts-Thomson, Benjamin Brady, Richard Kefford, Andrew Haydon, Jonathan Cebon
BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT)...
December 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27903124/diagnosis-and-management-of-craniopharyngiomas-in-the-era-of-genomics-and-targeted-therapy
#5
Juan Carlos Martinez-Gutierrez, Megan R D'Andrea, Daniel P Cahill, Sandro Santagata, Fred G Barker, Priscilla K Brastianos
Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute-sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma...
December 2016: Neurosurgical Focus
https://www.readbyqxmd.com/read/27902699/modeling-cellular-noise-underlying-heterogeneous-cell-responses-in-the-epidermal-growth-factor-signaling-pathway
#6
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/27902464/expression-of-rab1a-is-upregulated-in-human-lung-cancer-and-associated-with-tumor-size-and-t-stage
#7
Xinxin Wang, Feng Liu, Xiaoyu Qin, Tinglei Huang, Bo Huang, Yanjie Zhang, Bin Jiang
Rab1A expression is associated with malignant phenotypes in several human tumors; however, the role of Rab1A in lung cancer is still unclear. In this study, we attempted to establish the role of Rab1A in major human lung cancer subtypes. Rab1A expression in different histological types of human lung cancer was analyzed in lung cancer tissues with paired adjacent noncancerous tissues and a large panel of lung cancer cell lines. The effect of Rab1A expression on multiple cancer-associated signaling pathways was also examined...
November 29, 2016: Aging
https://www.readbyqxmd.com/read/27901111/optogenetic-clustering-of-cnk1-reveals-mechanistic-insights-in-raf-and-akt-signalling-controlling-cell-fate-decisions
#8
Adrian Fischer, Bettina Warscheid, Wilfried Weber, Gerald Radziwill
Scaffold proteins such as the multidomain protein CNK1 orchestrate the signalling network by integrating and controlling the underlying pathways. Using an optogenetic approach to stimulate CNK1 uncoupled from upstream effectors, we identified selective clusters of CNK1 that either stimulate RAF-MEK-ERK or AKT signalling depending on the light intensity applied. OptoCNK1 implemented in MCF7 cells induces differentiation at low light intensity stimulating ERK activity whereas stimulation of AKT signalling by higher light intensity promotes cell proliferation...
November 30, 2016: Scientific Reports
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
#9
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
#10
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/27895796/promotion-of-metastasis-of-thyroid-cancer-cells-via-nrp-2-mediated-induction
#11
Dom-Gene Tu, Wen-Wei Chang, Ming-Shiou Jan, Chi-Wen Tu, Yin-Che Lu, Chien-Kuo Tai
Tumor-node-metastasis is one of the leading causes of morbidity and mortality in thyroid cancer patients. Upregulation of vascular endothelial growth factor-C (VEGF-C) increases the migratory ability of thyroid cancer cells to lymph nodes. Expression of neuropilin-2 (NRP-2), the co-receptor of VEGF-C, has been reported to be correlated with lymph node metastasis in human thyroid cancer. The present study investigated the role of VEGF-C/NRP-2 signaling in the regulation of metastasis of two different types of human thyroid cancer cells...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#12
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27893585/conjunctival-melanoma-responsive-to-combined-systemic-braf-mek-inhibitors
#13
Lora R Dagi Glass, Donald P Lawrence, Frederick A Jakobiec, Suzanne K Freitag
This report demonstrates a unique case of conjunctival melanoma harboring a BRAF V600E mutation responsive to systemic therapy with BRAF and MEK inhibitors. While systemic therapy would not be appropriate in patients with local disease alone, it may act therapeutically in cases of higher stage ocular surface and eyelid melanoma.
November 23, 2016: Ophthalmic Plastic and Reconstructive Surgery
https://www.readbyqxmd.com/read/27892777/uveitis-and-papillitis-in-the-setting-of-dabrafenib-and-trametinib-therapy-for-metastatic-melanoma-a-case-report
#14
Jennifer Lim, Anna J Lomax, Catriona McNeil, Brian Harrisberg
PURPOSE: To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma. METHODS: Retrospective medical chart review including radiologic and ophthalmologic investigations. RESULTS: A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring...
November 28, 2016: Ocular Immunology and Inflammation
https://www.readbyqxmd.com/read/27889448/inhibition-of-ras-raf-mek-erk-pathway-signaling-by-a-stress-induced-phospho-regulatory-circuit
#15
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/27885401/-cutaneous-side-effects-of-targeted-cancer-drugs
#16
REVIEW
J Below, B Homey, P A Gerber
In the past decades many new drugs were approved for the treatment of cancer and have been established as essential parts of various therapeutic regimens. In particular targeted therapies and immune checkpoint inhibitors that aim at specific carcinogenic signaling pathways or modulate the tumor-immune response have revolutionized cancer therapy. Despite their targeted actions, these drugs may lead to diverse adverse reactions. In particular, cutaneous toxicities represent a serious threat to patients' quality of life and may lead to dose reduction or therapy cessation...
November 24, 2016: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
https://www.readbyqxmd.com/read/27884331/inhibition-of-acquired-resistance-hepatocellular-carcinoma-cell-growth-by-combining-sorafenib-with-phosphoinositide-3-kinase-and-rat-sarcoma-inhibitor
#17
Chang-Hao Wu, Xiang Wu, Hong-Wei Zhang
BACKGROUND: To provide support for combined usage of phosphoinositide 3-kinase (PI3K) inhibitors or mitogen-activated protein kinase pathway inhibitors together with sorafenib in treatment of sorafenib-resistant hepatocellular carcinoma. MATERIALS AND METHODS: The sorafenib-resistant cell lines were established to evaluate the effects of MK-2206 2HCL, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, and PD0325901, an rat sarcoma (RAS) and/or extracellular signal-regulated kinase (ERK) inhibitor, on cell proliferation and apoptosis, as both single and combined treatments with sorafenib...
December 2016: Journal of Surgical Research
https://www.readbyqxmd.com/read/27884160/the-d-domain-of-lrrc4-anchors-erk1-2-in-the-cytoplasm-and-competitively-inhibits-mek-erk-activation-in-glioma-cells
#18
Zeyou Wang, Qin Guo, Rong Wang, Gang Xu, Peiyao Li, Yingnan Sun, Xiaoling She, Qiang Liu, Qiong Chen, Zhibin Yu, Changhong Liu, Jing Xiong, Guiyuan Li, Minghua Wu
BACKGROUND: As a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear. METHODS: The interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro...
November 25, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27881782/consolidation-of-goal-directed-action-depends-on-mapk-erk-signaling-in-rodent-prelimbic-cortex
#19
Genevra Hart, Bernard W Balleine
: The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2-3 and 5-6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27879454/molecular-mechanisms-of-androstenediol-in-the-regulation-of-the-proliferative-process-of-human-endometrial-cells
#20
Francisca Plaza-Parrochia, Lorena Oróstica, Paula García, Carolina Vera, Carmen Romero, Luis Valladares, Margarita Vega
Proliferation in endometria of women with polycystic ovarian syndrome (PCOS) is increased, similar to the biosynthesis of androstenediol (estrogenic metabolite). As previously shown, in human endometrial cells, androstenediol increases CYCLIN D1 levels and KI67 and decreases P27 content. The objective of the present investigation was to determine the mechanisms by which androstenediol promotes endometrial cell-cycle progression. Estrogen receptor α (ERα) activation and changes in CYCLIN D1 and P27 levels were evaluated by Western blot in T-HESC and St-T1b endometrial cell lines, using receptor antagonists; activation of PI3K-protein kinase B (AKT) and mitogen-activated protein kinases-extracellular signal-regulated kinases (MAPK-ERK)1/2 pathways was evaluated using PI3K, MAPK/ERK kinase (MEK)1/2, and RNA-polymerase II inhibitors...
November 21, 2016: Reproductive Sciences
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