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https://www.readbyqxmd.com/read/28819643/membrane-localization-of-acetylated-cnk1-mediates-a-positive-feedback-on-raf-erk-signaling
#1
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/28819429/map2k1-mutation-in-colorectal-cancer-patients-therapeutic-challenge-using-patient-derived-tumor-cell-lines
#2
J E Kim, K K Kim, S Y Kim, J Lee, S H Park, J O Park, Y S Park, H Y Lim, W K Kang, S T Kim
BACKGROUND: The MAP2K1 K57T mutation is known to be a potential mechanism of primary and secondary resistance to EGFR inhibitors in metastatic colorectal cancer (CRC) and has also been reported to promote resistance to BRAF and MEK inhibitors. It is important to overcome therapeutic resistance to EGFR inhibitors to improve the treatment outcomes of metastatic CRC. METHODS: We established patient-derived tumor cells (PDCs) from metastatic lesions that newly appeared during treatment with a BRAF inhibitor (LGX-818) plus an EGFR inhibitor (cetuximab) in a patient with BRAF-mutant CRC...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28818668/a-bipolar-role-of-the-transcription-factor-erg-for-cnidarian-germ-layer-formation-and-apical-domain-patterning
#3
Aldine R Amiel, Hereroa Johnston, Taylor Chock, Paul Dahlin, Marta Iglesias, Michael Layden, Eric Röttinger, Mark Q Martindale
Germ layer formation and axial patterning are biological processes that are tightly linked during embryonic development of most metazoans. In addition to canonical WNT, it has been proposed that ERK-MAPK signaling is involved in specifying oral as well as aboral territories in cnidarians. However, the effector and the molecular mechanism underlying latter phenomenon is unknown. By screening for potential effectors of ERK-MAPK signaling in both domains, we identified a member of the ETS family of transcription factors, Nverg that is bi-polarily expressed prior to gastrulation...
August 14, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28818497/drp1-regulates-mitochondrial-morphology-and-cell-proliferation-in-cutaneous-squamous-cell-carcinoma
#4
Shinya Kitamura, Teruki Yanagi, Keisuke Imafuku, Hiroo Hata, Riichiro Abe, Hiroshi Shimizu
BACKGROUND: Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC). OBJECTIVE: To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS: We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1...
August 5, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28816409/genistein-represses-pepck-c-expression-in-an-insulin-independent-manner-in-hepg2-cells-and-in-alloxan-induced-diabetic-mice
#5
Barilin Dkhar, Kitboklang Khongsti, Daiahun Thabah, Donkupar Syiem, Kapaettu Satyamoorthy, Bidyadhar Das
Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of the genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to diferrent concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signalling pathways was studied...
August 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28815043/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#6
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28811486/detecting-human-melanoma-cell-re-differentiation-following-braf-or-heat-shock-protein-90-inhibition-using-photoacoustic-and-magnetic-resonance-imaging
#7
Anant Shah, Teresa Delgado-Goni, Teresa Casals Galobart, Slawomir Wantuch, Yann Jamin, Martin O Leach, Simon P Robinson, Jeffrey Bamber, Mounia Beloueche-Babari
Targeted therapies specific to the BRAF-MEK-ERK signaling pathway have shown great promise in the treatment of malignant melanoma in the last few years, with these drugs now commonly used in clinic. Melanoma cells treated using these agents are known to exhibit increased levels of melanin pigment and tyrosinase activity. In this study we assessed the potential of non-invasive imaging approaches (photoacoustic imaging (PAI) and magnetic resonance imaging (MRI)) to detect melanin induction in SKMEL28 human melanoma cells, following inhibition of Hsp90 and BRAF signaling using 17-AAG and vemurafenib, respectively...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808415/foxo-signaling-pathways-as-therapeutic-targets-in-cancer
#8
REVIEW
Mohd Farhan, Haitao Wang, Uma Gaur, Peter J Little, Jiangping Xu, Wenhua Zheng
Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28808038/the-phosphatidylinositol-3-kinase-pathway-as-a-potential-therapeutic-target-in-bladder-cancer
#9
Shuxiong Zeng, Yanjun Zhu, Ai-Hong Ma, Weimin Yu, Hongyong Zhang, Tzu-Yin Lin, Wei Shi, Clifford G Tepper, Paul T Henderson, Susan Airhart, Jianming Guo, Chuanliang Xu, Ralph de Vere White, Chong-Xian Pan
PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. EXPERIMENTAL DESIGN: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine...
August 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#10
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28801607/enhancing-nk-cell-mediated-cytotoxicity-to-cisplatin-resistant-lung-cancer-cells-via-mek-erk-signaling-inhibition
#11
Li Yang, MingJing Shen, Li Jun Xu, Xiaodong Yang, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell's function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28800603/genetic-variants-specific-to-aging-related-verbal-memory-insights-from-gwass-in-a-population-based-cohort
#12
Thalida E Arpawong, Neil Pendleton, Krisztina Mekli, John J McArdle, Margaret Gatz, Chris Armoskus, James A Knowles, Carol A Prescott
Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60...
2017: PloS One
https://www.readbyqxmd.com/read/28800030/response-to-targeted-therapy-in-two-patients-with-metastatic-melanoma-carrying-rare-braf-exon-15-mutations-a598_t599insv-and-v600_k601delinse
#13
Aljosja Rogiers, Sara Vander Borght, Krizia Tuand, Pascal Wolter, Marguerite Stas, Veerle Boecxstaens, Marjan Garmyn, Joost J van den Oord, Peter Vandenberghe, Oliver Bechter
Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway. This highlights the importance of using tests that detect both V600E/K and non-V600E/K BRAF mutations to keep open the possibility of treatment with targeted therapy in patients with uncommon, yet potentially actionable, BRAF exon 15 mutations...
August 10, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28798778/tumorigenic-and-differentiation-potentials-of-embryonic-stem-cells-depend-on-tgf%C3%AE-family-signaling-lessons-from-teratocarcinoma-cells-stimulated-to-differentiate-with-retinoic-acid
#14
Olga Gordeeva, Sergey Khaydukov
A significant challenge for the development of safe pluripotent stem cell-based therapies is the incomplete in vitro differentiation of the pluripotent stem cells and the presence of residual undifferentiated cells initiating teratoma development after transplantation in recipients. To understand the mechanisms of incomplete differentiation, a comparative study of retinoic acid-induced differentiation of mouse embryonic stem (ES) and teratocarcinoma (EC) cells was conducted. The present study identified differences in proliferative activity, differentiation, and tumorigenic potentials between ES and EC cells...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28798732/activation-of-erk-signaling-via-tlr11-induces-il-12p40-production-in-peritoneal-macrophages-challenged-by-neospora-caninum
#15
Xiaoxia Jin, Pengtao Gong, Xichen Zhang, Guojiang Li, Tao Zhu, Mengge Zhang, Jianhua Li
Neospora caninum, an obligate intracellular protozoan parasite, can infect a large variety of vertebrate hosts including the most economically important cattle. Infection with N. caninum is a main cause of abortion in both dairy and beef cattle, which causes great economic losses worldwide. However, the mechanism of host cell infection by N. caninum has not been fully elucidated, especially in terms of inflammatory responses. In this study, the effect of TLR-ERK signaling pathway on the synthesis of pro-inflammatory interleukin-12p40 in mouse peritoneal macrophages (PMϕ) challenged by N...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#16
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28797602/venlafaxine-exerts-antidepressant-effects-possibly-by-activating-mapk-erk1-2-and-p13k-akt-pathways-in-the-hippocampus
#17
Peng Shen, Qingchuan Hu, Meixue Dong, Shunjie Bai, Zihong Liang, Zhi Chen, Pengfei Li, Zicheng Hu, Xiaogang Zhong, Dan Zhu, Haiyang Wang, Peng Xie
Serotonin noradrenaline reuptake inhibitors are effective antidepressant drugs, which include venlafaxine and duloxetine. Venlafaxine is commonly used in a clinical context, but the molecular biological mechanisms behind its effects have not been fully determined. Here, we explored the potential biological effects of venlafaxine on mouse hippocampus. Mice were randomly divided into two groups and injected daily with 0.9% NaCl solution or venlafaxine. A GC-MS-based metabolomic approach was used to identify possible metabolic differences between these groups, and the key proteins involved in the relevant pathways were validated by western blotting...
August 8, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28797567/docosahexaenoic-acid-induces-glial-cell-line-derived-neurotrophic-factor-release-in-c6-glioma-cells-implications-of-antidepressant-effects-for-docosahexaenoic-acid
#18
Lanqiu Zhang, Zhuoran Zhu, Zhoubin Tan, Hongyan Luo, Xinwu Hu, Yan Li
Dietary deficiency of n-3 polyunsaturated fatty acids (PUFAs) is involved in the pathophysiology and etiology of major depressive disorder. Supplementation with docosahexaenoic acid (DHA) exerts antidepressant-like effect; however, the molecular mechanism of DHA action remains unclear. Here we examined the effects of DHA on the modulation of glial cell line-derived neurotrophic factor (GDNF), which is essential for neural development, plasticity, neurogenesis, and survival. We demonstrated that DHA treatment significantly increased GDNF release in a concentration dependent manner in rat C6 glioma cells (C6 cells) and primary cultured rat astrocytes, which is also associated with increased expression of GDNF mRNA...
August 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28797232/prognostic-significance-of-braf-and-nras-mutations-in-melanoma-a-german-study-from-routine-care
#19
Markus V Heppt, Timo Siepmann, Jutta Engel, Gabriele Schubert-Fritschle, Renate Eckel, Laura Mirlach, Thomas Kirchner, Andreas Jung, Anja Gesierich, Thomas Ruzicka, Michael J Flaig, Carola Berking
BACKGROUND: Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear. METHODS: The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing...
August 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28791489/metalloprotease-dependent-activation-of-egfr-modulates-cd44-cd24-populations-in-triple-negative-breast-cancer-cells-through-the-mek-erk-pathway
#20
Randi Wise, Anna Zolkiewska
PURPOSE: The CD44(+)/CD24(-) cell phenotype is enriched in triple negative breast cancers, is associated with tumor invasive properties, and serves as a cell surface marker profile of breast cancer stem-like cells. Activation of Epidermal Growth Factor Receptor (EGFR) promotes the CD44(+)/CD24(-) phenotype, but the specific signaling pathway downstream of EGFR responsible for this effect is not clear. The purpose of this study was to determine the role of the MEK/ERK pathway in the expansion of CD44(+)/CD24(-) populations in TNBC cells in response to EGFR activation...
August 8, 2017: Breast Cancer Research and Treatment
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