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https://www.readbyqxmd.com/read/29713055/a-kinome-wide-high-content-sirna-screen-identifies-mek5-erk5-signaling-as-critical-for-breast-cancer-cell-emt-and-metastasis
#1
Simona Pavan, Nathalie Meyer-Schaller, Maren Diepenbruck, Ravi Kiran Reddy Kalathur, Meera Saxena, Gerhard Christofori
An epithelial to mesenchymal transition (EMT) has been correlated to malignant tumor progression and metastasis by promoting cancer cell migration and invasion and chemoresistance. Hence, finding druggable EMT effectors is critical to efficiently interfere with metastasis formation and to overcome therapy resistance. We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells...
May 1, 2018: Oncogene
https://www.readbyqxmd.com/read/29595072/platycodin-d-reverses-pathological-cardiac-hypertrophy-and-fibrosis-in-spontaneously-hypertensive-rats
#2
Yuan-Chuan Lin, Yu-Chen Lin, Wei-Wen Kuo, Chia-Yao Shen, Yi-Chang Cheng, Yueh-Min Lin, Ruey-Lin Chang, Vijaya V Padma, Chih-Yang Huang, Chih-Yang Huang
Platycodin D (PD) is the main active saponin isolated from Platycodon grandiflorum (PG) and is reported to exhibit anticancer, anti-angiogenic, anti-inflammation and anti-obesity biological effects. The current study aims to evaluate the therapeutic efficacy of PD in cardiac fibrosis and for hypertrophy in spontaneous hypertension rats (SHRs) and to verify inhibition of the signaling pathway. Significant increases in the cardiac functional indices of left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs); the eccentric hypertrophy marker p-MEK5; concentric hypertrophy markers, such as CaMKII[Formula: see text] and calcineurin; and expression levels of NFATc3, p-GATA4 and BNP were observed in spontaneously hypertensive groups...
March 29, 2018: American Journal of Chinese Medicine
https://www.readbyqxmd.com/read/29567200/the-mek5-erk5-mitogen-activated-protein-kinase-cascade-is-an-effector-pathway-of-bone-sustaining-bisphosphonates-that-regulates-osteogenic-differentiation-and-mineralization
#3
Christian Adam, Lucia Glück, Regina Ebert, Matthias Goebeler, Franz Jakob, Marc Schmidt
Bisphosphonates play an important role in the treatment of metabolic bone diseases such as osteoporosis. In addition to their anti-resorptive activity by triggering osteoclast apoptosis, nitrogen-containing bisphosphonates (N-BP) may also influence osteogenic differentiation, which might rely on their capacity to inhibit the mevalonate pathway. In vascular endothelial cells inhibition of this pathway by cholesterol-lowering statins activates the MEK5/ERK5 mitogen-activated protein kinase cascade, which plays an important role in cellular differentiation, apoptosis or inflammatory processes...
March 19, 2018: Bone
https://www.readbyqxmd.com/read/29483645/erk5-is-activated-by-oncogenic-braf-and-promotes-melanoma-growth
#4
Ignazia Tusa, Sinforosa Gagliardi, Alessandro Tubita, Silvia Pandolfi, Carmelo Urso, Lorenzo Borgognoni, Jinhua Wang, Xianming Deng, Nathanael S Gray, Barbara Stecca, Elisabetta Rovida
Malignant melanoma is among the most aggressive cancers and its incidence is increasing worldwide. Targeted therapies and immunotherapy have improved the survival of patients with metastatic melanoma in the last few years; however, available treatments are still unsatisfactory. While the role of the BRAF-MEK1/2-ERK1/2 pathway in melanoma is well established, the involvement of mitogen-activated protein kinases MEK5-ERK5 remains poorly explored. Here we investigated the function of ERK5 signaling in melanoma...
May 2018: Oncogene
https://www.readbyqxmd.com/read/29467254/bdnf-activates-an-nfi-dependent-neurodevelopmental-timing-program-by-sequestering-nfatc4
#5
Baojin Ding, Paul R Dobner, Debra Mullikin-Kilpatrick, Wei Wang, Hong Zhu, Chi-Wing Chow, John W Cave, Richard M Gronostajski, Daniel L Kilpatrick
We show that BDNF regulates the timing of neurodevelopment via a novel mechanism of extranuclear sequestration of NFATc4 in Golgi. This leads to accelerated derepression of an NFI temporal occupancy gene program in cerebellar granule cells that includes Bdnf itself, revealing an autoregulatory loop within the program driven by BDNF and NFATc4.
April 15, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29309787/discovery-and-characterization-of-an-iminocoumarin-scaffold-as-an-inhibitor-of-mekk2-map3k2
#6
Syed Ahmad, Valentine R St Hilaire, Srinivasa R Dandepally, Gary L Johnson, Alfred L Williams, John E Scott
The kinase MEKK2 (MAP3K2) activates the MEK5/ERK5 cell signaling pathway and may play an important role in tumor growth and metastasis. Thus, MEKK2 may represent a novel kinase target for cancer. In order to identify inhibitors of MEKK2, we screened a library of compounds using a high throughput MEKK2 intrinsic ATPase enzyme assay. We identified two hits with validated structures and confirmed activity in the primary assay (IC50 values = 322 nM and 7.7 μM) and two orthogonal MEKK2 biochemical assays...
January 29, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29285799/biological-effects-of-melatonin-on-osteoblast-osteoclast-cocultures-bone-and-quality-of-life-implications-of-a-role-for-mt2-melatonin-receptors-mek1-2-and-mek5-in-melatonin-mediated-osteoblastogenesis
#7
Sifat Maria, Rebekah M Samsonraj, Fahima Munmun, Jessica Glas, Maria Silvestros, Mary P Kotlarczyk, Ryan Rylands, Amel Dudakovic, Andre J van Wijnen, Larry T Enderby, Holly Lassila, Bala Dodda, Vicki L Davis, Judy Balk, Matt Burow, Bruce A Bunnell, Paula A Witt-Enderby
The Melatonin Osteoporosis Prevention Study (MOPS) demonstrated that nightly melatonin resulted in a time-dependent decrease in equilibrium ratios of serum osteoclasts and osteoblasts in perimenopausal women. This study examines mechanisms related to the ratios of osteoblasts and osteoclasts using coculture models (transwell or layered) of human mesenchymal stem cell (MSC) and human peripheral blood monocytes (PBMCs). Human MSC/PBMC cocultures exposed to melatonin in osteogenic (OS+) medium for 21 days induced osteoblast differentiation and mineralization; however, only in layered cocultures did melatonin inhibit osteoclastogenesis...
April 2018: Journal of Pineal Research
https://www.readbyqxmd.com/read/29113229/fatty-acid-synthase-affects-expression-of-erbb-receptors-in-epithelial-to-mesenchymal-transition-of-breast-cancer-cells-and-invasive-ductal-carcinoma
#8
Tingting Chen, Lan Zhou, Hua Li, Yuan Tian, Junqin Li, Lihua Dong, Yuhua Zhao, Dapeng Wei
The aim of the present study was to investigate changes in the expression of ErbBs during epithelial-mesenchymal transition (EMT) of breast cancer cells and its association with the expression of fatty acid synthase (FASN). MCF-7-MEK5 cells were used as the experimental model, while MCF-7 cells were used as a control. Tumor cells were implanted into nude mice for in vivo analysis. Cerulenin was used as a FASN inhibitor. Reverse transcription-polymerase chain reaction and western blot analysis were used to detect expression levels of FASN and ErbB1-4...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29104011/oxytocin-inhibits-ox-ldl-induced-adhesion-of-monocytic-thp-1-cells-to-human-brain-microvascular-endothelial-cells
#9
Shuyan Liu, Shengying Pan, Jing Tan, Weina Zhao, Fengguo Liu
The attachment of monocytes to human brain microvascular endothelial cells (HBMVEs) caused by oxidized low-density lipoprotein (ox-LDL) is associated with an early event and the pathological progression of cerebrovascular diseases. Oxytocin (OT) is a human peptide hormone that is traditionally used as a medication to facilitate childbirth. However, little information is available regarding the physiological function of OT in brain endothelial dysfunction. In the present study, our results indicate that the oxytocin receptor (OTR) was expressed in human brain microvascular endothelial cells (HBMVEs) and was upregulated in response to ox-LDL in a concentration-dependent manner...
December 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29096169/lunasin-abrogates-monocytes-to-endothelial-cells
#10
Yongjun Zhu, Hui Li, Xuezhen Wang
The adherence of monocytes to endothelial cells plays a causal role in the early development of atherosclerosis and is driven by several inflammatory stimuli, which includes oxidized low-density lipoprotein (ox-LDL). Lunasin, a natural peptide identified in soybean seeds, soy-derived food products, other grains and herbal plants, has been found to exert numerous biological activities, including anti-inflammatory and antioxidant properties. However, little is known regarding the mechanism of action of lunasin in ox-LDL-induced endothelial inflammation...
December 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28639275/statin-regulated-erk5-stimulates-tight-junction-formation-and-reduces-permeability-in-human-cardiac-endothelial-cells
#11
Emma L Wilkinson, James E Sidaway, Michael J Cross
The MEKK3/MEK5/ERK5 signaling axis is required for cardiovascular development in vivo. We analyzed the physiological role of ERK5 in cardiac endothelial cells and the consequence of activation of this kinase by the statin class of HMG Co-A reductase inhibitor drugs. We utilized human cardiac microvascular endothelial cells (HCMECs) and altered ERK5 expression using siRNA mediated gene silencing or overexpression of constitutively active MEK5 and ERK5 to reveal a role for ERK5 in regulating endothelial tight junction formation and cell permeability...
January 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28540300/extracellular-signal-regulated-kinase-5-is-required-for-low-concentration-h-2-o-2-induced-angiogenesis-of-human-umbilical-vein-endothelial-cells
#12
Shan Jiang, Dongxin Zhang, Hong Huang, Yonghong Lei, Yan Han, Weidong Han
Background . The aim of this study was to assess the effects of low concentrations of H2 O2 on angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro and explore the underlying mechanisms. Methods . HUVECs were cultured and stimulated with different concentrations of H2 O2 . Flow cytometric analysis was used to select an optimal concentration of H2 O2 for the following experiments. Cell proliferation, migration, and tubule formation were evaluated by Cell Counting Kit-8 (CCK-8) assays, scratch wound assays, and Matrigel tubule formation assays, respectively...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28387310/targeting-bmk1-impairs-the-drug-resistance-to-combined-inhibition-of-braf-and-mek1-2-in-melanoma
#13
Chengli Song, Lina Wang, Qiang Xu, Kai Wang, Dan Xie, Zhe Yu, Kui Jiang, Lujian Liao, John R Yates, Jiing-Dwan Lee, Qingkai Yang
Combined inhibition of BRAF and MEK1/2 (CIBM) improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to CIBM is inevitable and the drug resistance mechanisms still remain to be elucidated. Here, we show that BMK1 pathway contributes to the drug resistance to CIBM. Considering that ERK1/2 pathway regulates cellular processes by phosphorylating, we first performed a SILAC phosphoproteomic profiling of CIBM. Phosphorylation of 239 proteins was identified to be downregulated, while phosphorylation of 47 proteins was upregulated...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28356344/yap-promotes-myogenic-differentiation-via-the-mek5-erk5-pathway
#14
Ting-Huan Chen, Chen-Yu Chen, Hui-Chin Wen, Chia-Chu Chang, Horng-Dar Wang, Chih-Pin Chuu, Chung-Ho Chang
Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. In this study, we generated C2C12 stable cell lines that expressed YAP (C2C12-YAP cells) and found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker...
July 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28286738/tsc2-rheb-signaling-mediates-erk-dependent-regulation-of-mtorc1-activity-in-c2c12-myoblasts
#15
Mitsunori Miyazaki, Tohru Takemasa
The enhanced rate of protein synthesis in skeletal muscle cells results in a net increase in total protein content that leads to skeletal muscle growth/hypertrophy. The mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent regulation of the activity of mechanistic target of rapamycin (mTOR) and subsequent protein synthesis has been suggested as a regulatory mechanism; however, the exact molecular processes underlying such a regulation are poorly defined. The purpose of this study was to investigate regulatory mechanisms involved in the MEK/ERK-dependent pathway leading to mTORC1 activation in skeletal muscle cells...
March 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28265860/neuregulin1%C3%AE-effects-on-brain-tissue-via-erk5-dependent-mapk-pathway-in-a-rat-model-of-cerebral-ischemia-reperfusion-injury
#16
Ning Gu, Keli Ge, Cui Hao, Yaqing Ji, Hongyun Li, Yunliang Guo
Neuregulin1β (NRG1β), a member of the excitomotor of tyrosine kinase receptor (erbB) family, was recently shown to play a neuroprotective role in cerebral ischemia-reperfusion injury. The present study analyzed the effects and its possible signaling pathway of NRG1β on brain tissues after cerebral ischemia-reperfusion injury. A focal cerebral ischemic model was established by inserting a monofilament thread to achieve middle cerebral artery occlusion, followed by an NRG1β injection via the internal carotid artery...
April 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28153789/oncogenic-signaling-of-mek5-erk5
#17
REVIEW
Van T Hoang, Thomas J Yan, Jane E Cavanaugh, Patrick T Flaherty, Barbara S Beckman, Matthew E Burow
Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents...
April 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27922189/optimal-arac-cytotoxicity-to-aml-cells-requires-erk5-activity
#18
Ruifang Zheng, George P Studzinski
Cytarabine (AraC) has been the primary treatment agent for acute myeloid leukemia (AML) in the past 30 years, but the precise mechanism of its action is not completely known. Here we assessed the role of ERK5 in AraC-induced cell death in AML cell lines HL60 and U937 using ERK5 inhibitors BIX02189 and XMD8-92. We report that inhibition of MEK5/ERK5 activity reduces AraC-induced cell death, DNA damage, the upregulated DNA damage biomarkers, and produced G2 phase cell cycle arrest. In addition, the pro-survival protein P-Bcl2 Ser70 was found to be associated with decreased AraC-induced cell death following XMD8-92 treatment, suggesting a regulatory role of ERK5 on Bcl2 phosphorylation...
June 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27878304/upregulation-of-mek5-by-stat3-promotes-breast-cancer-cell-invasion-and-metastasis
#19
Fang Liu, Hao Zhang, Hui Song
Mitogen extracellular-signal-regulated kinase kinase 5 (MEK5) plays an important role in promoting cell proliferation and tumorigenesis. The aberrant expression of MEK5 has been reported in various malignant diseases including cancers of breast, prostate, lung, colorectal and brain. However, the function and regulation of MEK5 signaling pathway are ambiguous and remain elusive with respect to its oncogenic roles in various cancers, especially in the regulation of the initiation and progression of cancer invasion and metastasis...
January 2017: Oncology Reports
https://www.readbyqxmd.com/read/27821723/c1q-tnf-related-protein-9-promotes-cardiac-hypertrophy-and-failure
#20
Mahesh Appari, Astrid Breitbart, Florian Brandes, Malgorzata Szaroszyk, Natali Froese, Mortimer Korf-Klingebiel, Mona Malek Mohammadi, Andrea Grund, Gesine M Scharf, Honghui Wang, Carolin Zwadlo, Daniela Fraccarollo, Ulrike Schrameck, Mona Nemer, G William Wong, Hugo A Katus, Kai C Wollert, Oliver J Müller, Johann Bauersachs, Joerg Heineke
RATIONALE: Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted CTRP9 (C1q-tumor necrosis factor-related protein-9) might act as endothelial-derived protein to modulate heart remodeling in response to pressure overload. OBJECTIVE: To examine the source of cardiac CTRP9 and its function during pressure overload...
January 6, 2017: Circulation Research
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