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https://www.readbyqxmd.com/read/29343759/incorporation-of-iloprost-in-phospholipase-resistant-phospholipid-scaffold-enhances-its-barrier-protective-effects-on-pulmonary-endothelium
#1
Olga Oskolkova, Nicolene Sarich, Yufeng Tian, Grzegorz Gawlak, Fanyong Meng, Valery N Bochkov, Evgeny Berdyshev, Anna A Birukova, Konstantin G Birukov
Correction of barrier dysfunction and inflammation in acute lung injury (ALI) represents an important problem. Previous studies demonstrate barrier-protective and anti-inflammatory effects of bioactive lipid prostacyclin and its stable analog iloprost (ILO). We generated a phospholipase resistant synthetic phospholipid with iloprost attached at the sn-2 position (ILO-PC) and investigated its biological effects. In comparison to free ILO, ILO-PC caused sustained endothelial cell (EC) barrier enhancement, linked to more prolonged activation of Rap1 and Rac1 GTPases and their cytoskeletal and cell junction effectors: cortactin, PAK1, p120-catenin and VE-cadherin...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330617/characterizing-genomic-differences-of-human-cancer-stratified-by-the-tp53-mutation-status
#2
Mengyao Wang, Chao Yang, Xiuqing Zhang, Xiangchun Li
The key roles of the TP53 mutation in cancer have been well established. TP53 is the most frequently mutated gene, and its inactivation is widespread among human cancer types. However, the landscape of genomic alterations in human cancers stratified by the TP53 mutation has not yet been described. We obtained somatic mutation and copy number change data of 6551 regular-mutated samples from the Cancer Genome Atlas (TCGA) and compared significantly mutated genes (SMGs), copy number alterations, mutational signatures and mutational strand asymmetries between cancer samples with and without the TP53 mutation...
January 12, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29330094/p21-activated-kinase-signaling-in-cancer
#3
REVIEW
Chetan K Rane, Audrey Minden
The p21 Activated Kinases (PAKs) are a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. The PAKs were originally identified as protein kinases that function downstream of the Ras related Rho GTPases Cdc42 and Rac. PAK1 and PAK4, which belong to Group I and Group II PAKs, respectively, are most often associated with tumorigenesis. On account of their well characterized roles in cancer, several small molecule inhibitors are being developed to inhibit the PAKs, and there is interest in investigating their efficacy as either first line or adjuvant treatments for cancer...
January 9, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29311744/mutations-in-vps15-perturb-neuronal-migration-in-mice-and-are-associated-with-neurodevelopmental-disease-in-humans
#4
Thomas Gstrein, Andrew Edwards, Anna Přistoupilová, Ines Leca, Martin Breuss, Sandra Pilat-Carotta, Andi H Hansen, Ratna Tripathy, Anna K Traunbauer, Tobias Hochstoeger, Gavril Rosoklija, Marco Repic, Lukas Landler, Viktor Stránecký, Gerhard Dürnberger, Thomas M Keane, Johannes Zuber, David J Adams, Jonathan Flint, Tomas Honzik, Marta Gut, Sergi Beltran, Karl Mechtler, Elliott Sherr, Stanislav Kmoch, Ivo Gut, David A Keays
The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling...
January 8, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29274909/cloning-and-functional-characterization-of-human-pak1-promoter-by-steroid-hormones
#5
Swetha Raghavan, Ganesh Venkatraman, Suresh K Rayala
P21-activated kinase 1 (Pak1) is known to be involved in a plethora of functions including cell growth, survival and can lead to cell transformation and tumor progression especially in breast tissue. Multiple studies have shown Pak1 dysregulation as a change in DNA copy number as well as gene expression levels, suggesting many regulatory mechanisms at transcriptional and translational level. However, very little is known about the transcriptional regulation of the human Pak1 promoter. Here, we focus on Pak1 promoter regulation by steroid hormones along with their respective receptors that are also crucial players in breast tissue function and tumorigenesis...
December 21, 2017: Gene
https://www.readbyqxmd.com/read/29190083/structure-based-design-of-6-chloro-4-aminoquinazoline-2-carboxamide-derivatives-as-potent-and-selective-p21-activated-kinase-4-pak4-inhibitors
#6
Chenzhou Hao, Fan Zhao, Hong Yan Song, Jing Guo, Xiaodong Li, Xiaolin Jiang, Ran Huan, Shuai Song, Qiaoling Zhang, Ruifeng Wang, Kai Wang, Yu Pang, Tongchao Liu, Tianqi Lu, Wanxu Huang, Jian Wang, Bin Lin, Zhonggui He, Haitao Li, Feng Li, Dongmei Zhao, Maosheng Cheng
Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2, 4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized...
November 30, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29187213/jmjd6-promotes-melanoma-carcinogenesis-through-regulation-of-the-alternative-splicing-of-pak1-a-key-mapk-signaling-component
#7
Xujun Liu, Wenzhe Si, Xinhua Liu, Lin He, Jie Ren, Ziran Yang, Jianguo Yang, Wanjin Li, Shumeng Liu, Fei Pei, Xiaohan Yang, Luyang Sun
BACKGROUND: Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. METHODS: We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis...
November 29, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/29179176/neurons-erythrocytes-and-beyond-the-diverse-functions-of-chorein
#8
Florian Lang, Lisann Pelzl, Ludger Schöls, Andreas Hermann, Michael Föller, Tilman E Schäffer, Christos Stournaras
Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases...
November 28, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/29152126/extracellular-atp-as-an-energy-and-phosphorylating-molecule-induces-different-types-of-drug-resistances-in-cancer-cells-through-atp-internalization-and-intracellular-atp-level-increase
#9
Xuan Wang, Yunsheng Li, Yanrong Qian, Yanyang Cao, Pratik Shriwas, Haiyun Zhang, Xiaozhuo Chen
Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival in drug treatment. However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29146188/old-drug-new-tricks-chlorhexidine-acts-as-a-potential-allosteric-inhibitor-toward-pak1
#10
Han-Wei Huang, Xiang-Yu Zhang, Pei-Lu Song, Hai-Lun Jiang, Wei Li, Peng-Liang Wang, Jian Wang, Fu-Nan Liu
This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor...
November 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29133945/microrna-7-5p-mediates-the-signaling-of-hepatocyte-growth-factor-to-suppress-oncogenes-in-the-mcf-10a-mammary-epithelial-cell
#11
Dawoon Jeong, Juyeon Ham, Sungbin Park, Seungyeon Lee, Hyunkyung Lee, Han-Sung Kang, Sun Jung Kim
MicroRNA-7 (miR-7) is a non-coding RNA of 23-nucleotides that has been shown to act as a tumor suppressor in various cancers including breast cancer. Although there have been copious studies on the action mechanisms of miR-7, little is known about how the miR is controlled in the mammary cell. In this study, we performed a genome-wide expression analysis in miR-7-transfected MCF-10A breast cell line to explore the upstream regulators of miR-7. Analysis of the dysregulated target gene pool predicted hepatocyte growth factor (HGF) as the most plausible upstream regulator of miR-7...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29114038/aberrant-rac1-cofilin-signaling-mediates-defects-in-dendritic-spines-synaptic-function-and-sensory-perception-in-fragile-x-syndrome
#12
Alexander Pyronneau, Qionger He, Jee-Yeon Hwang, Morgan Porch, Anis Contractor, R Suzanne Zukin
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29099290/fer-mediated-hgf-independent-regulation-of-hgfr-met-activates-rac1-pak1-pathway-to-potentiate-metastasis-in-ovarian-cancer
#13
Gaofeng Fan, Nicholas Nicholas
Uncontrolled metastasis significantly contributes to high lethality of patients suffering from ovarian cancer. To date, the detailed molecular mechanisms which account for ovarian tumor cell spreading and metastasis remain largely unknown. In a recent study, we have demonstrated that aberrantly high expression of the non-receptor tyrosine kinase FER is responsible for ovarian tumor cell metastasis both in vitro and in vivo. Mechanistically, we indentified Hepatocyte Growth Factor Receptor HGFR/MET as a novel substrate of FER, and through which the kinase FER modulates ovarian cancer cell motility and invasiveness in a ligand-independent manner...
November 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/29073233/transcriptional-and-post-translational-changes-in-the-brain-of-mice-deficient-in-cholesterol-removal-mediated-by-cytochrome-p450-46a1-cyp46a1
#14
Natalia Mast, Joseph B Lin, Kyle W Anderson, Ingemar Bjorkhem, Irina A Pikuleva
Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination...
2017: PloS One
https://www.readbyqxmd.com/read/29058761/c-abl-tyrosine-kinase-regulates-neutrophil-crawling-behavior-under-fluid-shear-stress-via-rac-pak-limk-cofilin-signaling-axis
#15
Haibin Tong, Dake Qi, Xingang Guan, Guiquan Jiang, Zhiyong Liao, Xu Zhang, Peichao Chen, Nan Li, Mingjiang Wu
The excessive recruitment and improper activation of polymorphonuclear neutrophils (PMNs) often induces serious injury of host tissues, leading to inflammatory disorders. Therefore, to understand the molecular mechanism on neutrophil recruitment possesses essential pathological and physiological importance. In this study, we found that physiological shear stress induces c-Abl kinase activation in neutrophils, and c-Abl kinase inhibitor impaired neutrophil crawling behavior on ICAM-1. We further identified Vav1 was a downstream effector phosphorylated at Y174 and Y267...
October 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29039592/inhibition-of-cell-migration-and-invasion-by-mir%C3%A2-29a%C3%A2-3p-in-a-colorectal-cancer-cell-line-through-suppression-of-cdc42bpa-mrna-expression
#16
Pei Yuan He, Wai Kien Yip, Boon Lee Chai, Boon Yean Chai, Mohd Faisal Jabar, Noraini Dusa, Norhafizah Mohtarrudin, Heng Fong Seow
The objective of this study was to determine the effect of miR‑29a‑3p inhibitor on the migration and invasion of colorectal cancer cell lines (CRC) and the underlying molecular mechanisms. miR‑29a‑3p was detected using reverse transcription-quantitative polymerase chain reaction (RT‑qPCR) in the CRC cell lines HCT11, CaCo2, HT29, SW480 and SW620. An invasive subpopulation designated SW480‑7 was derived from the parental cell line, detected by Transwell and Transwell Matrigel assays. Cytoskeleton Regulators RT2 profiler PCR array and western blot analysis were utilized to identify the alterations in expression of downstream mRNAs...
October 16, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29032114/epigallocatechin-3-gallate-reduces-the-proliferation-of-benign-prostatic-hyperplasia-cells-via-regulation-of-focal-adhesions
#17
Burcu Erbaykent Tepedelen, Elif Soya, Mehmet Korkmaz
AIMS: Benign prostatic hyperplasia (BPH) is the most common urological disease that is characterized by the excessive growth of prostatic epithelial and stromal cells. Pharmacological therapy for BPH has limited use due to the many side effects so there is a need for new agents including natural compounds such as epigallocatechin-3-gallate (EGCG). This study was undertaken to assess the role of EGCG, suppressing the formation of BPH by reducing inflammation and oxidative stress, in cytoskeleton organization and ECM interactions via focal adhesions...
October 11, 2017: Life Sciences
https://www.readbyqxmd.com/read/29024936/glucose-insult-elicits-hyperactivation-of-cancer-stem-cells-through-mir-424-cdc42-prdm14-signalling-axis
#18
Sushmita Bose Nandy, Alexis Orozco, Rebecca Lopez-Valdez, Rene Roberts, Ramadevi Subramani, Arunkumar Arumugam, Alok Kumar Dwivedi, Viktoria Stewart, Gautham Prabhakaran, Stephanie Jones, Rajkumar Lakshmanaswamy
BACKGROUND: Meta-analysis shows that women with diabetes have a 20% increased risk of breast cancer and also an increased risk for distant metastasis and mortality. The molecular mechanisms for distant metastasis and mortality in breast cancer patients with diabetes are not very well understood. METHODS: We compared the effect of physiological (5 mM) and diabetic (10 mM) levels of glucose on malignant breast epithelial cell invasion and stemness capabilities...
October 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28992163/pak1-mediates-the-stimulatory-effect-of-insulin-and-curcumin-on-hepatic-chrebp-expression
#19
Kejing Zeng, Lili Tian, Adam Sirek, Weijuan Shao, Ling Liu, Yu-Ting Chiang, Jonathan Chernoff, Dominic S Ng, Jianping Weng, Tianru Jin
Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein (ChREBP). As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can also be regulated by the dietary polyphenol curcumin. We also aimed to determine mechanisms underlying ChREBP stimulation by insulin and curcumin. The effect of insulin on ChREBP expression was assessed in mouse hepatocytes, while the effect of curcumin was assessed in mouse hepatocytes and with curcumin gavage in mice...
August 18, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28972183/the-actin-related-p41arc-subunit-contributes-to-p21-activated-kinase-1-pak1-mediated-glucose-uptake-into-skeletal-muscle-cells
#20
Ragadeepthi Tunduguru, Jing Zhang, Arianne Aslamy, Vishal A Salunkhe, Joseph T Brozinick, Jeffrey S Elmendorf, Debbie C Thurmond
Defects in translocation of the glucose transporter GLUT4 are associated with peripheral insulin resistance, pre-clinical diabetes, and progression to type 2 diabetes. GLUT4 recruitment to the plasma membrane of skeletal muscle cells requires filamentous (F)-actin remodeling. Insulin signaling in muscle requires p21-activated kinase-1 (PAK1), whose downstream signaling triggers actin remodeling that promotes GLUT4 vesicle translocation and glucose uptake into skeletal muscle cells. Actin remodeling is a cyclic process, and while PAK1 is known to initiate changes to the cortical actin-binding protein cofilin to stimulate the depolymerizing arm of the cycle, how PAK1 might trigger the polymerizing arm of the cycle remains unresolved...
September 25, 2017: Journal of Biological Chemistry
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