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https://www.readbyqxmd.com/read/29146188/old-drug-new-tricks-chlorhexidine-acts-as-a-potential-allosteric-inhibitor-toward-pak1
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28972170/%C3%AE-1-integrin-dependent-rac-group-i-pak-signaling-mediates-yap-activation-of-yes-associated-protein-1-yap1-via-nf2-merlin
#12
Hiba Sabra, Molly Brunner, Vinay Mandati, Bernhard Wehrle Haller, Dominique Lallemand, Anne-Sophie Ribba, Genevieve Chevalier, Philippe Guardiola, Marc R Block, Daniel Bouvard
Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation, and is critical for proper tissue homeostasis. An important pathway in adhesion-dependent cell proliferation is the Hippo signaling cascade, which is coregulated by the transcription factors Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ). However, how cells integrate extracellular information at the molecular level to regulate YAP1 nuclear localization is still puzzling...
September 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28969640/arf1-recruits-rac1-to-leading-edge-in-neutrophil-chemotaxis
#13
Yuichi Mazaki, Yasuhito Onodera, Tsunehito Higashi, Takahiro Horinouchi, Tsukasa Oikawa, Hisataka Sabe
BACKGROUND: The small GTPase ARF1 mediates membrane trafficking mostly from the Golgi, and is essential for the G protein-coupled receptor (GPCR)-mediated chemotaxis of neutrophils. In this process, ARF1 is activated by the guanine nucleotide exchanger GBF1, and is inactivated by the GTPase-activating protein GIT2. Neutrophils generate the Gβγ-PAK1-αPIX-GIT2 linear complex during GPCR-induced chemotaxis, in which αPIX activates RAC1/CDC42, which then employs PAK1. However, it has remained unclear as to why GIT2 is included in this complex...
October 2, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28919558/cellular-uptake-of-extracellular-vesicles-is-mediated-by-clathrin-independent-endocytosis-and-macropinocytosis
#14
Helena Costa Verdera, Jerney J Gitz-Francois, Raymond M Schiffelers, Pieter Vader
Recent evidence has established that extracellular vesicles (EVs), including exosomes and microvesicles, form an endogenous transport system through which biomolecules, including proteins and RNA, are exchanged between cells. This endows EVs with immense potential for drug delivery and regenerative medicine applications. Understanding the biology underlying EV-based intercellular transfer of cargo is of great importance for the development of EV-based therapeutics. Here, we sought to characterize the cellular mechanisms involved in EV uptake...
September 14, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28918037/a-novel-pak1-atf2-mir-132-signaling-axis-is-involved-in-the-hematogenous-metastasis-of-gastric-cancer-cells
#15
Funan Liu, Zhenguo Cheng, Xiaodong Li, Yanshu Li, Hongyan Zhang, Jiabin Li, Furong Liu, Huimian Xu, Feng Li
We, along with others, have shown previously that P21-activated kinase 1 (Pak1) plays a pivotal role in gastric cancer progression and metastasis. However, whether Pak1 controls gastric cancer metastasis by regulating microRNAs (miRNAs) has never been explored. Here, we report a novel mechanism of Pak1 in tumor metastasis. A detailed examination revealed that Pak1 interacts with and phosphorylates the serine 62 residue of ATF2 and then blocks its translocation into the nucleus. We also confirmed that ATF2 binds to the promoter of miR-132 and tightly regulates its transcription, thus explaining the regulatory mechanism of miR-132 by Pak1...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28854418/a-comparative-proteomic-analysis-of-erinacine-a-s-inhibition-of-gastric-cancer-cell-viability-and-invasiveness
#16
Hsing-Chun Kuo, Yur-Ren Kuo, Kam-Fai Lee, Meng-Chiao Hsieh, Cheng-Yi Huang, Yung-Yu Hsieh, Ko-Chao Lee, Hsiang-Lan Kuo, Li-Ya Lee, Wan-Ping Chen, Chin-Chu Chen, Shui-Yi Tung
Background / Aims: Erinacine A, isolated from the ethanol extract of the Hericium erinaceus mycelium, has been demonstrated as a new alternative anticancer medicine. Drawing upon current research, this study presents an investigation of the molecular mechanism of erinacine A inhibition associated with gastric cancer cell growth. METHODS: Cell viability was determined by Annexin V-FITC/propidium iodide staining and migration using a Boyden chamber assay to determine the effects of erinacine A treatment on the proliferation capacity and invasiveness of gastric cancer cells...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28842430/switching-of-the-substrate-specificity-of-protein-tyrosine-phosphatase-n12-by-cyclin-dependent-kinase-2-phosphorylation-orchestrating-2-oncogenic-pathways
#17
Hui Li, Duxiao Yang, Shanglei Ning, Yinghui Xu, Fan Yang, Rusha Yin, Taihu Feng, Shouqing Han, Lu Guo, Pengju Zhang, Wenjie Qu, Renbo Guo, Chen Song, Peng Xiao, Chengjun Zhou, Zhigang Xu, Jin-Peng Sun, Xiao Yu
The protein tyrosine phosphatase N (PTPN)-12 is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12-insert-loop harboring a cyclin-dependent kinase (CDK)-2 phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions...
August 24, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28814374/from-bench-laboratory-to-bed-hospital-home-how-to-explore-effective-natural-and-synthetic-pak1-blockers-longevity-promoters-for-cancer-therapy
#18
REVIEW
Hiroshi Maruta, Mok-Ryeon Ahn
PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called PAK1 has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan...
August 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28806779/a-mutation-in-nischarin-causes-otitis-media-via-limk1-and-nf-%C3%AE%C2%BAb-pathways
#19
Michael Crompton, Tom Purnell, Hayley E Tyrer, Andrew Parker, Greg Ball, Rachel E Hardisty-Hughes, Richard Gale, Debbie Williams, Charlotte H Dean, Michelle M Simon, Ann-Marie Mallon, Sara Wells, Mahmood F Bhutta, Martin J Burton, Hilda Tateossian, Steve D M Brown
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28803992/p-rex1-amplification-promotes-progression-of-cutaneous-melanoma-via-the-pak1-p38-mmp-2-pathway
#20
Jinhua Wang, Hajime Hirose, Guanhua Du, Kelly Chong, Eiji Kiyohara, Isaac P Witz, Dave S B Hoon
P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P-REX1 CN...
October 28, 2017: Cancer Letters
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