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https://www.readbyqxmd.com/read/27798271/wnk-cab39-nkcc1-signaling-increases-the-susceptibility-to-ischemic-brain-damage-in-hypertensive-rats
#1
Mohammad Iqbal H Bhuiyan, Shanshan Song, Hui Yuan, Gulnaz Begum, Julia Kofler, Kristopher T Kahle, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, Arohan R Subramanya, Dandan Sun
With-no-lysine kinase (WNK) and Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion...
October 26, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27592479/blood-dna-methylation-markers-in-potentially-identified-chinese-patients-with-hepatocellular-carcinoma
#2
Zongying Liu, Haixiu Yan, Jinshu Zhang
To determine whether blood DNA methylation is associated with hepatocellular carcinoma (HCC) for Chinese patients, we used genome-wide DNA methylation detection to access the blood samples of Chinese patients by Illumina Human methylation 450K arrays. Sixty potentially gene locis which had different methylated levels significantly among tumor and adjacent normal tissues would be tested in this study. A previous study was conducted in China communities and followed with 7 years. The DNA from white blood cells (WBC) from 192 patients with HCC and 215 matched controls were assayed in this study...
July 2016: Pakistan Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27131446/-wnk-ing-at-death-with-no-lysine-wnk-kinases-in-neuropathies-and-neuronal-survival
#3
REVIEW
Bor Luen Tang
Members of With-no-lysine (WNK) family of serine-threonine kinase are key regulators of chloride ion transport in diverse cell types, controlling the activity and the surface expression of cation-chloride (Na(+)/K(+)-Cl(-)) co-transporters. Mutations in WNK1 and WNK4 are linked to a hereditary form of hypertension, and WNKs have been extensively investigated pertaining to their roles in renal epithelial ion homeostasis. However, some members of the WNK family and their splice isoforms are also expressed in the mammalian brain, and have been implicated in aspects of hereditary neuropathy as well as neuronal and glial survival...
July 2016: Brain Research Bulletin
https://www.readbyqxmd.com/read/25714620/a-rapid-and-high-content-assay-that-measures-cyto-id-stained-autophagic-compartments-and-estimates-autophagy-flux-with-potential-clinical-applications
#4
Sujuan Guo, Yanping Liang, Susan F Murphy, Angela Huang, Haihong Shen, Deborah F Kelly, Pablo Sobrado, Zhi Sheng
The lack of a rapid and quantitative autophagy assay has substantially hindered the development and implementation of autophagy-targeting therapies for a variety of human diseases. To address this critical issue, we developed a novel autophagy assay using the newly developed Cyto-ID fluorescence dye. We first verified that the Cyto-ID dye specifically labels autophagic compartments with minimal staining of lysosomes and endosomes. We then developed a new Cyto-ID fluorescence spectrophotometric assay that makes it possible to estimate autophagy flux based on measurements of the Cyto-ID-stained autophagic compartments...
2015: Autophagy
https://www.readbyqxmd.com/read/25596741/silencing-of-the-tumor-suppressor-gene-wnk2-is-associated-with-upregulation-of-mmp2-and-jnk-in-gliomas
#5
Angela Margarida Costa, Filipe Pinto, Olga Martinho, Maria José Oliveira, Peter Jordan, Rui Manuel Reis
Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2...
January 30, 2015: Oncotarget
https://www.readbyqxmd.com/read/24289130/a-review-of-epigenetic-and-gene-expression-alterations-associated-with-intracranial-meningiomas
#6
REVIEW
Shuhan He, Martin H Pham, Matthew Pease, Gabriel Zada, Steven L Giannotta, Kai Wang, William J Mack
OBJECT: A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide useful targets for molecular classification and development of targeted therapies for meningiomas. METHODS: The authors performed a review of the current literature to identify the epigenetic modifications associated with the formation and/or progression of meningiomas. RESULTS: Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with meningiomas...
December 2013: Neurosurgical Focus
https://www.readbyqxmd.com/read/23912455/early-epigenetic-downregulation-of-wnk2-kinase-during-pancreatic-ductal-adenocarcinoma-development
#7
C Dutruel, F Bergmann, I Rooman, M Zucknick, D Weichenhan, L Geiselhart, T Kaffenberger, P S Rachakonda, A Bauer, N Giese, C Hong, H Xie, J F Costello, J Hoheisel, R Kumar, M Rehli, P Schirmacher, J Werner, C Plass, O Popanda, P Schmezer
Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression...
June 26, 2014: Oncogene
https://www.readbyqxmd.com/read/23797875/wnk-kinases-are-positive-regulators-of-canonical-wnt-%C3%AE-catenin-signalling
#8
Ekatherina Serysheva, Hebist Berhane, Luca Grumolato, Kubilay Demir, Sophie Balmer, Maxime Bodak, Michael Boutros, Stuart Aaronson, Marek Mlodzik, Andreas Jenny
Wnt/β-catenin signalling is central to development and its regulation is essential in preventing cancer. Using phosphorylation of Dishevelled as readout of pathway activation, we identified Drosophila Wnk kinase as a new regulator of canonical Wnt/β-catenin signalling. WNK kinases are known for regulating ion co-transporters associated with hypertension disorders. We demonstrate that wnk loss-of-function phenotypes resemble canonical Wnt pathway mutants, while Wnk overexpression causes gain-of-function canonical Wnt-signalling phenotypes...
August 2013: EMBO Reports
https://www.readbyqxmd.com/read/23035050/loss-of-wnk2-expression-by-promoter-gene-methylation-occurs-in-adult-gliomas-and-triggers-rac1-mediated-tumour-cell-invasiveness
#9
Sónia Moniz, Olga Martinho, Filipe Pinto, Bárbara Sousa, Cláudia Loureiro, Maria José Oliveira, Luís Ferreira Moita, Mrinalini Honavar, Célia Pinheiro, Manuel Pires, José Manuel Lopes, Chris Jones, Joseph F Costello, Joana Paredes, Rui Manuel Reis, Peter Jordan
The gene encoding protein kinase WNK2 was recently identified to be silenced by promoter hypermethylation in gliomas and meningiomas, suggesting a tumour-suppressor role in these brain tumours. Following experimental depletion in cell lines, WNK2 was further found to control GTP-loading of Rac1, a signalling guanosine triphosphatase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29 out of 166) of adult gliomas, whereas it is infrequent in its paediatric forms (1...
January 1, 2013: Human Molecular Genetics
https://www.readbyqxmd.com/read/22032326/spak-osr1-regulate-nkcc1-and-wnk-activity-analysis-of-wnk-isoform-interactions-and-activation-by-t-loop-trans-autophosphorylation
#10
Jacob O Thastrup, Fatema H Rafiqi, Alberto C Vitari, Eulalia Pozo-Guisado, Maria Deak, Youcef Mehellou, Dario R Alessi
Mutations in the WNK [with no lysine (K) kinase] family instigate hypertension and pain perception disorders. Of the four WNK isoforms, much of the focus has been on WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). WNK isoforms phosphorylate and activate the related SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) protein kinases. In the present study, we first describe the generation of double-knockin ES (embryonic stem) cells, where SPAK and OSR1 cannot be activated by WNK1...
January 1, 2012: Biochemical Journal
https://www.readbyqxmd.com/read/21733846/wnk2-kinase-is-a-novel-regulator-of-essential-neuronal-cation-chloride-cotransporters
#11
Jesse Rinehart, Norma Vázquez, Kristopher T Kahle, Caleb A Hodson, Aaron M Ring, Erol E Gulcicek, Angeliki Louvi, Norma A Bobadilla, Gerardo Gamba, Richard P Lifton
NKCC1 and KCC2, related cation-chloride cotransporters (CCC), regulate cell volume and γ-aminobutyric acid (GABA)-ergic neurotranmission by modulating the intracellular concentration of chloride [Cl(-)]. These CCCs are oppositely regulated by serine-threonine phosphorylation, which activates NKCC1 but inhibits KCC2. The kinase(s) that performs this function in the nervous system are not known with certainty. WNK1 and WNK4, members of the WNK (with no lysine [K]) kinase family, either directly or via the downstream SPAK/OSR1 Ste20-type kinases, regulate the furosemide-sensitive NKCC2 and the thiazide-sensitive NCC, kidney-specific CCCs...
August 26, 2011: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/21625442/methylation-profile-of-single-hepatocytes-derived-from-hepatitis-b-virus-related-hepatocellular-carcinoma
#12
Ran Tao, Jun Li, Jiaojiao Xin, Jian Wu, Jing Guo, Liyuan Zhang, Longyan Jiang, Wu Zhang, Zhe Yang, Lanjuan Li
BACKGROUND: With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis...
2011: PloS One
https://www.readbyqxmd.com/read/21508686/a-comprehensive-sirna-screen-for-kinases-that-suppress-macroautophagy-in-optimal-growth-conditions
#13
Piotr Szyniarowski, Elisabeth Corcelle-Termeau, Thomas Farkas, Maria Høyer-Hansen, Jesper Nylandsted, Tuula Kallunki, Marja Jäättelä
Macroautophagy is a catabolic process that maintains cellular homeostasis and protects cells against various external stresses including starvation. Except for the identification of the Akt-mTORC1 pathway as a major negative regulator, little is known about signaling networks that control macroautophagy under optimal growth conditions. Therefore, we screened a human kinome siRNA library for siRNAs that increase the number of autophagosomes in normally growing MCF-7 human breast carcinoma cells, and identified 10 kinases as regulators of constitutive macroautophagy...
August 2011: Autophagy
https://www.readbyqxmd.com/read/20198315/association-of-genetic-variants-with-hemorrhagic-stroke-in-japanese-individuals
#14
Tetsuro Yoshida, Kimihiko Kato, Kiyoshi Yokoi, Mitsutoshi Oguri, Sachiro Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Yukitoshi Aoyagi, Yoshinori Nozawa, Yoshiji Yamada
Although genetic epidemiological studies have implicated several genetic variants as risk factors for hemorrhagic stroke, the genetic determinants of this condition remain largely unknown. We examined an association of genetic variants with intracerebral or subarachnoid hemorrhage among Japanese individuals. The study population comprised 4,304 unrelated Japanese individuals, including 377 subjects with intracerebral hemorrhage, 205 subjects with subarachnoid hemorrhage, and 3,722 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of ischemic stroke and myocardial infarction with the use of the GeneChip Human Mapping 500K Array Set...
April 2010: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/19763917/arsenic-trioxide-induces-apoptosis-in-nb-4-an-acute-promyelocytic-leukemia-cell-line-through-up-regulation-of-p73-via-suppression-of-nuclear-factor-kappa-b-mediated-inhibition-of-p73-transcription-and-prevention-of-nf-kappab-mediated-induction-of-xiap-ciap2
#15
Majid Momeny, Majid Zakidizaji, Reza Ghasemi, Ahmad R Dehpour, Maryam Rahimi-Balaei, Yassan Abdolazimi, Ardeshir Ghavamzadeh, Kamran Alimoghaddam, Seyed H Ghaffari
The purpose of the present study is to evaluate the effects of arsenic trioxide (ATO) on human acute promyelocytic leukemia NB-4 cells. Microculture tetrazolium test, bromodeoxyuridine (BrdU) cell proliferation assay, caspase 3 activity assay, cell-based nuclear factor kappa B (NF-kappaB) phosphorylation measurement by ELISA and real-time RT-PCR were employed to appraise the effects of ATO on metabolic activity, DNA synthesis, induction of programmed cell death and NF-kappaB activation. The suppressive effects of ATO on metabolic potential, cell proliferation and NF-kappaB activation were associated with induction of apoptosis in NB-4 cells...
September 2010: Medical Oncology
https://www.readbyqxmd.com/read/19001526/epigenetic-silencing-of-the-kinase-tumor-suppressor-wnk2-is-tumor-type-and-tumor-grade-specific
#16
Peter Jun, Chibo Hong, Anita Lal, Judith M Wong, Michael W McDermott, Andrew W Bollen, Christoph Plass, William A Held, Dominic J Smiraglia, Joseph F Costello
Both genetic and epigenetic mechanisms contribute to meningioma development by altering gene expression and protein function. To determine the relative contribution of each mechanism to meningioma development, we used an integrative approach measuring copy number and DNA methylation changes genomewide. We found that genetic alterations affected 1.9%, 7.4%, and 13.3% of the 691 loci studied, whereas epigenetic mechanisms affected 5.4%, 9.9%, and 10.3% of these loci in grade I, II, and III meningiomas, respectively...
August 2009: Neuro-oncology
https://www.readbyqxmd.com/read/18843116/the-regulation-of-salt-transport-and-blood-pressure-by-the-wnk-spak-osr1-signalling-pathway
#17
REVIEW
Ciaran Richardson, Dario R Alessi
It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl- conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs...
October 15, 2008: Journal of Cell Science
https://www.readbyqxmd.com/read/18593598/wnk2-modulates-mek1-activity-through-the-rho-gtpase-pathway
#18
Sónia Moniz, Paulo Matos, Peter Jordan
WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAK1, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2...
October 2008: Cellular Signalling
https://www.readbyqxmd.com/read/18312414/distinct-pathways-for-the-involvement-of-wnk4-in-the-signaling-of-hypertonicity-and-egf
#19
Miriam Shaharabany, Eliezer J Holtzman, Haim Mayan, Koret Hirschberg, Rony Seger, Zvi Farfel
WNK4 kinase mutations produce the autosomal dominant disorder familial hyperkalemia and hypertension (FHH), also known as pseudohypoaldosteronism type II, by a molecular mechanism that is not completely understood. In vitro experiments in frog oocytes showed that WNK4 affects ion transport systems such as the Na-Cl cotransporter and the renal outer medullary potassium channel. Some features of FHH suggest that long-term effects are involved in WNK4 signaling. In addition, WNK1 and WNK2, paralogs of WNK4, were shown to be involved in MAP kinase signaling...
April 2008: FEBS Journal
https://www.readbyqxmd.com/read/17667937/protein-kinase-wnk2-inhibits-cell-proliferation-by-negatively-modulating-the-activation-of-mek1-erk1-2
#20
S Moniz, F Veríssimo, P Matos, R Brazão, E Silva, L Kotelevets, L Kotevelets, E Chastre, C Gespach, P Jordan
The recently identified subfamily of WNK protein kinases is characterized by a unique sequence variation in the catalytic domain and four related human WNK genes were identified. Here, we describe the cloning and functional analysis of the human family member WNK2. We show that the depletion of endogenous WNK2 expression by RNA interference in human cervical HeLa cancer cells led to the activation of the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases but, in contrast to the depletion of WNK1, had no effect on ERK5...
September 6, 2007: Oncogene
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