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https://www.readbyqxmd.com/read/29150539/ros-and-glutathionylation-balance-cytoskeletal-dynamics-in-neutrophil-extracellular-trap-formation
#1
Darko Stojkov, Poorya Amini, Kevin Oberson, Christiane Sokollik, Andrea Duppenthaler, Hans-Uwe Simon, Shida Yousefi
The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein-deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release...
November 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29146903/wiskott-aldrich-syndrome-protein-regulates-autophagy-and-inflammasome-activity-in-innate-immune-cells
#2
Pamela P Lee, Damián Lobato-Márquez, Nayani Pramanik, Andrea Sirianni, Vanessa Daza-Cajigal, Elizabeth Rivers, Alessia Cavazza, Gerben Bouma, Dale Moulding, Kjell Hultenby, Lisa S Westerberg, Michael Hollinshead, Yu-Lung Lau, Siobhan O Burns, Serge Mostowy, Mona Bajaj-Elliott, Adrian J Thrasher
Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29127144/disruption-of-thrombocyte-and-t-lymphocyte-development-by-a-mutation-in-arpc1b
#3
Raz Somech, Atar Lev, Yu Nee Lee, Amos J Simon, Ortal Barel, Ginette Schiby, Camila Avivi, Iris Barshack, Michele Rhodes, Jiejing Yin, Minshi Wang, Yibin Yang, Jennifer Rhodes, Nufar Marcus, Ben-Zion Garty, Jerry Stein, Ninette Amariglio, Gideon Rechavi, David L Wiest, Yong Zhang
Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency...
November 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29115573/fibroblast-activation-protein-%C3%AE-promotes-the-growth-and-migration-of-lung-cancer-cells-via-the-pi3k-and-sonic-hedgehog-pathways
#4
Jun Jia, Tracey A Martin, Lin Ye, Lin Meng, Nan Xia, Wen G Jiang, Xiaodong Zhang
A characteristic of the epithelial-to-mesenchymal transition in cancer cells is the upregulation of mesenchymal markers. Fibroblast activation protein α (FAPα) is predominantly expressed by stromal fibroblasts. Previous studies have demonstrated that FAPα is also expressed by certain epithelium-derived cancer cells and is involved in the regulation of certain signaling pathways. One of our previous studies showed that FAPα promoted the proliferation of breast cancer cells via the phosphatidylinositol-3-kinase (PI3K) signaling pathway...
October 27, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29100377/secreted-gelsolin-desensitizes-and-induces-apoptosis-of-infiltrated-lymphocytes-in-prostate-cancer
#5
Chun-Chi Chen, Shiow-Her Chiou, Cheng-Lin Yang, Kuan-Chih Chow, Tze-Yi Lin, Hui-Wen Chang, Weir-Chiang You, Hisu-Wen Huang, Chien-Min Chen, Nien-Cheng Chen, Fen-Pi Chou, Ming-Chih Chou
Loss of immunosurveillance is a major cause of cancer progression. Here, we demonstrate that gelsolin, a constituent of ejaculate, induces apoptosis of activated lymphocytes in prostate cancer. Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. In vitro, secreted gelsolin inactivated CD4(+) T cells by binding to CD37, and induced apoptosis of activated CD8(+) T lymphocytes by binding to Fas ligand during cell contact dependent on major histocompatibility complex I...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29078804/nuclear-wiskott-aldrich-syndrome-protein-co-regulates-t-cell-factor-1-mediated-transcription-in-t-cells
#6
Nikolai V Kuznetsov, Bader Almuzzaini, Joanna S Kritikou, Marisa A P Baptista, Mariana M S Oliveira, Marton Keszei, Scott B Snapper, Piergiorgio Percipalle, Lisa S Westerberg
BACKGROUND: The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined. METHODS: We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4(+) T cells. RESULTS: WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes...
October 27, 2017: Genome Medicine
https://www.readbyqxmd.com/read/29023566/cardiac-leiomodin2-binds-to-the-sides-of-actin-filaments-and-regulates-the-atpase-activity-of-myosin
#7
Dávid Szatmári, Beáta Bugyi, Zoltán Ujfalusi, László Grama, Réka Dudás, Miklós Nyitrai
Leiomodin proteins are vertebrate homologues of tropomodulin, having a role in the assembly and maintenance of muscle thin filaments. Leiomodin2 contains an N-terminal tropomodulin homolog fragment including tropomyosin-, and actin-binding sites, and a C-terminal Wiskott-Aldrich syndrome homology 2 actin-binding domain. The cardiac leiomodin2 isoform associates to the pointed end of actin filaments, where it supports the lengthening of thin filaments and competes with tropomodulin. It was recently found that cardiac leiomodin2 can localise also along the length of sarcomeric actin filaments...
2017: PloS One
https://www.readbyqxmd.com/read/29022901/bcr-abl1-induced-downregulation-of-wasp-in-chronic-myeloid-leukemia-involves-epigenetic-modification-and-contributes-to-malignancy
#8
Welbert O Pereira, Daniel D De Carvalho, Maria Emilia Zenteno, Beatriz F Ribeiro, Jacqueline F Jacysyn, Luiz R Sardinha, Maria A Zanichelli, Nelson Hamerschlak, Gareth E Jones, Katia B Pagnano, Fabiola A Castro, Yolanda Calle, Gustavo P Amarante-Mendes
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR-ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR-ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Wiskott-Aldrich syndrome protein (WASP) is an important regulator of signaling transduction in hematopoietic cells and was shown to be an endogenous inhibitor of the c-ABL TK...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29022827/descending-aortic-aneurysm-in-wiskott-aldrich-syndrome-options-for-repair
#9
Greta Wood, Karen Booth, Zahid Khan, Tina Biss, Chandrika Roysam, John Dark
We report open surgical repair of a previously stented descending thoracic aneurysm in a patient with Wiskott-Aldrich syndrome and a platelet count <10 × 10(9)·L(-1). The same patient was described previously in a report of the first endovascular stent in this form of vasculitis. We describe the pre- and intraoperative management, and suggest a change in strategy in this setting.
January 1, 2017: Asian Cardiovascular & Thoracic Annals
https://www.readbyqxmd.com/read/28978898/therapeutic-drug-monitoring-simulator-for-antibiotic-dosage-for-methicillin-resistant-staphylococcus-aureus-sepsis-in-a-patient-with-primary-immunodeficiency-on-peritoneal-dialysis
#10
Hidehiko Narazaki, Yusuke Terada, Kiyohiko Kaizu, Toyo Jitsukawa, Yasuhiko Ito, Takeshi Asano
Bacterial infections often cause fatal systemic infections in patients with primary immunodeficiency. To prevent unfortunate results, the selection, dose, and dosage of antibiotics are extremely important. Here, we report a case of Wiskott-Aldrich syndrome in a patient undergoing peritoneal dialysis because of chronic renal failure in whom methicillin-resistant Staphylococcus aureus sepsis developed. Because of the primary disease and complications, teicoplanin was the only chosen anti-S. aureus drug to prevent side effects...
2017: Journal of Nippon Medical School, Nippon Ika Daigaku Zasshi
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/28955984/expression-of-n-wasp-is-regulated-by-hif1%C3%AE-through-the-hypoxia-response-element-in-the-n-wasp-promoter
#12
Amrita Salvi, Thirumaran Thanabalu
Cancer cell migration and invasion involves temporal and spatial regulation of actin cytoskeleton reorganization, which is regulated by the WASP family of proteins such as N-WASP (Neural- Wiskott Aldrich Syndrome Protein). We have previously shown that expression of N-WASP was increased under hypoxic conditions. In order to characterize the regulation of N-WASP expression, we constructed an N-WASP promoter driven GFP reporter construct, N-WASP(pro)-GFP. Transfection of N-WASP(pro)-GFP construct and plasmid expressing HiF1α (Hypoxia Inducible factor 1α) enhanced the expression of GFP suggesting that increased expression of N-WASP under hypoxic conditions is mediated by HiF1α...
March 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28938008/vca-nanobodies-target-n-wasp-to-reduce-invadopodium-formation-and-functioning
#13
Tim Hebbrecht, Isabel Van Audenhove, Olivier Zwaenepoel, Adriaan Verhelle, Jan Gettemans
Invasive cancer cells develop small actin-based protrusions called invadopodia, which perform a primordial role in metastasis and extracellular matrix remodelling. Neural Wiskott-Aldrich syndrome protein (N-WASp) is a scaffold protein which can directly bind to actin monomers and Arp2/3 and is a crucial player in the formation of an invadopodium precursor. Expression modulation has pointed to an important role for N-WASp in invadopodium formation but the role of its C-terminal VCA domain in this process remains unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28931895/defective-thymic-output-in-was-patients-is-associated-with-abnormal-actin-organization
#14
Wenyan Li, Xiaoyu Sun, Jinzhi Wang, Qin Zhao, Rongxin Dai, Yanping Wang, Lina Zhou, Lisa Westerberg, Yuan Ding, Xiaodong Zhao, Chaohong Liu
Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton. Defective T - cell function is a major cause for immune deficiency in Wiskott-Aldrich syndrome (WAS) patients. T cells originate in the bone marrow and develop in the thymus, and then migrate to peripheral tissues. TCR excision circles (TRECs) present in thymic output cells stably, which is used as a molecular marker for thymic output. We found that CD8(+) T naïve cells of classic WAS patients were significantly reduced, and TRECs in patients with classic WAS and X-linked thrombocytopenia (XLT) dramatically decreased compared with that of HCs...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28922955/comparison-of-zinc-finger-nucleases-versus-crispr-specific-nucleases-for-genome-editing-of-the-wiskott-aldrich-syndrome-locus
#15
Alejandra Gutierrez-Guerrero, Sabina Sanchez-Hernandez, Giuseppe Galvani, Javier Pinedo-Gomez, Rocio Martin-Guerra, Almudena Sanchez-Gilabert, Araceli Aguilar-González, Marién Cobo, Philip Gregory, Michael Holmes, Karim Benabdellah, Francisco Martin
Primary immunodeficiencies, including Wiskott-Aldrich syndrome (WAS), are a main target for genome-editing strategies using specific nucleases (SNs) because a small number of corrected hematopoietic stem cells could cure patients. In this work, we have designed various WAS gene-specific CRISPR/Cas9 systems and compared their efficiency and specificity with homodimeric and heterodimeric WAS-specific zinc finger nucleases (ZFNs), using K-562 cells as a cellular model and plasmid nucleofection or integration-deficient lentiviral vectors (IDLVs) for delivery...
October 25, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28914471/wash-overexpression-enhances-cancer-stem-cell-properties-and-correlates-with-poor-prognosis-of-esophageal-carcinoma
#16
Lan Huang, Jingyao Lian, Xinfeng Chen, Guohui Qin, Yujia Zheng, Yi Zhang
There is increasing evidence that cytoskeleton remodeling is involved in cancer progression. Wiskott-Aldrich syndrome Protein (WASP) family represents a key regulator of actin cytoskeleton remodeling. However, the underlying mechanism of WASP family in cancer progression remains elusive. Here, we studied the role of WASP and SCAR Homolog (WASH), a recently identified WASP family member, in human esophageal squamous cell carcinoma (ESCC). Using three human ESCC cell lines, we found that WASH expression was significantly elevated in cancer stem-like cells enriched by sphere formation assay...
September 15, 2017: Cancer Science
https://www.readbyqxmd.com/read/28901470/tlr5-7-mediated-pi3k-activation-triggers-epithelial-mesenchymal-transition-of-ovarian-cancer-cells-through-wave3-dependent-mesothelin-or-oct4-sox2-expression
#17
Ga Bin Park, Daejin Kim
Toll-like receptor (TLR)-mediated signaling induces cell migration or invasion in several tumors and various stages of cancer. Interactions of mesothelin, a 40-kDa cell surface glycoprotein, with cancer antigen 125 (CA125) is associated with drug resistance, metastasis, and poor clinical outcome of ovarian cancer patients. In this study, we examined the role of TLR5 and TLR7 in the metastasis of ovarian cancer through the induction of mesothelin/CA125 expression and investigated its underlying mechanism. TLR5 agonist (flagellin) and TLR7 agonist (imiquimod) upregulated mesenchymal phenotypes and produced epithelial-mesenchymal transition (EMT)-related cytokines in the SKOV3 cells; however, TLR7 expressing CaOV3 cells had no response to the specific ligand, imiquimod, for enhancing its EMT processes...
November 2017: Oncology Reports
https://www.readbyqxmd.com/read/28901403/whole-wiskott%C3%A2-aldrich-syndrome-protein-gene-deletion-identified-by-high-throughput-sequencing
#18
Xiangling He, Runying Zou, Bing Zhang, Yalan You, Yang Yang, Xin Tian
Wiskott‑Aldrich syndrome (WAS) is a rare X‑linked recessive immunodeficiency disorder, characterized by thrombocytopenia, small platelets, eczema and recurrent infections associated with increased risk of autoimmunity and malignancy disorders. Mutations in the WAS protein (WASP) gene are responsible for WAS. To date, WASP mutations, including missense/nonsense, splicing, small deletions, small insertions, gross deletions, and gross insertions have been identified in patients with WAS. In addition, WASP‑interacting proteins are suspected in patients with clinical features of WAS, in whom the WASP gene sequence and mRNA levels are normal...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28895850/gene-therapy-approaches-to-immunodeficiency
#19
REVIEW
Sujal Ghosh, H Bobby Gaspar
Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28874467/an-evolutionarily-conserved-pathway-essential-for-orsay-virus-infection-of-caenorhabditis-elegans
#20
Hongbing Jiang, Kevin Chen, Luis E Sandoval, Christian Leung, David Wang
Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280...
September 5, 2017: MBio
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