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neurofibromin 1

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https://www.readbyqxmd.com/read/28425622/targeted-disruption-of-nf1-in-osteocyte-increases-fgf23-and-osteoid-with-osteomalacia-like-bone-phenotype
#1
Nobuhiro Kamiya, Ryosuke Yamaguchi, Olumide Aruwajoye, Audrey Kim, Gen Kuroyanagi, Matthew Phipps, Naga Suresh Adapala, Jian Q Feng, Harry K W Kim
Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype...
April 20, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28423318/oligodendrocyte-nf1-controls-aberrant-notch-activation-and-regulates-myelin-structure-and-behavior
#2
Alejandro López-Juárez, Haley E Titus, Sadiq H Silbak, Joshua W Pressler, Tilat A Rizvi, Madeleine Bogard, Michael R Bennett, Georgianne Ciraolo, Michael T Williams, Charles V Vorhees, Nancy Ratner
The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice...
April 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28407626/exogenous-mirna-146a-enhances-the-therapeutic-efficacy-of-human-mesenchymal-stem-cells-by-increasing-vascular-endothelial-growth-factor-secretion-in-the-ischemia-reperfusion-injured-heart
#3
Hyang-Hee Seo, Se-Yeon Lee, Chang Youn Lee, Ran Kim, Pilseog Kim, Sekyung Oh, Hojin Lee, Min Young Lee, Jongmin Kim, Lark Kyun Kim, Ki-Chul Hwang, Woochul Chang
Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSCmiR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1)...
April 14, 2017: Journal of Vascular Research
https://www.readbyqxmd.com/read/28380429/ccl5-establishes-an-autocrine-high-grade-glioma-growth-regulatory-circuit-critical-for-mesenchymal-glioblastoma-survival
#4
Yuan Pan, Laura J Smithson, Yu Ma, Dolores Hambardzumyan, David H Gutmann
Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a median survival of 15 months. These poor clinical outcomes have prompted the development of drugs that block neoplastic cancer cell growth; however, non-neoplastic cell-derived signals (chemokines and cytokines) in the tumor microenvironment may also represent viable treatment targets. One such chemokine, Ccl5, produced by low-grade tumor-associated microglia, is responsible for maintaining neurofibromatosis type 1 (NF1) mouse optic glioma growth in vivo...
March 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28329564/polydactyly-in-neurofibromatosis-type-i-a-potential-clue-to-diagnosis
#5
Kate L Kimes, Marie J Han, Patrick J Brown
Neurofibromatosis type 1 is a genetic disorder characterized by variable phenotypic manifestations. The diagnostic criteria, 25 established in 1987, are broad to encompass these pleiotropic findings. Included are the specific osseous manifestations of 26 sphenoid dysplasia and dysplasia or thinning of the cortex of long bones. This review highlights recent evidence on the role of 27 neurofibromin in bone development and suggests consideration for additional diagnostic criteria.
November 15, 2016: Dermatology Online Journal
https://www.readbyqxmd.com/read/28295484/who-2016-classification-changes-and-advancements-in-the-diagnosis-of-miscellaneous-primary-cns-tumours
#6
Felix Sahm, David E Reuss, Caterina Giannini
This short review highlights significant changes and recent findings incorporated to varying extent in the WHO 2016 definition of a variety of tumours, including peripheral nerve sheath tumours, meningiomas, mesenchymal non-meningothelial tumours, melanocytic tumours, lymphomas and histiocytic tumours, germ cell tumours and non-neuroendocrine pituitary tumours. Most notable classification changes include: adding "hybrid nerve sheath tumours" to the spectrum of benign nerve sheath tumours; an updated definition of atypical meningioma (WHO grade II), including cases with brain invasion; recognizing dural solitary fibrous tumour (SFT) and haemangiopericytoma (HPC) as a single tumour entity characterized by NAB2 and STAT6 gene fusions for which the term solitary SFT/HPC was chosen; recognizing that pituitary granular cell tumour, spindle cell oncocytoma, and pituicytoma all share nuclear expression of TTF-1, possibly representing a spectrum of a single nosological entity derived from posterior pituitary glial cells...
March 12, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28166733/a-machine-learning-classifier-trained-on-cancer-transcriptomes-detects-nf1-inactivation-signal-in-glioblastoma
#7
Gregory P Way, Robert J Allaway, Stephanie J Bouley, Camilo E Fadul, Yolanda Sanchez, Casey S Greene
BACKGROUND: We have identified molecules that exhibit synthetic lethality in cells with loss of the neurofibromin 1 (NF1) tumor suppressor gene. However, recognizing tumors that have inactivation of the NF1 tumor suppressor function is challenging because the loss may occur via mechanisms that do not involve mutation of the genomic locus. Degradation of the NF1 protein, independent of NF1 mutation status, phenocopies inactivating mutations to drive tumors in human glioma cell lines. NF1 inactivation may alter the transcriptional landscape of a tumor and allow a machine learning classifier to detect which tumors will benefit from synthetic lethal molecules...
February 6, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28143781/phenformin-enhances-the-efficacy-of-erk-inhibition-in-nf1-mutant-melanoma
#8
Sebastian Trousil, Shuang Chen, Chan Mu, Fiona M Shaw, Zhan Yao, Yuping Ran, Tiwari Shakuntala, Taha Merghoub, Dieter Manstein, Neal Rosen, Lewis C Cantley, Jonathan H Zippin, Bin Zheng
Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis...
May 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28099845/absence-of-neurofibromin-induces-an-oncogenic-metabolic-switch-via-mitochondrial-erk-mediated-phosphorylation-of-the-chaperone-trap1
#9
Ionica Masgras, Francesco Ciscato, Anna Maria Brunati, Elena Tibaldi, Stefano Indraccolo, Matteo Curtarello, Federica Chiara, Giuseppe Cannino, Elena Papaleo, Matteo Lambrughi, Giulia Guzzo, Alberto Gambalunga, Marco Pizzi, Vincenza Guzzardo, Massimo Rugge, Stefania Edith Vuljan, Fiorella Calabrese, Paolo Bernardi, Andrea Rasola
Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28067895/the-nf1-gene-in-tumor-syndromes-and-melanoma
#10
Maija Kiuru, Klaus J Busam
Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS...
February 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27980226/novel-phenotypes-of-nf1-patients-from-unrelated-chinese-families-with-tibial-pseudarthrosis-and-anemia
#11
Santasree Banerjee, Dongzhu Lei, Shengran Liang, Li Yang, Saijun Liu, Zhu Wei, Jian Ping Tang
Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body...
December 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27941538/nf1-and-neurofibromin-emerging-players-in-the-genetic-landscape-of-desmoplastic-melanoma
#12
REVIEW
Meera Mahalingam
Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase-activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and "triple-wild-type" subtypes...
January 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/27827403/mir-107-regulates-tumor-progression-by-targeting-nf1-in-gastric-cancer
#13
Shizhi Wang, Gaoxiang Ma, Haixia Zhu, Chunye Lv, Haiyan Chu, Na Tong, Dongmei Wu, Fulin Qiang, Weida Gong, Qinghong Zhao, Guoquan Tao, Jianwei Zhou, Zhengdong Zhang, Meilin Wang
Our previous genome-wide miRNA microarray study revealed that miR-107 was upregulated in gastric cancer (GC). In this study we aimed to explore its biological role in the pathogenesis of GC. Integrating in silico prediction algorithms with western blotting assays revealed that miR-107 inhibition enhanced NF1 (neurofibromin 1) mRNA and protein levels, suggesting that NF1 is one of miR-107 targets in GC. Luciferase reporter assay revealed that miR-107 suppressed NF1 expression by binding to the first potential binding site within the 3'-UTR of NF1 mRNA...
November 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27791021/physical-interaction-between-neurofibromin-and-serotonin-5-ht6-receptor-promotes-receptor-constitutive-activity
#14
Wissem Deraredj Nadim, Séverine Chaumont-Dubel, Fahima Madouri, Laetitia Cobret, Marie-Ludivine De Tauzia, Pawel Zajdel, Hélène Bénédetti, Philippe Marin, Séverine Morisset-Lopez
Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27785414/von-recklinghausen-disease-one-patient-various-problems
#15
B Bergler-Czop, B Miziołek, L Brzezińska-Wcisło
von Recklinghausen disease (vRD), more widely known as neurofibromatosis type 1, belongs to a group of genetic disorders and it is considered to be the most common genodermatosis. The disease has an autosomal dominant pattern of inheritance that involves mutations within the NF1 gene located on chromosome 17 in locus q11.2. The product of the NF1 gene is neurofibromin and the protein is well known to be a tumor suppressor factor. This counteracts possible overactivity of RAS (protein)/MAPK (mitogen-activated protein kinase) and RAS/PI3K/AKT/mTOR (phoshatydyloinositol-3-kinase/V-akt murine thy-moma viral oncogene homologue/mammalian target of rapamycin) signaling transduction pathways, preventing from uncontrolled cell proliferation and subsequent tumor formation...
July 1, 2016: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/27773919/high-dose-intravenous-vitamin-c-treatment-of-a-child-with-neurofibromatosis-type-1-and-optic-pathway-glioma-a-case-report
#16
Nina Mikirova, Ronald Hunnunghake, Ruth C Scimeca, Charles Chinshaw, Faryal Ali, Chris Brannon, Neil Riordan
BACKGROUND In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. CASE REPORT We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year...
October 24, 2016: American Journal of Case Reports
https://www.readbyqxmd.com/read/27773571/nf1-is-a-direct-g-protein-effector-essential-for-opioid-signaling-to-ras-in-the-striatum
#17
Keqiang Xie, Lesley A Colgan, Maria T Dao, Brian S Muntean, Laurie P Sutton, Cesare Orlandi, Sanford L Boye, Shannon E Boye, Chien-Cheng Shih, Yuqing Li, Baoji Xu, Roy G Smith, Ryohei Yasuda, Kirill A Martemyanov
It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We find that binding of Gβγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR-signaling pathway...
November 21, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27688987/hypoplastic-internal-carotid-artery-co-presenting-with-neurofibromatosis-and-intracranial-masses
#18
Arvin R Wali, David R Santiago-Dieppa, Jeffrey A Steinberg, Ali Alattar, Vincent J Cheung, Royya Modir, Alexander A Khalessi, J Scott Pannell
Neurofibromatosis type 1 (NF1) is associated with systemic vascular disease, and it can also affect intracranial vasculature in a small percentage of patients. Very rarely, NF1 may co-present with hypoplasia of the internal carotid artery (ICA). Prior reports have documented NF1 with bilateral optic gliomas and a unilateral hypoplastic internal carotid artery; however, we report a case with the aforementioned findings in addition to a right-sided lentiform mass. This case report further suggests a common congenital pathway related to neurofibromin loss of function resulting in both nerve sheath tumors and cerebrovascular anomalies...
August 26, 2016: Curēus
https://www.readbyqxmd.com/read/27622733/neurofibromatosis-type-1-nf1-gene-beyond-caf%C3%A3-au-lait-spots-and-dermal-neurofibromas
#19
Sirkku Peltonen, Roope A Kallionpää, Juha Peltonen
Neurofibromatosis 1 (NF1) occurs in 1:2000 births. The main diagnostic signs are visible on the skin, and this opens several interesting aspects for dermatological point of view. The NF1 syndrome is caused by mutations in the NF1 gene which encodes the tumor suppressor protein neurofibromin. Neurofibromin functions as a Ras-GTPase-activating protein (RasGAP), and NF1 mutations lead to overactivation of the Ras signalling pathway. The NF1 gene and neurofibromin have intriguing functions in keratinocytes and melanocytes...
September 13, 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27446380/a-novel-alternative-splicing-isoform-of-nf2-identified-in-human-schwann-cells
#20
Fang Su, Zhengguang Zhou, Wen Su, Zishu Wang, Qiong Wu
Vestibular schwannoma (VS) is a benign, slow-growing cranial tumor that originates from the hypertrophy of Schwann cells. The majority of sporadic VS are unilateral, and the mechanisms underlying VS tumorigenesis are not fully understood. The human neurofibromin 2 (NF2) gene encodes the tumor suppressor protein merlin and the NF2 transcript can be alternatively spliced to form numerous isoforms. The present study investigated human Schwann cells (HSCs) at the mRNA and protein level to understand the function of the alternative splicing (AS) isoform of NF2...
August 2016: Oncology Letters
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