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https://www.readbyqxmd.com/read/28710231/tuberin-regulates-prostaglandin-receptor-mediated-viability-via-rheb-in-mtorc1-hyperactive-cells
#1
Chenggang Li, Xiaolei Liu, Yang Liu, Erik Zhang, Kantha Medepalli, Kohei Masuda, Na Li, Elizabeth J Kopras, David J Kwiatkowski, Michael T Borchers, Kathryn A Wikenheiser-Brokamp, Andrew Osterburg, Maxwell Mays, Yang Sun, David R Plas, Julia L Sun, David N Franz, Jamie K Capal, Anya Alayev, Marina K Holz, Darcy A Krueger, Brian J Siroky, Jane J Yu
Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2 resulting in hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulate that the action of excess PGE2 and its cognate receptors (EPs) contribute to cell survival...
July 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28706137/assessment-of-pancreatic-neuroendocrine-tumor-cytologic-genotype-diversity-to-guide-personalized-medicine-using-a-custom-gastroenteropancreatic-next-generation-sequencing-panel
#2
Ferga C Gleeson, Jesse S Voss, Benjamin R Kipp, Sarah E Kerr, John S Van Arnam, John R Mills, Cherisse A Marcou, Amber R Schneider, Zheng Jin Tu, Michael R Henry, Michael J Levy
BACKGROUND: Recent genetic studies have highlighted that alterations in MEN1, chromatin remodeling genes, and mammalian target of rapamycin (mTOR) pathway genes are the most frequent molecular events identified in pancreas neuroendocrine tumors (pNETs). The prognostic or predictive impact of these biomarkers and other less frequently observed aberrations, i.e. PTEN, TSC2 and PIK3CA are relatively unknown. The aims of this targeted next generation sequencing (NGS) study were to assess tumor cytology genotype diversity, to survey for potential adverse prognostic biomarkers and the prevalence of mTOR pathway variants...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28701918/striatal-transcriptome-and-interactome-analysis-of-shank3-overexpressing-mice-reveals-the-connectivity-between-shank3-and-mtorc1-signaling
#3
Yeunkum Lee, Sun Gyun Kim, Bokyoung Lee, Yinhua Zhang, Yoonhee Kim, Shinhyun Kim, Eunjoon Kim, Hyojin Kang, Kihoon Han
Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28699893/hyperactivated-mtorc1-downregulation-of-foxo3a-pdgfr%C3%AE-akt-cascade-restrains-tuberous-sclerosis-complex-associated-tumor-development
#4
Li Wang, Zhaofei Ni, Yujie Liu, Shuang Ji, Fuquan Jin, Keguo Jiang, Junfang Ma, Cuiping Ren, Hongbing Zhang, Zhongdong Hu, Xiaojun Zha
Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28695825/tsc2-disruption-in-mesenchymal-progenitors-results-in-tumors-with-vascular-anomalies-overexpressing-lgals3
#5
Peter J Klover, Rajesh L Thangapazham, Jiro Kato, Ji-An Wang, Stasia A Anderson, Victoria Hoffmann, Wendy K Steagall, Shaowei Li, Elizabeth McCart, Neera Nathan, Joshua D Bernstock, Matthew D Wilkerson, Clifton L Dalgard, Joel Moss, Thomas N Darling
Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption of Tsc2 in craniofacial and limb bud mesenchymal progenitors. Tsc2cKO(Prrx1-cre) mice had shortened lifespans and extensive hamartomas containing abnormal tortuous, dilated vessels prominent in the forelimbs. Abnormalities were blocked by the mTORC1 inhibitor sirolimus. A Tsc2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database...
July 11, 2017: ELife
https://www.readbyqxmd.com/read/28694500/resistance-exercise-initiates-mechanistic-target-of-rapamycin-mtor-translocation-and-protein-complex-co-localisation-in-human-skeletal-muscle
#6
Zhe Song, Daniel R Moore, Nathan Hodson, Carl Ward, Jessica R Dent, Mary F O'Leary, Andrew M Shaw, D Lee Hamilton, Sovan Sarkar, Yann-Gaël Gangloff, Troy A Hornberger, Lawrence L Spriet, George J Heigenhauser, Andrew Philp
The mechanistic target of rapamycin (mTOR) is a central mediator of protein synthesis in skeletal muscle. We utilized immunofluorescence approaches to study mTOR cellular distribution and protein-protein co-localisation in human skeletal muscle in the basal state as well as immediately, 1 and 3 h after an acute bout of resistance exercise in a fed (FED; 20 g Protein/40 g carbohydrate/1 g fat) or energy-free control (CON) state. mTOR and the lysosomal protein LAMP2 were highly co-localised in basal samples...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28694334/loss-of-tuberous-sclerosis-complex1-in-adult-oligodendrocyte-progenitor-cells-enhances-axon-remyelination-and-increases-myelin-thickness-after-a-focal-demyelination
#7
Lauren E McLane, Jennifer N Bourne, Angelina V Evangelou, Luipa Khandker, Wendy B Macklin, Teresa L Wood
While the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we utilized the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin demyelinated lesion in adult male mice...
July 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28684424/il-4-upregulates-cyclooxygenase-1-expression-in-macrophages
#8
Ashley E Shay, Bastihalli T Diwakar, Bo-Jhih Guan, Vivek Narayan, Joseph F Urban, K Sandeep Prabhu
Macrophages use various cell-surface receptors to sense their environment and undergo polarized responses. The cytokines IL-4 and IL-13, released from T-helper type 2 (Th2) cells, drive macrophage polarization toward an alternatively activated phenotype (M2). This phenotype is associated with the expression of potent pro-resolving mediators, such as the prostaglandin (PG) D2-derived cyclopentenone metabolite, 15d-PGJ2, produced by the cyclooxygenase (Ptgs; Cox) pathway. Interestingly, IL-4 treatment of bone marrow-derived macrophages significantly downregulates Cox-2 protein expression, while Cox-1 levels are significantly increased...
July 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28683327/exosomes-mediate-mobilization-of-autocrine-wnt10b-to-promote-axonal-regeneration-in-the-injured-cns
#9
Nardos G Tassew, Jason Charish, Alireza P Shabanzadeh, Valbona Luga, Hidekiyo Harada, Nahal Farhani, Philippe D'Onofrio, Brian Choi, Ahmad Ellabban, Philip E B Nickerson, Valerie A Wallace, Paulo D Koeberle, Jeffrey L Wrana, Philippe P Monnier
Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28667702/tuberous-sclerosis-complex-recent-advances-in-manifestations-and-therapy
#10
REVIEW
Mari Wataya-Kaneda, Motohide Uemura, Kazutoshi Fujita, Haruhiko Hirata, Keigo Osuga, Kuriko Kagitani-Shimono, Norio Nonomura
Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions...
July 1, 2017: International Journal of Urology: Official Journal of the Japanese Urological Association
https://www.readbyqxmd.com/read/28665395/alternative-splicing-promotes-tumour-aggressiveness-and-drug-resistance-in-african-american-prostate-cancer
#11
Bi-Dar Wang, Kristin Ceniccola, SuJin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A Garcia-Blanco, Steven R Patierno, Norman H Lee
Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants...
June 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28663780/new-insights-into-the-pathogenesis-and-prevention-of-tuberous-sclerosis-associated-neuropsychiatric-disorders-tand
#12
REVIEW
Tanjala T Gipson, Michael V Johnston
Tuberous sclerosis complex (TSC) is a multi-system disorder resulting from mutations in either the TSC1 or TSC2 genes leading to hyperactivation of mechanistic target of rapamycin (mTOR) signaling. TSC is commonly associated with autism (61%), intellectual disability (45%), and behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties that are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). More than 90% of children with TSC have epilepsy, including infantile spasms, and early onset of seizures, especially infantile spasms, is associated with greater impairment in intellectual development compared with individuals with TSC without seizures...
2017: F1000Research
https://www.readbyqxmd.com/read/28659645/single-giant-mediastinal-rhabdomyoma-as-a-sole-manifestation-of-tsc-in-foetus
#13
Marek Godava, Hana Filipova, Lubomir Dubrava, Radek Vrtel, Kamila Michalkova, Maria Janikova, Lenka Bakaj-Zbrozkova, Jiri Navratil
BACKGROUND: Presence of multiple cardiac rhabdomyomas is one of the major features of Tuberous sclerosis (TSC), but isolated progressing single giant rhabdomyoma is very rare and not typical of TSC. CASE REPORT: This report presents family without obvious history of TSC with occurrence of giant mediastinal rhabdomyoma affecting the haemodynamics in male foetus, without other TSC symptoms. Girl from the next gravidity had prenatally detected multiple rhabdomyomas and small subcortical tuber of brain detected after birth...
June 12, 2017: Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia
https://www.readbyqxmd.com/read/28646232/inhibition-of-erk1-2-restores-gsk3%C3%AE-activity-and-protein-synthesis-levels-in-a-model-of-tuberous-sclerosis
#14
Rituraj Pal, Vitaliy V Bondar, Carolyn J Adamski, George G Rodney, Marco Sardiello
Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal-regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28643795/the-genomic-landscape-of-tuberous-sclerosis-complex
#15
Katie R Martin, Wanding Zhou, Megan J Bowman, Juliann Shih, Kit Sing Au, Kristin E Dittenhafer-Reed, Kellie A Sisson, Julie Koeman, Daniel J Weisenberger, Sandra L Cottingham, Steven T DeRoos, Orrin Devinsky, Mary E Winn, Andrew D Cherniack, Hui Shen, Hope Northrup, Darcy A Krueger, Jeffrey P MacKeigan
Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist...
June 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28643793/genomic-rearrangements-in-sporadic-lymphangioleiomyomatosis-an-evolving-genetic-story
#16
Stephen J Murphy, Simone B Terra, Faye R Harris, Aqsa Nasir, Jesse S Voss, James B Smadbeck, Sarah H Johnson, Vishnu Serla, Jay H Ryu, Eunhee S Yi, Benjamin R Kipp, George Vasmatzis, Eva M Carmona
Sporadic lymphangioleiomyomatosis is a progressive pulmonary cystic disease resulting from the infiltration of smooth muscle-like lymphangioleiomyomatosis cells into the lung. The migratory/metastasizing properties of the lymphangioleiomyomatosis cell together with the presence of somatic mutations, primarily in the tuberous sclerosis complex gene (TSC2), lead many to consider this a low-grade malignancy. As malignant tumors characteristically accumulate somatic structural variations, which have not been well studied in sporadic lymphangioleiomyomatosis, we utilized mate pair sequencing to define structural variations within laser capture microdissected enriched lymphangioleiomyomatosis cell populations from five sporadic lymphangioleiomyomatosis patients...
June 23, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28637240/tfeb-activation-restores-migration-ability-to-tsc1-deficient-adult-neural-stem-progenitor-cells
#17
Alessandro Magini, Alice Polchi, Danila Di Meo, Giuseppina Mariucci, Krizia Sagini, Federico De Marco, Tommaso Cassano, Stefano Giovagnoli, Diego Dolcetta, Carla Emiliani
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs)...
June 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28623545/analysis-of-genotypes-and-phenotypes-in-chinese-children-with-tuberous-sclerosis-complex
#18
Dayong Bai, Junyang Zhao, Li Li, Jun Gao, Xu Wang
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children (7.00±5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children...
June 14, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28620021/correction-for-wolff-et-al-cell-type-dependent-regulation-of-mtorc1-by-redd1-and-the-tumor-suppressors-tsc1-tsc2-and-lkb1-in-response-to-hypoxia
#19
Nicholas C Wolff, Silvia Vega-Rubin-de-Celis, Xian-Jin Xie, Diego H Castrillon, Wareef Kabbani, James Brugarolas
No abstract text is available yet for this article.
July 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28613922/apparent-sporadic-lymphangioleiomyomatosis-in-a-man-as-a-result-of-extreme-mosaicism-for-a-tsc2-mutation
#20
MeiLan K Han, Magdalena E Tyburczy, Thomas N Darling, Ella A Kazerooni, Jeffrey L Myers, Francis X McCormack, Joel Moss, David J Kwiatkowski
No abstract text is available yet for this article.
July 2017: Annals of the American Thoracic Society
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