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https://www.readbyqxmd.com/read/27907099/analysis-of-a-mouse-skin-model-of-tuberous-sclerosis-complex
#1
Yanan Guo, John R Dreier, Juxiang Cao, Heng Du, Scott R Granter, David J Kwiatkowski
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis...
2016: PloS One
https://www.readbyqxmd.com/read/27906092/alterations-to-mtorc1-signaling-in-the-skeletal-muscle-differentially-affect-whole-body-metabolism
#2
Maitea Guridi, Barbara Kupr, Klaas Romanino, Shuo Lin, Denis Falcetta, Lionel Tintignac, Markus A Rüegg
BACKGROUND: The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism. RESULTS: We characterized the metabolic phenotype of young and old raptor muscle knock-out (RAmKO) and TSC1 muscle knock-out (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively...
March 21, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27890237/mosaic-disorders-of-the-pi3k-pten-akt-tsc-mtorc1-signaling-pathway
#3
REVIEW
Neera Nathan, Kim M Keppler-Noreuil, Leslie G Biesecker, Joel Moss, Thomas N Darling
Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells...
January 2017: Dermatologic Clinics
https://www.readbyqxmd.com/read/27871249/benign-clear-cell-sugar-tumor-of-the-lung-in-a-patient-with-birt-hogg-dub%C3%A3-syndrome-a-case-report
#4
Yoko Gunji-Niitsu, Toshio Kumasaka, Shigehiro Kitamura, Yoshito Hoshika, Takuo Hayashi, Hitoshi Tokuda, Riichiro Morita, Etsuko Kobayashi, Keiko Mitani, Mika Kikkawa, Kazuhisa Takahashi, Kuniaki Seyama
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal genodermatosis and caused by germline mutation of the folliculin (FLCN) gene, a tumor suppressor gene of which protein product is involved in mechanistic target of rapamycin (mTOR) signaling pathway regulating cell growth and metabolism. Clinical manifestations in BHD syndrome is characterized by fibrofolliculomas of the skin, pulmonary cysts with or without spontaneous pneumothorax, and renal neoplasms. There has been no pulmonary neoplasm reported in BHD syndrome, although the condition is due to deleterious sequence variants in a tumor suppressor gene...
November 21, 2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27863419/tsc-loss-distorts-dna-replication-programme-and-sensitises-cells-to-genotoxic-stress
#5
Govind M Pai, Alexandra Zielinski, Dennis Koalick, Kristin Ludwig, Zhao-Qi Wang, Kerstin Borgmann, Helmut Pospiech, Ignacio Rubio
Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27862655/mourning-dr-alfred-g-knudson-the-two-hit-hypothesis-tumor-suppressor-genes-and-the-tuberous-sclerosis-complex
#6
REVIEW
Okio Hino, Toshiyuki Kobayashi
On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome...
November 11, 2016: Cancer Science
https://www.readbyqxmd.com/read/27860216/somatic-overgrowth-disorders-of-the-pi3k-akt-mtor-pathway-therapeutic-strategies
#7
Kim M Keppler-Noreuil, Victoria E R Parker, Thomas N Darling, Julian A Martinez-Agosto
The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis...
November 18, 2016: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/27859028/phenotypic-and-genotypic-characterization-of-chinese-children-diagnosed-withtuberous-sclerosis-complex
#8
Guang Yang, ZeNing Shi, Yan Meng, XiuYu Shi, LingYu Pang, ShuFang Ma, MengNa Zhang, YanYan Wang, LiPing Zou
We investigated the clinical phenotypes and genetic mutations in Chinese children diagnosed with tuberous sclerosis complex (TSC). Sequencing of TSC1 and TSC2 genes was performed in 117 children with TSC and their parents. Association of TSC gene mutations with clinical manifestations was investigated. All gene mutations were heterozygous including in 16 patients (13.7%) with mutations in TSC1 gene and 101 patients (86.3%) with mutations in TSC2 gene. Among the 16 patients with TSC1 gene mutations, 15 different types of mutations were found, which included five novel mutations; all patients had skin manifestations and epilepsy...
November 8, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27845047/tuberous-sclerosis-complex-protein-1-expression-is-affected-by-vhl-gene-alterations-and-hif-1%C3%AE-production-in-sporadic-clear-cell-renal-cell-carcinoma
#9
Svetozar S Damjanovic, Bojana B Ilic, Bojana B Beleslin Cokic, Jadranka A Antic, Jovana Z Bankovic, Ivana T Milicevic, Gordana S Rodic, Dusan S Ilic, Vera N Todorovic, Nela Puskas, Cane D Tulic
Alterations in von Hippel-Lindau gene (VHL) do not determine deregulation of hypoxia-inducible factors (HIFs) in clear-cell renal carcinoma (ccRCC). Their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expressions in sporadic ccRCC are unknown. Therefore, we analyze the impact of VHL alterations and HIF-α production on the expression of TSC proteins and Hsp90 in these tumors. Alterations in VHL gene region exhibited 37/47 (78.7%) tumors. Monoallelic inactivation (intragenic mutation or LOH) was found in 10 (21...
November 12, 2016: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/27833825/epidemiology-pathogenesis-and-diagnosis-of-lymphangioleiomyomatosis
#10
Angelo M Taveira-DaSilva, Joel Moss
INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a disease of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas. AREAS COVERED: LAM is caused by proliferation of abnormal smooth muscle-like LAM cells containing mutations and perhaps epigenetic modifications of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins controlling the mechanistic target of rapamycin (mTOR) signaling pathway...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27824141/nesfatin-1-promotes-brown-adipocyte-phenotype
#11
Yuexin Wang, Ziru Li, Xinyu Zhang, Xinxin Xiang, Yin Li, Michael W Mulholland, Weizhen Zhang
Nesfatin-1, an 82 amino acid gastric peptide, is involved in regulation of food uptake and in multiple metabolic activities. Whether nesfatin-1 modulates the differentiation and lipid metabolism of brown adipocytes remains unknown. In the present study, we found that nesfatin-1 mRNA and protein were detectable in isolated brown adipocytes and gradually decreased during differentiation (95% CI 0.6057 to 1.034, p = 0.0001). The decrease in nesfatin-1 was associated with a significant reduction in p-S6. Exposure to nesfatin-1 promoted differentiation of brown adipocytes as revealed by a significant increase in UCP1 mRNA (p = 0...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27819329/mtor-overactivation-in-mesenchymal-cells-aggravates-ccl4-induced-liver-fibrosis
#12
Lanlan Shan, Yan Ding, You Fu, Ling Zhou, Xiaoying Dong, Shunzhi Chen, Hongyuan Wu, Wenqing Nai, Hang Zheng, Wanfu Xu, Xiaochun Bai, Chunhong Jia, Meng Dai
Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells...
November 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27809914/efficacy-and-safety-of-everolimus-in-children-with-tsc-associated-epilepsy-pilot-data-from-an-open-single-center-prospective-study
#13
Sharon Samueli, Klaus Abraham, Anastasia Dressler, Gudrun Gröppel, Angelika Mühlebner-Fahrngruber, Theresa Scholl, Gregor Kasprian, Franco Laccone, Martha Feucht
BACKGROUND: Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options. The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It's anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies...
November 3, 2016: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/27797139/tuberous-sclerosis-complex-from-molecular-biology-to-novel-therapeutic-approaches
#14
REVIEW
Katarzyna Switon, Katarzyna Kotulska, Aleksandra Janusz-Kaminska, Justyna Zmorzynska, Jacek Jaworski
Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients often suffer from epilepsy, mental retardation, and autism spectrum disorder (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of functional Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells...
October 31, 2016: IUBMB Life
https://www.readbyqxmd.com/read/27795403/the-andes-virus-nucleocapsid-protein-directs-basal-endothelial-cell-permeability-by-activating-rhoa
#15
Elena E Gorbunova, Matthew J Simons, Irina N Gavrilovskaya, Erich R Mackow
: Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases...
October 25, 2016: MBio
https://www.readbyqxmd.com/read/27793946/treatment-of-advanced-malignant-uterine-perivascular-epithelioid-cell-tumor-with-mtor-inhibitors-single-institution-experience-and-review-of-the-literature
#16
Kristen D Starbuck, Richard D Drake, G Thomas Budd, Peter G Rose
: Uterine perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors. Many have malignant behavior, and no successful treatment strategy has been established. Identification of mutations in the tuberous sclerosis 1 (TSC1) and TSC2 genes producing constitutive activation of the mammalian target of rapamycin (mTOR) pathway presents an opportunity for targeted therapy. Patients with advanced malignant uterine PEComa treated with mTOR inhibitors were identified and records were retrospectively reviewed for treatment response based on radiographic assessment...
November 2016: Anticancer Research
https://www.readbyqxmd.com/read/27776463/a-novel-de-novo-mutation-in-the-tsc2-gene-in-a-chinese-patient-with-tuberous-sclerosis-complex
#17
Wenzao Li, Peng Zhou, Congmin Zhao, Yuping Zhang
Tuberous sclerosis complex (TSC), a multisystem genetic syndrome, often affects the central nervous system. The age of onset of TSC ranges from 0 to 15 years. The clinical features manifest as a combination of seizures, mental retardation, facial angiofibroma, renal angiomyolipoma, and cardiac rhabdomyoma. Most cases of TSC are caused by mutations of the TSC1 or TSC2 genes. We characterized a Chinese patient with a novel de novo mutation in the TSC2 gene associated with the TSC detected by next-generation sequencing...
October 25, 2016: Journal of Neurogenetics
https://www.readbyqxmd.com/read/27768862/inactivation-of-tsc2-in-mesoderm-derived-cells-causes-polycystic-kidney-lesions-and-impairs-lung-alveolarization
#18
Siying Ren, Yongfeng Luo, Hui Chen, David Warburton, Hilaire C Lam, Larry Wang, Ping Chen, Elizabeth P Henske, Wei Shi
The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mTORC1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver...
October 18, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27760312/impaired-mitochondrial-dynamics-and-mitophagy-in-neuronal-models-of-tuberous-sclerosis-complex
#19
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Alessia Di Nardo, Daria Turner, Tommy L Lewis, Christopher Conrad, Jonathan M Rothberg, Jonathan O Lipton, Stefan Kölker, Georg F Hoffmann, Min-Joon Han, Franck Polleux, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27756752/tsc2-deficiency-unmasks-a-novel-necrosis-pathway-that-is-suppressed-by-the-rip1-rip3-mlkl-signaling-cascade
#20
Piotr T Filipczak, Cynthia L Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
October 18, 2016: Cancer Research
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