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https://www.readbyqxmd.com/read/27760312/impaired-mitochondrial-dynamics-and-mitophagy-in-neuronal-models-of-tuberous-sclerosis-complex
#1
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
#2
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
https://www.readbyqxmd.com/read/27756573/the-cochaperone-bag3-coordinates-protein-synthesis-and-autophagy-under-mechanical-strain-through-spatial-regulation-of-mtorc1
#3
Barbara Kathage, Sebastian Gehlert, Anna Ulbricht, Laura Lüdecke, Victor E Tapia, Zacharias Orfanos, Daniela Wenzel, Wilhelm Bloch, Rudolf Volkmer, Bernd K Fleischmann, Dieter O Fürst, Jörg Höhfeld
The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1)...
October 15, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27557496/dual-targeting-of-androgen-receptor-and-mtorc1-by-salinomycin-in-prostate-cancer
#4
Nooshin Mirkheshti, Sulgi Park, Shoulei Jiang, Jodie Cropper, Sherry L Werner, Chung S Song, Bandana Chatterjee
Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors...
August 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27499730/meta-analysis-of-tourette-syndrome-and-attention-deficit-hyperactivity-disorder-provides-support-for-a-shared-genetic-basis
#5
Fotis Tsetsos, Shanmukha S Padmanabhuni, John Alexander, Iordanis Karagiannidis, Margaritis Tsifintaris, Apostolia Topaloudi, Dimitrios Mantzaris, Marianthi Georgitsi, Petros Drineas, Peristera Paschou
Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3)...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27226234/tuberous-sclerosis-complex
#6
Elizabeth P Henske, Sergiusz Jóźwiak, J Christopher Kingswood, Julian R Sampson, Elizabeth A Thiele
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability...
May 26, 2016: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/26975583/rapamycin-requires-ampk-activity-and-p27-expression-for-promoting-autophagy-dependent-tsc2-null-cell-survival
#7
Tania Campos, Javiera Ziehe, Francisco Fuentes-Villalobos, Orlando Riquelme, Daniela Peña, Rodrigo Troncoso, Sergio Lavandero, Violeta Morin, Roxana Pincheira, Ariel F Castro
Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment...
June 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26713679/lymphangioleiomyomatosis-current-understanding-and-potential-treatments
#8
REVIEW
Lyn M Moir
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting predominantly young women. Clinical symptoms of this progressive disease include dyspnoea, cough, recurrent pneumothorax, hemoptysis and chylothorax. LAM is generally aggressive in nature and ultimately results in respiratory failure. Important hallmark features of this metastatic disease include the formation of lesions of abnormal smooth muscle cells, cystic destruction of the lung tissue and lymphangiogenesis affecting the lungs, abdomen and lymphatics...
February 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/26146406/n-myc-and-stat-interactor-regulates-autophagy-and-chemosensitivity-in-breast-cancer-cells
#9
Brandon J Metge, Aparna Mitra, Dongquan Chen, Lalita A Shevde, Rajeev S Samant
We have previously reported that expression of NMI (N-myc and STAT interactor) is compromised in invasive breast cancers. We also demonstrated that loss of NMI expression promotes epithelial-mesenchymal-transition and results in enhanced invasive ability of breast cancer cells. Additionally we had demonstrated that restoration of NMI expression reduced breast cancer xenograft growth and downregulated Wnt and TGFβ/SMAD signaling. Here we present our observations that NMI expression drives autophagy. Our studies were promoted by our observation that NMI expressing breast cancer cells showed autophagic vacuoles and LC3 processing...
July 6, 2015: Scientific Reports
https://www.readbyqxmd.com/read/26051878/mammalian-target-of-rapamycin-and-tuberous-sclerosis-complex
#10
REVIEW
Mari Wataya-Kaneda
Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is a member of the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 has emerged as a central regulator of cellular metabolism, cell proliferation, cellular differentiation, autophagy and immune response regulation. In contrast to mTORC1, mTORC2, which is not well understood, participates in cell survival and the regulation of actin and cytokeratin organization...
August 2015: Journal of Dermatological Science
https://www.readbyqxmd.com/read/25897262/clinical-features-epidemiology-and-therapy-of-lymphangioleiomyomatosis
#11
REVIEW
Angelo M Taveira-DaSilva, Joel Moss
Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, characterized by proliferation of abnormal smooth muscle-like LAM cells, leading to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics (eg, lymphangioleiomyomas), and renal angiomyolipomas. LAM is caused by mutations of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins with a major role in control of the mammalian target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex, an autosomal-dominant syndrome characterized by widespread hamartomatous lesions...
2015: Clinical Epidemiology
https://www.readbyqxmd.com/read/25565629/pharmacological-inhibition-of-polo-like-kinase-1-plk1-by-bi-2536-decreases-the-viability-and-survival-of-hamartin-and-tuberin-deficient-cells-via-induction-of-apoptosis-and-attenuation-of-autophagy
#12
Matthildi Valianou, Andrew M Cox, Benjamin Pichette, Shannon Hartley, Unmesha Roy Paladhi, Aristotelis Astrinidis
The mechanistic target of rapamycin complex 1 (mTORC1) increases translation, cell size and angiogenesis, and inhibits autophagy. mTORC1 is negatively regulated by hamartin and tuberin, the protein products of the tumor suppressors TSC1 and TSC2 that are mutated in Tuberous Sclerosis Complex (TSC) and sporadic Lymphangioleiomyomatosis (LAM). Hamartin interacts with the centrosomal and mitotic kinase polo-like kinase 1 (PLK1). Hamartin and tuberin deficient cells have abnormalities in centrosome duplication, mitotic progression, and cytokinesis, suggesting that the hamartin/tuberin heterodimer and mTORC1 signaling are involved in centrosome biology and mitosis...
2015: Cell Cycle
https://www.readbyqxmd.com/read/25524627/synthetic-lethality-of-combined-glutaminase-and-hsp90-inhibition-in-mtorc1-driven-tumor-cells
#13
Jing Li, Alfredo Csibi, Sun Yang, Gregory R Hoffman, Chenggang Li, Erik Zhang, Jane J Yu, John Blenis
The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid synthesis; and autophagy. Deregulation of the mTORC1 pathway is found in cancer as well as genetic disorders such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally suppress proliferation rather than induce apoptosis...
January 6, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25324725/rtp801-redd1-a-stress-coping-regulator-that-turns-into-a-troublemaker-in-neurodegenerative-disorders
#14
REVIEW
Mercè Canal, Joan Romaní-Aumedes, Núria Martín-Flores, Víctor Pérez-Fernández, Cristina Malagelada
Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts...
2014: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/25298408/therapeutic-targeting-of-cellular-metabolism-in-cells-with-hyperactive-mtorc1-a-paradigm-shift
#15
REVIEW
Doug Medvetz, Carmen Priolo, Elizabeth P Henske
mTORC1 is an established master regulator of cellular metabolic homeostasis, via multiple mechanisms that include altered glucose and glutamine metabolism, and decreased autophagy. mTORC1 is hyperactive in the human disease tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by germline mutations in the TSC1 or TSC2 gene. In TSC-deficient cells, metabolic wiring is extensively disrupted and rerouted as a consequence of mTORC1 hyperactivation, leading to multiple vulnerabilities, including "addiction" to glutamine, glucose, and autophagy...
January 2015: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/25288394/regulation-of-yap-by-mtor-and-autophagy-reveals-a-therapeutic-target-of-tuberous-sclerosis-complex
#16
Ning Liang, Chi Zhang, Patricia Dill, Ganna Panasyuk, Delphine Pion, Vonda Koka, Morgan Gallazzini, Eric N Olson, Hilaire Lam, Elizabeth P Henske, Zheng Dong, Udayan Apte, Nicolas Pallet, Randy L Johnson, Fabiola Terzi, David J Kwiatkowski, Jean-Yves Scoazec, Guido Martignoni, Mario Pende
Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC...
October 20, 2014: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/25105207/taking-aim-at-alzheimer-s-disease-through-the-mammalian-target-of-rapamycin
#17
REVIEW
Kenneth Maiese
A significant portion of the world's population suffers from sporadic Alzheimer's disease (AD) with available present therapies limited to symptomatic care that does not alter disease progression. Over the next decade, advancing age of the global population will dramatically increase the incidence of AD and severely impact health care resources, necessitating novel, safe, and efficacious strategies for AD. The mammalian target of rapamycin (mTOR) and its protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) offer exciting and unique avenues of intervention for AD through the oversight of programmed cell death pathways of apoptosis, autophagy, and necroptosis...
December 2014: Annals of Medicine
https://www.readbyqxmd.com/read/25020588/19analysis-of-tsc2-deficient-hearts-revealed-the-importance-of-autophagy-in-not-only-the-quality-but-also-the-quantity-control-of-mitochondria
#18
M Taneike, K Otsu
PURPOSE: Mammalian target of rapamycin complex 1 (mTORC1) is extremely important for cell growth and proliferation by activating protein synthesis. In addition, it also regulates protein degradation. There are two protein degradation systems in mammalian cells, namely autophagy and ubiquitin/proteasome systems. mTORC1 suppresses autophagic activity. We have previously reported that autophagy has a crucial role in maintaining cardiac structure and function in the heart. Tuberous sclerosis complex 1 (TSC1) and 2 heterodimer can inactivate ras homologue enriched in brain (Rheb) by the conversion of Rheb-GTP to Rheb-GDP in intracellular signalling pathway towards mTORC1, resulting in the inhibition of mTORC1 activity...
July 15, 2014: Cardiovascular Research
https://www.readbyqxmd.com/read/24599401/neuronal-tsc1-2-complex-controls-autophagy-through-ampk-dependent-regulation-of-ulk1
#19
Alessia Di Nardo, Mary H Wertz, Erica Kwiatkowski, Peter T Tsai, Jarrett D Leech, Emily Greene-Colozzi, June Goto, Pelin Dilsiz, Delia M Talos, Clary B Clish, David J Kwiatkowski, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of hamartomas in various organs and neurological manifestations including epilepsy, intellectual disability and autism. TSC1/2 protein complex negatively regulates the mammalian target of rapamycin complex 1 (mTORC1) a master regulator of protein synthesis, cell growth and autophagy. Autophagy is a cellular quality-control process that sequesters cytosolic material in double membrane vesicles called autophagosomes and degrades it in autolysosomes...
July 15, 2014: Human Molecular Genetics
https://www.readbyqxmd.com/read/24515783/tbc1d7-mutations-are-associated-with-intellectual-disability-macrocrania-patellar-dislocation-and-celiac-disease
#20
Ali Abdullah Alfaiz, Lucia Micale, Barbara Mandriani, Bartolomeo Augello, Maria Teresa Pellico, Jacqueline Chrast, Ioannis Xenarios, Leopoldo Zelante, Giuseppe Merla, Alexandre Reymond
TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild ID, they share osteoarticular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia, and astigmatism...
April 2014: Human Mutation
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