The tuberous sclerosis complex
Ksenia A. Orlova,Peter B. Crino +1 more
TLDR
Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.Abstract:
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. Progress over the past 15 years has demonstrated that the TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth-factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.read more
Citations
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Journal Article
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]
Sung Hee Um,Francesca Frigerio,Mitsuhiro Watanabe,Frédéric Picard,Manel Joaquin,Melanie Sticker,Stefano Fumagalli,Peter R. Allegrini,Sara C. Kozma,Johan Auwerx +9 more
TL;DR: In this article, S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation, but on a high fat diet, levels of glucose and free fatty acids still rise in S6k1-dependent mice, resulting in insulin receptor desensitization.
Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1
Katrin Düvel,Jessica L. Yecies,Suchithra Menon,Pichai Raman,Ellen Triantafellow,Qicheng Ma,Regina Gorski,Stephen Cleaver,Jeffrey P. MacKeigan,Peter Finan,Leon Murphy,Brendan D. Manning,Alex Lipovsky,Amanda Souza,Matthew G. Vander Heiden,Clary B. Clish +15 more
Abstract: Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1alpha) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease.
Journal ArticleDOI
Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress
TL;DR: In this paper, the authors focus on the key components of the mTOR complex 1 pathway and how various stresses impinge upon them and how they are implicated in the progression of stress-associated phenotypes and diseases, such as aging, tumorigenesis, and diabetes.
Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress
TL;DR: This review focuses on the key components of the mTOR complex 1 pathway and on how various stresses impinge upon them.
Journal ArticleDOI
Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis
Darcy A. Krueger,Marguerite M. Caré,Katherine D. Holland,Karen Agricola,Cynthia Tudor,Prajakta Mangeshkar,Kimberly Wilson,Anna W. Byars,Tarek Sahmoud,David Neal Franz +9 more
TL;DR: Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed.
References
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Journal ArticleDOI
p53, the Cellular Gatekeeper for Growth and Division
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
Journal ArticleDOI
Mutation and Cancer: Statistical Study of Retinoblastoma
TL;DR: The hypothesis is developed that retinoblastoma is a cancer caused by two mutational events, in the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells.
Journal ArticleDOI
TOR signaling in growth and metabolism.
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
Journal ArticleDOI
AKT/PKB signaling: navigating downstream.
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
PatentDOI
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
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