Редактирование: TSC1 (раздел)

==Publications==

{{medline-entry
|title=[i]Tsc1[/i] Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32927859
|abstract=[[TSC1]] is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). [i][[TSC1]][/i] mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. [[TSC1]] modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells ([[MSC]]s) are unknown. We investigated the impact of [i]Tsc1[/i] inactivation in murine bone marrow (BM)-[[MSC]]s, using tissue-specific, transgelin ([i]Tagln[/i])-mediated cre-recombination, targeting both BM-[[MSC]]s and smooth muscle cells. [i]Tsc1[/i] mutants were viable, but homozygous inactivation led to a dwarfed appearance with TSC-like pathologies in multiple organs and reduced survival. In young (28 day old) mice, [i]Tsc1[/i] deficiency-induced significant cell expansion of non-hematopoietic BM in vivo, and [[MSC]] colony-forming potential in vitro, that was normalized upon treatment with the mTOR inhibitor, everolimus. The hyperproliferative BM-[[MSC]] phenotype was lost in aged (1.5 yr) mice, and [i]Tsc1[/i] inactivation was also accompanied by elevated ROS and increased senescence. ShRNA-mediated knockdown of [i]Tsc1[/i] in BM-[[MSC]]s replicated the hyperproliferative BM-[[MSC]] phenotype and led to impaired adipogenic and myogenic differentiation. Our data show that [i]Tsc1[/i] is a negative regulator of BM-[[MSC]] proliferation and support a pivotal role for the Tsc1-mTOR axis in the maintenance of the mesenchymal progenitor pool.

|keywords=* TSC1
* mammalian target of rapamycin (mTOR)
* mesenchymal stem cell
* senescence
* stem cell proliferation
* tuberous sclerosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565438
}}
{{medline-entry
|title=mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30924297
|abstract=Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in [[TSC1]] knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased [[GDF15]] is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of [[GDF15]] via phosphorylation of [[STAT3]]. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and [[STAT3]]'s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Humans
* Mechanistic Target of Rapamycin Complex 1
* Mice
* Mice, Knockout
* Mice, Transgenic
* Muscle Fibers, Skeletal
* Oxidative Stress
* Tuberous Sclerosis Complex 1 Protein
|keywords=* aging
* mTORC1
* oxidative stress
* signal transduction
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516169
}}
{{medline-entry
|title=[[FTO]] is involved in Alzheimer's disease by targeting [[TSC1]]-mTOR-Tau signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29501742
|abstract=Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein ([[FTO]]) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of [[FTO]] promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that [[FTO]] activated the phosphorylation of Tau in a mTOR-dependent manner because [[FTO]] activated mTOR and its downstream signaling and rapamycin blocked [[FTO]]-mediated phosphorylation of Tau. [[FTO]] promoted the activation of mTOR by increasing the mRNA level of [[TSC1]] but not [[TSC2]], the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that [[FTO]] is critically involved in insulin defects-related AD.
|mesh-terms=* Aging
* Alpha-Ketoglutarate-Dependent Dioxygenase FTO
* Alzheimer Disease
* Animals
* Brain
* Diabetes Mellitus
* Male
* Mice, Knockout
* Obesity
* Phosphorylation
* Signal Transduction
* TOR Serine-Threonine Kinases
* Tuberous Sclerosis Complex 1 Protein
* Tumor Suppressor Proteins
* tau Proteins
|keywords=* AD
* Diabetes
* FTO
* Insulin resistance
* TSC1
* Tau
* mTOR
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2018.02.201
}}
{{medline-entry
|title=Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29023667
|abstract=Epilepsy is one of the most prominent symptoms of tuberous sclerosis complex (TSC), a genetic disorder, and may be related to developmental defects resulting from impaired [[TSC1]] or [[TSC2]] gene function in astrocytes and neurons. Inactivation of the Tsc1 gene driven by a glial-fibrillary acidic protein ([[GFAP]]) promoter during embryonic brain development leads to widespread pathologic effects on astrocytes and neurons, culminating in severe, progressive epilepsy in mice (Tsc1  mice). However, the developmental timing and cellular specificity relevant to epileptogenesis in this model has not been well defined. The present study evaluates the effect of postnatal Tsc1 gene inactivation on pathologic features of astrocytes and neurons and development of epilepsy. An inducible Tsc1 knock-out mouse was created utilizing a tamoxifen-driven [[GFAP]]-CreER line (Tsc1  mice) with [[TSC1]] reduction induced postnatally at 2 and 6 weeks of age, and compared to conventional Tsc1  mice with prenatal [[TSC1]] reduction. Western blotting, immunohistochemistry, histology, and video-electroencephalography (EEG) assessed mechanistic target of rapamycin (mTOR) pathway activation, astrogliosis, neuronal organization, and spontaneous seizures, respectively. Tsc1 gene inactivation at 2 weeks of age was sufficient to cause astrogliosis and mild epilepsy in Tsc1  mice, but the phenotype was much less severe than that observed with prenatal Tsc1 gene inactivation in Tsc1  mice. Both astrocytes and neurons were affected by prenatal and postnatal Tsc1 gene activation to a degree similar to the severity of epilepsy, suggesting that both cellular types may contribute to epileptogenesis. These findings support a model in which the developmental timing of [[TSC1]] loss dictates the severity of neuronal and glial abnormalities and resulting epilepsy.
|mesh-terms=* Aging
* Animals
* Astrocytes
* Brain Chemistry
* Electroencephalography
* Estrogen Antagonists
* Glial Fibrillary Acidic Protein
* Gliosis
* Hippocampus
* Mice
* Mice, Knockout
* Neuroglia
* Neurons
* Seizures
* TOR Serine-Threonine Kinases
* Tamoxifen
* Tuberous Sclerosis Complex 1 Protein
* Tumor Suppressor Proteins
|keywords=* Astrocyte
* Epilepsy
* Mice
* Neuron
* Rapamycin
* Seizure
* Tuberous sclerosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716871
}}
{{medline-entry
|title=Moderate lifelong overexpression of tuberous sclerosis complex 1 ([[TSC1]]) improves health and survival in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28400571
|abstract=The tuberous sclerosis complex 1/2 ([[TSC1]]/2) is an endogenous regulator of the mechanistic target of rapamycin (mTOR). While mTOR has been shown to play an important role in health and aging, the role of [[TSC1]]/2 in aging has not been fully investigated. In the current study, a constitutive [[TSC1]] transgenic (Tsc1   ) mouse model was generated and characterized. mTORC1 signaling was reduced in majority of the tissues, except the brain. In contrast, mTORC2 signaling was enhanced in Tsc1   mice. Tsc1   mice are more tolerant to exhaustive exercises and less susceptible to isoproterenol-induced cardiac hypertrophy at both young and advanced ages. Tsc1   mice have less fibrosis and inflammation in aged as well as isoproterenol-challenged heart than age-matched wild type mice. The female Tsc1   mice exhibit a higher fat to lean mass ratio at advanced ages than age-matched wild type mice. More importantly, the lifespan increased significantly in female Tsc1   mice, but not in male Tsc1   mice. Collectively, our data demonstrated that moderate increase of [[TSC1]] expression can enhance overall health, particularly cardiovascular health, and improve survival in a gender-specific manner.
|mesh-terms=* Adiposity
* Animals
* Brain
* Cardiomegaly
* Female
* Isoproterenol
* Longevity
* Male
* Mechanistic Target of Rapamycin Complex 1
* Mechanistic Target of Rapamycin Complex 2
* Mice
* Mice, Inbred C57BL
* Physical Exertion
* Sex Factors
* Signal Transduction
* Tuberous Sclerosis Complex 1 Protein
* Tuberous Sclerosis Complex 2 Protein
* Tumor Suppressor Proteins
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429778
}}
{{medline-entry
|title=mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23810968
|abstract=Pseudolaric acid B (PAB), the primary biologically active compound isolated from the root bark of P. kaempferi Gordon, has been reported to exhibit anti-tumor effect primarily via cell cycle arrest and apoptosis. Our previous study demonstrated that PAB triggered mitotic catastrophe in L929 cells. In addition, a small percentage of the cells undergoing mitotic catastrophe displayed an apoptotic phenotype. Therefore, we continued to investigate the fate of the other cells. The results indicated that PAB induced senescence through p19-p53-p21 and p16-Rb pathways in L929 cells. PAB also triggered autophagy via inhibiting Akt-mammalian target of rapamycin (mTOR) activity in L929 cells. In addition, autophagy was demonstrated to reinforce senescence through regulating the senescence pathways. Thus, we focused on the detailed molecular mechanisms whereby autophagy promoted senescence. Reactive oxygen species (ROS) plays an important in autophagy and senescence. We found that PAB triggered a ROS-JNK-p53 positive feedback loop and this feedback loop played a crucial role in autophagy via repressing the activation of mTOR. Furthermore, ROS-JNK-p53 positive feedback loop was demonstrated to regulate senescence. Tuberous sclerosis proteins1 and 2, also known as [[TSC1]] and [[TSC2]], form a protein-complex. [[TSC1]]/[[TSC2]] heterodimer is a downstream target of growth factor-phosphoinositide 3-kinase-Akt signaling which negatively regulates mTOR activity. Activation of mTOR by insulin or inhibition of endogenous [[TSC2]] levels by siRNA obviously delayed PAB-induced senescence. In conclusion, mTOR inactivation by ROS-JNK-p53 pathway played an important role in autophagy-dependent senescence in PAB-treated L929 cells.
|mesh-terms=* Animals
* Autophagy
* Cell Line, Tumor
* Cellular Senescence
* Diterpenes
* Feedback, Physiological
* Fibrosarcoma
* JNK Mitogen-Activated Protein Kinases
* MAP Kinase Signaling System
* Mice
* Proto-Oncogene Proteins c-akt
* Reactive Oxygen Species
* TOR Serine-Threonine Kinases
* Tumor Suppressor Protein p53
|keywords=* Autophagy
* Pseudolaric acid B
* ROS-JNK-p53 pathway
* Senescence
* mTOR inactivation
|full-text-url=https://sci-hub.do/10.1016/j.ejphar.2013.05.051
}}
{{medline-entry
|title=Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23744272
|abstract=Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, [[TSC1]] or [[TSC2]]. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either [[TSC1]] or [[TSC2]] is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as [[STAT3]]-dependent and -independent developmental-stage-specific defects in the differentiation potential of ex-vivo-derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development. 
|mesh-terms=* Animals
* Animals, Newborn
* Cell Differentiation
* Cell Proliferation
* Cell Size
* Cerebral Cortex
* Disease Models, Animal
* Embryo, Mammalian
* Embryonic Development
* Enzyme Activation
* Epilepsy
* Gene Silencing
* Longevity
* Megalencephaly
* Mice
* Mutagenesis
* Myelin Sheath
* Neuroglia
* Neurons
* STAT3 Transcription Factor
* Sirolimus
* TOR Serine-Threonine Kinases
* Time Factors
* Tuberous Sclerosis
* Tuberous Sclerosis Complex 1 Protein
* Tumor Suppressor Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759338
}}