Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberous sclerosis complex (TSC) is caused by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene. Among the multisystemic manifestations of TSC, the neurodevelopmental features cause the most morbidity and mortality, presenting a considerable clinical challenge. Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation. Hyperactivated mTORC1 signaling, an important feature of TSC, has prompted a number of preclinical and clinical studies with the mTORC1 inhibitor rapamycin. Equally exciting is the prospect of treating TSC in the perinatal period to block the progression of brain pathologies and allow normal brain development to proceed. We hypothesized that low-dose rapamycin given prenatally and/or postnatally in a well-established neuroglial (Tsc2-hGFAP) model of TSC would rescue brain developmental defects. We developed three treatment regimens with low-dose intraperitoneal rapamycin (0.1 mg/kg): prenatal, postnatal and pre/postnatal (combined). Combined rapamycin treatment resulted in almost complete histologic rescue, with a well-organized cortex and hippocampus almost identical to control animals. Other treatment regimens yielded less complete, but significant improvements in brain histology. To assess how treatment regimens affected cognitive function, we continued rapamycin treatment after weaning and performed behavioral testing. Surprisingly, the animals treated with the combined therapy did not perform as well as postnatally-treated animals in learning and memory tasks. These results have important translational implications in the optimization of the timing and dosage of rapamycin treatment in TSC affected children.
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PMID:The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. 2253 72

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.
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PMID:Molecular therapies for tuberous sclerosis and neurofibromatosis. 2254 7

The tuberous sclerosis complex (TSC) is caused by mutation in either of 2 tumor suppressor genes, TSC-1 (encodes hamartin) and TSC-2 (encodes tuberin). In humans, deficiency in TSC1/2 is associated with benign tumors in many organs, including renal angiomyolipoma (AML) but rarely renal cell carcinoma (RCC). In contrast, deficiency of TSC function in the Eker rat is associated with RCC. Here, we have investigated the activity of PI 3-K and the expression of PTEN, p53, tuberin, p-mTOR, and p-p70S6K in both Eker rat RCC and human renal AML. Compared to normal tissue, increased PI 3-K activity was detected in RCC of Eker rats but not in human AML tissue. In contrast, PTEN was highly expressed in AML but significantly reduced in the renal tumors of Eker rats. Phosphorylation on Ser(2448) of mTOR and Thr(389) of p70S6K were significantly increased in both RCC and AML compared to matching control tissue. Total tuberin was significantly decreased in AML while completely lost in RCC of Eker rats. Our data also show that while p53 protein expression is lost in rat RCC, it was highly elevated in AML. These novel data provide evidence that loss of TSC-2, PTEN, and p53 as well as activation of PI 3-K and mTOR is associated with kidney cancer in the Eker rat, while sustained expression of TSC-2, PTEN, and p53 may prevent progression of kidney cancer in TSC patients.
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PMID:Regulation of PI 3-K, PTEN, p53, and mTOR in Malignant and Benign Tumors Deficient in Tuberin. 2273 71

Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five controls of cortical tissue taken from non-TSC patients with epilepsy. Immunoblotting demonstrated a marked reduction of LC3B-I and LC3B-II in tubers relative to the controls. In tubers, strong, diffuse and dot-like immunoreactivity (IR) for LC3B was observed in dysmorphic neurons and balloon cells, but LC3B-IR in other neurons with normal morphology was significantly weaker than that in neurons in the controls. Immunoelectron microscopy revealed diffuse distribution of LC3B-IR within the cytoplasm of balloon cells. The dot-like pattern may correspond to abnormal aggregation bodies involving LC3. In an autopsy patient with TSC, we observed that LC3B-IR in neurons located outside of the tubers was preserved. Thus, autophagy is suppressed in tubers presumably through the mTOR pathway, and possibly a pathological autophagy reaction occurs in the dysmorphic neurons and balloon cells.
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PMID:Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex. 2297 35

Neurodegenerative disorders affect a significant portion of the world's population leading to either disability or death for almost 30 million individuals worldwide. One novel therapeutic target that may offer promise for multiple disease entities that involve Alzheimer's disease, Parkinson's disease, epilepsy, trauma, stroke, and tumors of the nervous system is the mammalian target of rapamycin (mTOR). mTOR signaling is dependent upon the mTORC1 and mTORC2 complexes that are composed of mTOR and several regulatory proteins including the tuberous sclerosis complex (TSC1, hamartin/TSC2, tuberin). Through a number of integrated cell signaling pathways that involve those of mTORC1 and mTORC2 as well as more novel signaling tied to cytokines, Wnt, and forkhead, mTOR can foster stem cellular proliferation, tissue repair and longevity, and synaptic growth by modulating mechanisms that foster both apoptosis and autophagy. Yet, mTOR through its proliferative capacity may sometimes be detrimental to central nervous system recovery and even promote tumorigenesis. Further knowledge of mTOR and the critical pathways governed by this serine/threonine protein kinase can bring new light for neurodegeneration and other related diseases that currently require new and robust treatments.
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PMID:Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. 2298 37

Quercetin is an abundant micronutrient in our daily diet. Several beneficial health effects are associated with the dietary uptake of this bioflavonoid, including alleviating effects on chronic inflammation and atherosclerosis. A variety of in vitro data indicate a possible use of quercetin for cancer treatment purposes through its interaction with multiple cancer-related pathways. Among these, recent data reveal that quercetin can inhibit mTOR activity in cancer cells. Inhibition of the mTOR signaling pathway by quercetin has directly been described and can further be deduced from its interference with PI3K-dependent Akt stimulation, AMP-dependent protein kinase activation and hamartin upregulation. The ability of quercetin to interfere with both mTOR activity and activation of the PI3K/Akt signaling pathway gives quercetin the advantage to function as a dual-specific mTOR/PI3K inhibitor. The mTOR complex, often hyperactivated in cancer, is a crucial regulator of homeostasis controlling essential pathways leading to cell growth, protein biosynthesis and autophagy. The ability of quercetin to inhibit mTOR activity by multiple pathways makes this otherwise safe bioflavonoid an interesting tool for the treatment of cancers and other diseases associated with mTOR deregulation.
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PMID:Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. 2327 7

Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in-frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1(Cre) have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, though GAP-deficient tuberin protein, appear unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability.
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PMID:Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. 2335 22

Memory consolidation has been suggested to be protein synthesis dependent. Previous data indicate that BDNF-induced dendritic protein synthesis is a key event in memory formation through activation of the mammalian target of rapamycin (mTOR) pathway. BDNF also activates calpain, a calcium-dependent cysteine protease, which has been shown to play a critical role in learning and memory. This study was therefore directed at testing the hypothesis that calpain activity is required for BDNF-stimulated local protein synthesis, and at identifying the underlying molecular mechanism. In rat hippocampal slices, cortical synaptoneurosomes, and cultured neurons, BDNF-induced mTOR pathway activation and protein translation were blocked by calpain inhibition. BDNF treatment rapidly reduced levels of hamartin and tuberin, negative regulators of mTOR, in a calpain-dependent manner. Treatment of brain homogenates with purified calpain-1 and calpain-2 truncated both proteins. BDNF treatment increased phosphorylation of both Akt and ERK, but only the effect on Akt was blocked by calpain inhibition. Levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect. Calpain-2, but not calpain-1, treatment of brain homogenates resulted in PTEN degradation. In cultured cortical neurons, knockdown of calpain-2, but not calpain-1, by small interfering RNA completely suppressed the effect of BDNF on mTOR activation. Our results reveal a critical role for calpain-2 in BDNF-induced mTOR signaling and dendritic protein synthesis via PTEN, hamartin, and tuberin degradation. This mechanism therefore provides a link between proteolysis and protein synthesis that might contribute to synaptic plasticity.
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PMID:Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis. 2346 48

Tuberous sclerosis is an autosomal dominant disorder characterized by involvement of skin, nervous system, kidneys, and lungs. It results from mutations in 1 of 2 genes: TSC1 (encoding hamartin) or TSC2 (encoding tuberin), leading to dysregulation and activation of the mammalian target of rapamycin (mTOR) pathway. Constitutive activation of mTOR signaling has recently been reported in systemic lupus erythematosus (SLE), and inhibition of this pathway may benefit patients with SLE nephritis. We report a case of a young woman with tuberous sclerosis who developed fulminant SLE, with lower extremity edema, massive proteinuria, and class IV lupus glomerulonephritis. She died despite treatment with high-dose steroids, plasmapheresis, and cyclophosphamide. Although there are no prior reports of coexistence of these 2 rare diseases, this case is of considerable interest because of the possibility that activation of mTOR by the TSC mutations may have led to activation of the immune system and the development of unusually severe SLE.
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PMID:Tuberous sclerosis and fulminant lupus in a young woman. 2351 78

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with variable expressivity. Heterozygous mutations in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for most cases. Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) kinase. Genotype-phenotype studies suggest that TSC2 mutations are associated with a more severe neurologic phenotype, although the biologic basis for the difference between TSC1- and TSC2-based disease is unclear. Here we performed a study to compare and contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants. Using Tsc1 and Tsc2 floxed alleles and a radial glial transgenic Cre driver (FVB-Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells. Single and double mutants had remarkably similar phenotypes: early postnatal mortality, brain overgrowth, laminar disruption, astrogliosis, a paucity of oligodendroglia, and myelination defects. Double Tsc1/Tsc2 mutants died earlier than single mutants, and single mutants showed differences in the location of heterotopias and the organization of the hippocampal stratum pyramidale. The differences were not due to differential mTORC1 activation or feedback inhibition on Akt. These data provide further genetic evidence for individual hamartin and tuberin functions that may explain some of the genotype-phenotype differences seen in the human disease.
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PMID:Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants. 2374 4


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