These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.
This finding, together with earlier work, strongly suggests that a major form of negative feedback inhibition of PI3K results from activated growth signalling via mammalian target of rapamycin (mTOR) and the p70 S6 kinase (S6K) - a pathway that could have consequences for the development of type 2 diabetes and tuberous sclerosis complex.
High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome.
At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2-dependent inhibition of the mammalian target of rapamycin kinase.
The mechanism by which 6-OHDA and RTP801 induce neuron death appears to involve repression of mammalian target of rapamycin (mTOR) kinase activity, and such death is inhibited by shRNAs targeting TSC2 (tuberous sclerosis complex), a protein with which RTP801 interacts to block mTOR activation.
We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis.
Genetic loss of TSC1/TSC2 function in tuberous sclerosis complex (TSC) results in overactivation of the mammalian target of rapamycin complex 1 pathway, leading to cellular dysplasia.
Tuberous sclerosis (TS), neurological disorder manifesting with the formation of tumors in numerous organ systems, is a disease associated with the upregulation of mammalian target of rapamycin (mTOR) pathway.
Insulin-like growth factor-I plays a key role in this balance by activating the Akt/tuberous sclerosis complex 2/mammalian target of rapamycin pathway.
Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR).
Our results provide novel evidence that Pam can function as an E3 Ub ligase toward tuberin and regulate mTOR signaling, suggesting that Pam can in turn regulate cell growth and proliferation as well as neuronal function through the TSC/mTOR pathway in mammalian cells.
Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH.
Tuberous sclerosis complex (TSC) is a genetic disorder linked to mutations of either the TSC1 or TSC2 gene, which encode proteins that form a complex to negatively regulate mammalian target of rapamycin complex 1 (mTORC1).
Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors.
Mutations in several mTOR pathway component genes are known to cause specific monogenic human genetic diseases and this signalling cascade has been shown to be of relevance for Alzheimer's disease, type 2 diabetes, obesity and hypertrophy.Consequently, e.g. clinical trials for the treatment with rapamycin, a negative regulator of mTOR, of hamartomas in TSC have already been initiated.
When compared with monotherapy, combinatorial application of rapamycin and PD98059 had greater inhibitory effects on Tsc2 deficient cell proliferation, suggesting that combined suppression of mTOR and ERK/MAPK signaling pathways may have advantages over single mTOR inhibition in the treatment of TSC patients.
We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity.
Although it remains to be seen whether use of mammalian target of rapamycin complex 1 inhibitors will revolutionize the care of patients with TSC, the application of basic and translational research towards a specific clinical disorder emphasizes the potential and promise of molecular medicine.
The importance of the mTOR pathway in epileptogenesis is best illustrated by tuberous sclerosis complex (TSC), one of the most common genetic causes of epilepsy.
Loss of heterozygosity on TSC genes and immunohistochemistry for mTOR-related proteins (phospho-mTOR, phospho-p70S6K, phospho-S6, and phospho-Akt) were analyzed in 42 lesions: 16 multifocal micronodular pneumocyte hyperplasia (7 patients with TSC, 1 TSCnot confirmed), 14 atypical adenomatous hyperplasia, and 12 bronchioloalveolar carcinoma (9 and 12 patients, respectively).
Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma.