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

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.
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PMID:TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. 1217 53

PTEN is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signalling pathway. Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti-apoptotic and pro-cell cycle entry pathways believed to be essential in tumourigenesis. Whilst PTEN mutations are frequent in a variety of sporadic cancers and inherited cancer syndromes, it is not clear how frequently PTEN mutations and immunohistochemical loss of PTEN expression occur in sporadic breast cancer. This study used tissue microarrays (TMAs) to assess wild-type PTEN and pAKT immunohistochemical staining in 670 and 691 cases, respectively, of primary operable breast cancer. Scores of 0, 1, and 2 were given for negative, weakly positive, and strongly positive degrees of immunoreactivity, respectively. In addition, immunohistochemical assessment of epidermal growth factor receptor (EGFR), Her2, and proliferation by MIB1 expression was performed on the same TMAs and the scores were compared with those of PTEN and pAKT. Eight per cent of cases did not express wild-type PTEN. No correlation was observed between patient, tumour and outcome variables and PTEN. pAKT expression correlated inversely with adverse tumour variables such as tumour grade (p< 0.001) and correlated positively with ER status (p< 0.001). No correlation was seen between either PTEN or AKT and EGFR, Her2 or MIB1. No association of PTEN or pAKT was seen in Kaplan-Meier or multivariate analysis for overall survival. The results indicate that loss of PTEN expression is infrequent in breast cancer. PTEN and AKT do not appear to be prognostic markers. The study argues against the current model of a simple linear tumourigenic PTEN-PI3K-AKT-mTOR pathway in breast cancer. It also suggests that, in this group of breast cancers, the most common upstream regulator of AKT may be ER rather than PTEN, EGFR or Her2.
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PMID:The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. 1530 42

Tuberous sclerosis is an autosomal dominant human disorder caused by inactivating mutations to either the TSC1 or TSC2 tumour suppressor gene. Hamartin and tuberin, the TSC1 and TSC2 gene products, interact and the tuberin-hamartin complex inhibits cell growth by antagonising signal transduction to downstream effectors of the mammalian target of rapamycin (mTOR) through the small GTPase rheb. Previously, we showed that pathogenic tuberin amino-acid substitutions disrupt the tuberin-hamartin complex. Here, we investigate how these mutations affect the role of tuberin in the control of signal transduction through mTOR. Our data indicate that specific amino-acid substitutions have distinct effects on tuberin function.
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PMID:Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. 1548 52

Gene deletion studies in mice and in Drosophila have shown that the 40S ribosomal protein S6 Kinases, dS6K in Drosophila and S6K1 and S6K2 in mice are important regulators of cell growth in response to insulin stimulation and nutrition availability. Here we chiefly focus on dS6k and S6K1, whose activities are regulated by an upstream kinase termed the mammalian target of rapamycin (mTOR, or dTOR in Drosophila). Our understanding of the mechanisms regulating the mTOR/S6K1-signalling pathway will be fundamental in determining the mechanisms which control cell growth in response to insulin signalling. Recent findings from this laboratory and others suggests that the tumour suppressor complex made of two proteins TSC1/hamartin and TSC2/tuberin, acts as a negative regulator of mTOR/S6K1 signalling. Mutations in either TSC1 or TSC2 are genetically linked to tuberous sclerosis complex (TSC) syndrome, which can lead to severe pathological consequences, including mental retardation, epilepsy and autism, as well as cardiac, pulmonary and renal failure. Despite a large number of initial reports on the TSC1/TSC2 complex, and the finding that its activity is regulated by protein kinase B (PKB), the direct target of the TSC1/TSC2 inhibitory complex was unknown until recently. Since TSC2 has a GTPase-activating domain, or GAP-like sequence, others and we searched for a small GTP binding protein, which may serve as the target of TSC1/TSC2 inhibitory complex. In our case we took advantage of a genome wide screen in Drosophila for effectors of cell growth and in parallel searched for a small GTPase whose activity is up-regulated in TSC2-deficient cells. The identified gene was a member of the Ras family of GTPases termed Ras homologue enriched in brain or Rheb. Here we review recent findings demonstrating that the TSC1/TSC2 inhibitory complex normally acts on Rheb to mediate mTOR/S6K1-signalling.
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PMID:The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. 1556 27

Growth factors provide permission signals that allow mammalian cells to grow, proliferate and survive. One mechanism by which growth factors maintain this control is through the regulation of cell surface nutrient transporter expression. Following growth factor withdrawal, nutrient transporters are endocytosed and degraded in the lysosome, effectively terminating the cell's ability to obtain nutrients. This results in a state of pseudostarvation in which cells atrophy and initiate a catabolic metabolic programme in the midst of abundant extracellular nutrients. Oncogenic forms of Akt can support growth factor-independent nutrient transporter expression through a mechanism that depends upon mTOR (mammalian target of rapamycin). The ability of activated Akt to support nutrient transporter expression is an essential component of its prosurvival function. When the destruction of nutrient transporters is inhibited, cells are capable of long-term growth-factor-independent cell survival in the absence of receptor-dependent signal transduction. These results imply that proteins involved in nutrient transporter turnover in response to growth factor withdrawal are components of a novel tumour suppressor pathway. Preliminary data suggest that Rab7, a GTPase required for transporter degradation, functions as a tumour suppressor protein, as inhibiting Rab7 activity promotes colony formation in soft agar. These studies indicate that drugs affecting this pathway might have utility as anti-cancer chemotherapeutic agents.
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PMID:Growth factors regulate cell survival by controlling nutrient transporter expression. 1566 13

The prostate is a highly androgen-dependent tissue that in humans exhibits marked susceptibility to carcinogenesis. The malignant epithelium generated from this tissue ultimately loses dependence on androgens despite retention or amplification of the androgen receptor. Accumulating evidence support that transforming growth factor-beta (TGF-beta) plays key roles in the control of androgen dependence and acquisition of resistance to such hormonal control. Although TGF-beta functions as a key tumour suppressor of the prostate, it can also promote malignant progression and metastasis of the advanced disease, through undefined mechanisms. In addition to giving an overview of the TGF-beta field as related to its function in prostate cancer, this Review focuses on novel findings that support the tumour suppressor function of TGF-beta is lost or altered by changes in the activity of the androgen receptor, insulin-like growth factor-I, Akt, and mTOR during malignant progression. Understanding the mechanisms of cross-talk between TGF-beta and such growth modulators has important implications for the rational therapeutics of prostate cancer.
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PMID:Functions and regulation of transforming growth factor-beta (TGF-beta) in the prostate. 1580 54

Tuberous sclerosis complex (TSC) is an autosomal dominant benign tumour syndrome caused by mutations to either the TSC1 or TSC2 tumour suppressor gene. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that integrates inputs from multiple signalling cascades to inactivate the small GTPase rheb, and thereby inhibit mTOR-dependent cell growth. We have used matrix-assisted laser desorption/ionisation time-of-flight and Fourier transform mass spectrometry to identify TSC1 and TSC2 phosphorylation sites and candidate TSC1 and TSC2 interacting proteins. We identified three sites of TSC2 phosphorylation and a novel site of TSC1 phosphorylation, and investigated the roles of these sites in regulating the activity of the TSC1-TSC2 complex. In addition, we identified three TSC1-TSC2 interacting proteins, including DOCK7 a putative rhebGEF.
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PMID:Phosphorylation and binding partner analysis of the TSC1-TSC2 complex. 1596 62

TSC1 and TSC2 are two recently identified tumour suppressor genes encoding hamartin and tuberin, respectively, and involved in pathogenesis of tuberous sclerosis, neurological disorder connected with the development of hamartomas in numerous organ systems, including the brain, kidneys, heart and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein, Ras homologue enriched in brain (Rheb). Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression. Tuberin, possessing the Rheb-GAP domain, is phosphorylated by several kinases that confer the signals of growth factor stimulation or low cellular energy levels. Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation. Current article describes biochemical properties of hamartin and tuberin, their known regulatory phosphorylation sites and binding partners.
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PMID:Hamartin and tuberin: working together for tumour suppression. 1620 76

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.
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PMID:Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. 1672 49

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
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PMID:AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. 1661 76


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