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)

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G1 phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy.
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PMID:New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists. 1531 29

Here, we demonstrated that inhibition of mTOR with rapamycin has negative effects on adipocyte differentiation and insulin signaling. Rapamycin significantly reduced expression of most adipocyte marker genes including PPARgamma, adipsin, aP2, ADD1/SREBP1c, and FAS, and decreased intracellular lipid accumulation in 3T3-L1 and 3T3-F442A cells, suggesting that rapamycin would affect both lipogenesis and adipogenesis. Contrary to the previous report that suppressive effect of rapamycin on adipogenesis is limited to the clonal expansion, we revealed that its inhibitory effect persisted throughout the process of adipocyte differentiation. Thus, it is likely that constitutive activation of mTOR might be required for the execution of adipogenic programming. In differentiated 3T3-L1 adipocytes, chronic treatment of rapamycin blunted the phosphorylation of AKT and GSK, which is stimulated by insulin, and reduced insulin-dependent glucose uptake activity. Taken together, these results suggest that rapamycin not only prevents adipocyte differentiation by decrease of adipogenesis and lipogenesis but also downregulates insulin action in adipocytes, implying that mTOR would play important roles in adipogenesis and insulin action.
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PMID:Regulation of adipocyte differentiation and insulin action with rapamycin. 1535 18

mTOR is a downstream mediator in the PI3K/Akt signalling pathway, which plays a critical role in regulating basic cellular functions. These include cell proliferation, survival, mobility and angiogenesis. Rapamycin and its analogues (CCI-779, RAD001 and AP23573) have specific antagonistic action on the function of mTOR. This leads to inhibition of the downstream signalling elements and results in the cell cycle arrest in the G1 phase. This group of drugs may have a place in Oncology for the treatment of cancers, which occur as a result of increased activity of the PI3 kinase/Akt/m-TOR pathway. The basic structure of the pathway was reviewed in this article, together with results of the clinical studies targeting mTOR for cancer therapy. This is an exciting area for development and poses many challenges to researchers.
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PMID:Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. 1536 68

Bone-marrow-derived, circulating endothelial precursor cells contribute to neoangiogenesis in various diseases. Rapamycin has recently been shown to have anti-angiogenic effects in an experimental tumor model. Our group has developed a culture system that allows expansion and endothelial differentiation of human CD133(+) precursor cells. We could show by PCR analysis that mTOR, the rapamycin-binding protein, was expressed in fresh CD133(+) cells, in expanded cells after 28 days, and in differentiated endothelial cells. Rapamycin inhibited proliferation of CD133(+) cells dose dependently at similar concentrations as hematopoietic Jurkat or HL-60 cells. Apoptosis was induced by rapamycin after 48 h of treatment, which could be reduced by preincubation with FK 506. Furthermore, the development of adherent endothelial cells from expanded CD133(+) cells was dose dependently inhibited. Expression of endothelial antigens CD144 and von Willebrand factor on differentiating endothelial precursors was reduced by rapamycin. In summary, rapamycin inhibits proliferation and differentiation of human endothelial precursor cells underlining its anti-angiogenic effects.
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PMID:Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. 1538 15

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.
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PMID:Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. 1546 72

The mammalian target of rapamycin (mTOR) is a central regulator of ribosome biogenesis, protein synthesis, cell growth and neurite plasticity. The mTOR kinase controls the translation machinery, in response to amino acids and growth factors, via activation of p70 ribosomal S6 kinase (p70S6K) and inhibition of eIF-4E binding protein (4E-BP1). The mTOR protein belongs to the PI3K pathway activated by insulin, nutrients and growth factors. The PI3K pathway involves the Akt kinase, an upstream regulator of mTOR. Rapamycin is a potent immunosuppressant and investigational anticancer drug, which inhibits mTOR, blocking protein synthesis and arresting the cell cycle in G1 phase. A wide body of evidence supports the role of mTOR in cell signaling related to cell growth and proliferation. Nevertheless, our recent findings have revealed that mTOR may be also involved in a signaling pathway activated by microtubule-damaging drugs, including taxol and nocodazole. It is known that agents affecting the integrity of microtubules activate apoptotic program by inducing phosphorylation and inactivation of the antiapoptotic Bcl-2 protein in G2-M phase. We have some evidence that mTOR is involved in the enzymatic cascade that, starting from damaged microtubules, induces downstream phosphorylation of the Bcl-2 protein. We also found that the level of activity of Akt can regulate Bcl-2 phosphorylation, through the mTOR kinase. Since mTOR activation by survival signals occurs in G1 phase and damaged microtubules activate proapoptotic signals in G2-M phase, we suggest that mTOR might mediate these two different pathways in two different phases of the cell cycle.
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PMID:mTOR: a protein kinase switching between life and death. 1550 91

Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process. Rapamycin specifically disrupted the positive transcriptional feedback loop between CCAAT/enhancer-binding protein-alpha and peroxisome proliferator-activated receptor-gamma (PPAR-gamma), two key transcription factors in adipogenesis, by directly targeting the transactivation activity of PPAR-gamma. In addition, we demonstrate for the first time that PPAR-gamma activity is dependent on amino acid sufficiency, revealing a molecular link between nutrient status and adipogenesis. The results of our further investigation have led us to propose a model in which the mTOR pathway and the phosphatidylinositol 3-kinase/Akt pathway act in parallel to regulate PPAR-gamma activation during adipogenesis by mediating nutrient availability and insulin signals, respectively. It is interesting that troglitazone (a thiazolidinedione drug) reversed the inhibitory effects of rapamycin and amino acid deprivation, implicating therapeutic values of thiazolidinedione drugs to counter certain side effects of rapamycin as an immunosuppressant.
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PMID:regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. 1550 54

Akt is a serine/threonine kinase that plays a critical role in cell survival and proliferation. Three isoforms of Akt have been identified and have been shown to be up-regulated in human malignancies. We examined the requirement of these pathways for Akt transformation. We generated NIH-3T3 cells over-expressing constitutively active Myr-Akt1 (3T3-Akt1 cells) or Myr-Akt2 (3T3-Akt2 cells). These cells are able to form colonies in soft-agar and 3T3-Akt1 cells formed tumors in SCID mice. Rapamycin efficiently inhibited the activation of the mTOR-p70S6K pathway and the anchorage-independent growth of both 3T3-Akt cells, demonstrating the importance of the mTOR-p70S6K pathway for transformation by Akt1 as well as by Akt2. Moreover, rapamycin dramatically inhibited the tumor formation by 3T3-Akt1 cells in SCID mice. Thus, we demonstrated the importance of mTOR-p70S6 kinase pathway in the transformation by Akt, both in tissue-cultured cells and in animal tumor models. In contrast, neither the MAPK pathway nor the p38 MAPK pathway is required for Akt-dependent transformation of NIH3T3 cells.
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PMID:Rapamycin inhibits Akt-mediated oncogenic transformation and tumor growth. 1551 74

Depending on the type of external signals, T cells can initiate multiple intracellular signaling pathways that can be broadly classified into two groups based on their sensitivity to the immunosuppressive drug cyclosporin A (CsA). Interleukin (IL)-12-mediated interferon (IFN)-gamma production by activated T cells has been shown to be CsA-insensitive. In this report, we demonstrate that the IL-12-induced CsA-resistant pathway of IFN-gamma production is sensitive to rapamycin. Rapamycin treatment resulted in the aberrant recruitment of Stat3, Stat4, and phospho-c-Jun to the genomic promoter region resulting in decreased IFN-gamma transcription. IL-12-induced phosphorylation of Stat3 on Ser-727 was affected by rapamycin, which may be due to the effect of rapamycin on the IL-12-induced interaction between mammalian target of rapamycin (mTOR) and Stat3. In accordance with this, reduction in the mTOR protein level by small interfering RNA resulted in suppression of Stat3 phosphorylation and decreased production of IFN-gamma after IL-12 stimulation. These results suggest that mTOR may play a major role in IL-12-induced IFN-gamma production by activated T cells.
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PMID:Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). 1552 80

Tuberous sclerosis complex (TSC) presents in the pediatric population with a constellation of benign tumors that affect the brain, heart, kidney, lung, and skin. No therapy has been shown to halt disease progression or to prevent its onset. The pathogenesis of TSC stems from the inactivation of one of the two TSC genes, TSC1 and TSC2. A key function of these genes is to regulate the mammalian target of rapamycin (mTOR) pathway in response to cellular energy and nutrient and growth factor availability. Consequently, TSC-related tumors exhibit uncontrolled activation of mTOR and its effectors. Previous work has shown that a specific mTOR inhibitor, rapamycin, effectively down-regulated mTOR activity in renal tumors of Eker rats that carry a germline Tsc2 mutation. Using this model, we investigated the effects of rapamycin on pituitary and renal tumors. We observed that rats with pituitary tumors had significantly shorter survival than those without pituitary pathology. Treatment with rapamycin effectively improved their clinical state and prolonged their survival. Rapamycin also resulted in a significant decrease in the size of the Tsc2-related renal tumors. In both types of pathology, tumor response was accompanied by down-regulation of ribosomal S6 kinase activity, reduction in cell size, and induction of apoptosis. Evidence for drug resistance was found in a small percentage of lesions after prolonged therapy. When rapamycin was given before onset of disease, subsequent development of macroscopic renal tumors was reduced, but no effect on the number of microscopic precursor lesions was found. We conclude that rapamycin-sensitive mTOR activity was critical to tumor progression in the Eker rat model, but rapamycin is unlikely to eradicate all disease as a result of the development of drug resistance. Our data also suggest the role of a rapamycin-insensitive pathway during tumor initiation.
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PMID:Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. 1555 9


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