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)

Multiple signaling pathways are engaged by the type I and II IFN receptors, but their specific roles and possible coordination in the generation of IFN-mediated biological responses remain unknown. We provide evidence that activation of Akt kinases is required for IFN-inducible engagement of the mTOR/p70 S6 kinase pathway. Our data establish that Akt activity is essential for up-regulation of key IFN-alpha- and IFN-gamma-inducible proteins, which have important functional consequences in the induction of IFN responses. Such effects of the Akt pathway are unrelated to regulatory activities on IFN-dependent STAT phosphorylation/activation or transcriptional regulation. By contrast, they reflect regulatory activities on mRNA translation via direct control of the mTOR pathway. In studies using Akt1 and Akt2 double knockout cells, we found that the absence of Akt kinases results in dramatic reduction in IFN-induced antiviral responses, establishing a critical role of the Akt pathway in IFN signaling. Thus, activation of the Akt pathway by the IFN receptors complements the function of IFN-activated JAK-STAT pathways, by allowing mRNA translation of IFN-stimulated genes and, ultimately, the induction of the biological effects of IFNs.
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PMID:Role of the Akt pathway in mRNA translation of interferon-stimulated genes. 1833 7

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.
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PMID:Improving outcomes in patients with advanced renal cell carcinoma. 1836 95

Metastatic renal cell cancer is associated with a poor prognosis and is very resistant to conventional cytotoxic chemotherapy. Progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The recent approval of sunitinib, sorafenib, temsirolimus and bevacizumab in combination with IFN-alpha has revolutionized the management of renal cell carcinoma. In this review, we describe the status of current treatment strategies for metastatic renal cell cancer and we focus on the new compounds including targeted therapy such as new anti-angiogenic and mTOR inhibitors.
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PMID:New therapeutic developments in renal cell cancer. 1875 71

Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs.
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PMID:Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. 1875 66

The mammalian target of rapamycin (mTOR) can be viewed as cellular master complex scoring cellular vitality and stress. Whether mTOR controls also innate immune-defenses is currently unknown. Here we demonstrate that TLR activate mTOR via phosphoinositide 3-kinase/Akt. mTOR physically associates with the MyD88 scaffold protein to allow activation of interferon regulatory factor-5 and interferon regulatory factor-7, known as master transcription factors for pro-inflammatory cytokine- and type I IFN-genes. Unexpectedly, inactivation of mTOR did not prevent but increased lethality of endotoxin-mediated shock, which correlated with increased levels of IL-1beta. Mechanistically, mTOR suppresses caspase-1 activation, thus inhibits release of bioactive IL-1beta. We have identified mTOR as indispensable component of PRR signal pathways, which orchestrates the defense program of innate immune cells.
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PMID:Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. 1892 32

Patients with metastatic renal cell carcinoma (RCC) generally show a poor prognosis; treatment approaches have not significantly improved patient survival. Temsirolimus inhibits the mammalian target of rapamycin kinase. Clinical studies have shown positive results when the drug is administered to patients with this disease. The clinical benefit of temsirolimus for poor-risk, advanced RCC patients was demonstrated in a Phase III study comparing temsirolimus with interferon alpha (IFN-alpha) or combined temsirolimus plus IFN-alpha as first-line treatment of advanced RCC, showed that treatment with temsirolimus alone significantly increased median overall survival in poor-risk, advanced RCC patients (10.9 vs 7.3 vs 8.4 months). This was the first Phase III trial to demonstrate an overall improvement in survival using an agent as "targeted therapy" for patients with advanced RCC. By November 2007, 200 patients with advanced RCC had been treated with temsirolimus before its approval by the European Medicines Agency (EMEA) within a compassionate use program. The single-center treatment experiences using temsirolimus in patients for compassionate use are described herein. The treatment was generally well tolerated; side effects (mucositis, diabetes, and peripheral edema) were within the range expected from the pivotal trials and manageable with supportive care. Further development strategies for temsirolimus in patients with RCC include its evaluation with bevacizumab and also as second-line therapy in patients who have failed first-line therapy with sunitinib.
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PMID:Temsirolimus in renal cell carcinoma. 1910 Sep 5

Foxp3, forkhead/winged helix transcription factor 3, is a master transcription factor for the development and function of regulatory T cells. Foxp3 has been proved to be associated with immunoregulation, autoimmune diseases, infections, and tumor immune evasion/escape. Foxp3 regulates other critical gene transcriptions. However, the mechanism how the transcription of Foxp3 itself is regulated remains partly clear. In this article, we provided an overview of the current understanding of the transcriptional regulation of Foxp3 gene, including signaling pathways initiated by TCR, IL-2R/STAT pathway, TGF-beta/Smad pathway, PI3K/Akt/mTOR axis, Notch signal pathway, IFN/IRF and IFN/nitric oxide axis, and epigenetic mechanisms. Some therapeutic agents on Foxp3 regulation were also reviewed. Points for attention in further study of Foxp3 transcription regulation, such as the combinations/cross-talks, the bi-directional functions, and species specificity of these pathways, were discussed as well.
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PMID:Transcriptional regulation of Foxp3 gene: multiple signal pathways on the road. 1926

Elucidation of the crucial role of the PI3K/Akt/mTOR pathway in the pathogenesis of cancer has led to the development of various drugs targeting this signaling cascade at distinct levels. mTOR, a serine/threonine kinase plays a pivotal role in coupling growth stimuli to cell cycle progression. There are two distinct macromolecular complexes of mTOR: mTORC1, which is rapamycin-sensitive and contains raptor; and mTORC2, which is rapamycin-insensitive and contains rictor. However, in recent preclinical studies a sustained exposure of cancer cells to rapamycin has been shown to inhibit the function of both mTORC1 and mTORC2 complexes. Downstream targets of these complexes, which involve HIF-1alpha and HIF-2alpha, cyclin D1 and PKC-alpha, are responsible for the activation of various intracellular processes leading to the activation of cell proliferation, and induction of angiogenesis, metastasis or chemoresistance. Since the biology of renal cell cancer (RCC) is tightly controlled by mTOR, targeted inhibition of mTOR function appeared to be a promising therapeutic approach for RCC patients. To date, results of two, large, Phase III clinical trials evaluating the efficacy of rapamycin derivatives (i.e., temsirolimus and everolimus) in the treatment of RCC have been published. First-line temsirolimus (CCI-779) administered to metastatic, poor-prognosis RCC patients significantly prolonged overall and progression-free survival when compared with IFN-alpha. Treatment of metastatic RCC patients refractory to tyrosine kinase inhibitors with everolimus (RAD-001) significantly prolonged progression-free survival when compared with placebo. Therapeutic strategies based on mTOR inhibition in RCC demonstrated a significant clinical activity. However, there are still patients refractory to mTOR inhibitors. Various molecular mechanisms of resistance to rapalogues have been identified and will have to be targeted simultaneously with mTOR in order to achieve a complete inhibition of signaling pathways crucial for the pathogenesis of RCC. Such clinical trials evaluating a combination of mTOR inhibitors with other targeted therapies are ongoing.
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PMID:mTOR in renal cell cancer: modulator of tumor biology and therapeutic target. 1937 82

The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present.
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PMID:[Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]. 1962 Jul 95

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in at least 50% of sporadic clear-cell renal cell carcinoma (RCC). This leads to a pseudohypoxic state in which the pVHL complex does not degrade hypoxia-inducible factor. Subsequent intracellular hypoxia-inducible factor accumulation results in increased production of growth factors such as VEGF, responsible for angiogenesis, tumor proliferation and mitogenesis. Recently, a number of strategies have been designed to specifically target these pathways. The VEGF, its related receptor and the mammalian target of rapamycin (mTOR) signal transduction pathway, in particular, have been utilized as therapeutic targets. Clinical trials have demonstrated the survival benefit of these agents, particularly in clear-cell RCC. Today, sunitinib is recommended as first-line therapy for intermediate- or low-risk patients with metastatic RCC. Sorafenib is advised as second-line therapy, whereas temsirolimus is generally recommended as first-line treatment in high-risk patients. Everolimus is the new standard following sunitinib. High-risk patients appeared to benefit less than low-risk patients from bevacizumab plus IFN-alpha therapy. High-dose IL-2 has been proven effective in prolonging progression-free survival or overall survival, depending on risk group selection criteria. Although novel agents show a consistent effect as measured by objective response, no currently available data demonstrate that these agents will cure any patient.
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PMID:Systemic therapy of kidney cancer: tyrosine kinase inhibitors, antiangiogenesis or IL-2? 1966 36


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