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)

Renal cell carcinoma has made considerable progress in the past years, and new emerging strategies are coming almost every year since 2005. Development of targeted therapies in renal cell cancer is largely due to the fact that Von Hippel Lindau gene is often mutated in sporadic renal cell cancer. Von Hippel Lindau protein abnormalities lead to accumulation of hypoxia inducible factor-alpha, and activation of a series of gene, including vascular endothelial growth factor, and thus induce angiogenesis. Results from many recent studies with new agents, blocking the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway, have been recently reported and offer new strategic options for the patients with metastatic renal cell carcinoma. Sunitinib, sorafenib, and combination of bevacizumab and interferon improves progression free survival in either first or second line treatment of renal cell cancer and have been approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating hypoxia inducible factor-alpha, improves survival in renal cancer with poor risk features. Finally, everolimus improves progression free survival in patients who fail tyrosine kinase inhibitors. Overall, treatment of metastatic renal cell carcinoma is currently moving from the cytokine era to the targeted agent era. However, many questions still remain on the efficacy of combination treatments and on the best way to get complete remission, which is probably the best way to lead to cure of metastatic renal cell cancer in the future.
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PMID:Signaling inhibitors in metastatic renal cell carcinoma. 1883 38

The targeted therapies sunitinib, sorafenib, temsirolimus, and bevacizumab (when used in combination with interferon-alpha2a) have dramatically improved outcomes for patients with advanced renal cell carcinoma (RCC). Clinical application of these novel agents outside the trial setting, however, may present some challenges for treating individual patients with unique needs. In some patients, dose modifications may be considered for potential drug interactions and for management of severe cases of hematologic or nonhematologic toxicities. The more common grade 3 or 4 side effects with sunitinib and sorafenib include hypertension, fatigue, hand-foot syndrome, elevated lipase, lymphopenia, and neutropenia. Congestive heart failure is a less common but serious side effect that warrants treatment discontinuation. Temsirolimus exhibits a different side-effect profile, with the more common grade 3 or 4 side effects being metabolic in nature (i.e., elevated triglycerides, elevated glucose, hypophosphatemia) as a result of its inhibitory effects on the mammalian target of rapamycin-regulated lipid and glucose pathways. Asthenia, rash, and dyspnea also occur in patients receiving temsirolimus. Virtually all of the side effects associated with these agents can be managed effectively in the majority of patients with medical treatment or supportive interventions. Recognition and prompt management of side effects are important to avoid unnecessary dose reductions that may result in suboptimal efficacy.
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PMID:Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. 1883 39

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

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
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PMID:Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. 1900 81

The phosphatidylinositol-3 kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) pathway have long been recognised as critically regulating metabolism, growth or survival. Recent data indicate that these molecules are also integral players in coordinating defence mechanisms in the innate immune system. In this respect, PI3K and mTOR positively regulate immune cell activation in neutrophils and mast cells. In plasmacytoid dendritic cells, these pathways have recently emerged as important regulators for type I interferon production via activation of the interferon-regulatory factor 7. Interestingly, in myeloid immune cells, PI3K and mTOR seem to constrain full immune cell activation by upregulation of the key anti-inflammatory cytokine interleukin 10 and inhibition of proinflammatory cytokines. These new insights into innate immune cell regulation may pave the way for manipulating distinct features of the innate immune system for therapeutic treatment of various inflammatory diseases and for implementation of improved vaccination strategies.
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PMID:The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. 1902 19

Drugs that target the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) pathways have revolutionized the treatment of patients with metastatic renal cell cancer (RCC). Patients with clear cell RCC often have mutations or silencing of the von Hippel Lindau gene leading to an accumulation of HIF 1 alpha. This allows growth factors such as VEGF and PDGF to be upregulated to promote angiogenesis and endothelial stabilization. Both sunitinib and sorafenib target VEGF and PDGF receptor tyrosine kinases while bevacizumab is a monoclonal antibody to VEGF. These three agents have demonstrated superior progression free survival in patients with metastatic RCC when compared to interferon or placebo. Newer anti-VEGF agents such as axitinib, pazopanib and cediranib are currently under investigation to elucidate future treatment options. The mammalian target of rapamycin (mTOR) is downstream of the VEGF pathway and has been targeted with drugs including temsirolimus and everolimus. This review will detail the pharmacologic and molecular activity of these agents and how they translate into clinical efficacy.
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PMID:Anti-angiogenic targets in the treatment of advanced renal cell carcinoma. 1907 90

To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the molecular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17-50 microM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 microM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells.
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PMID:The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. 1929 23

FRAP1 (FK506-binding protein 12-rapamycin complex-associated protein 1), a component of the nutrient-sensing cell signaling pathway, is critical for cell growth and metabolism. The present study determined expression of FRAP1 and associated members of the mTORC1 and mTORC2 cell signaling pathways in uteri of cyclic and pregnant ewes and conceptuses, as well as effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on their expression. The mRNAs for FRAP1, LST8, MAPKAP1, RAPTOR, RICTOR, TSC1, TSC2, RHEB, and EIF4EBP1 were localized to luminal, superficial glandular, and glandular epithelia and stromal cells of uteri from cyclic and pregnant ewes, as well as trophectoderm and endoderm of conceptuses between Days 13 and 18 of pregnancy. The abundance of FRAP1, RAPTOR, RICTOR, TSC1, and TSC2 mRNAs in endometria was unaffected by pregnancy status or by day of the estrous cycle or pregnancy; however, levels of LST8, MAPKAP1, RHEB, and EIF4EBP1 mRNA increased in endometria during early pregnancy. In ovariectomized ewes, P4 and IFNT stimulated expression of RHEB and EIF4EBP1 in uterine endometria. Total endometrial FRAP1 protein and phosphorylated FRAP1 protein levels were affected by pregnancy status and by day after onset of estrus, and phosphorylated FRAP1 protein was detected in nuclei of uterine epithelia and conceptuses. In endometria of pregnant ewes, increases in abundance of mRNAs for RICTOR, RHEB, and EIF4EBP1, as well as RHEB protein, correlated with rapid conceptus growth and development during the peri-implantation period. These results suggest that the FRAP1 cell signaling pathway mediates interactions between the maternal uterus and peri-implantation conceptuses and that P4 and IFNT affect this pathway by regulating expression of RHEB and EIF4EBP1.
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PMID:Select nutrients in the ovine uterine lumen. VI. Expression of FK506-binding protein 12-rapamycin complex-associated protein 1 (FRAP1) and regulators and effectors of mTORC1 and mTORC2 complexes in ovine uteri and conceptuses. 1929 12

The mammalian target of rapamycin (mTOR) is a multifunctional kinase that promotes cell growth and division in response to growth factor and nutrient signals. Rapamycin exerts its potent immunosuppressive effects in part through direct effects on antigen-specific lymphocytes; however, rapamycin also modulates adaptive immunity through its effects on innate immune cells, including dendritic cells and macrophages. Studies have established rapamycin-sensitive functions of mTOR, downstream of Toll-like receptors, in shaping the cytokine response of myeloid cells and driving the production of interferon by plasmacytoid dendritic cells. These findings point to new strategies for boosting or suppressing specific immune responses.
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PMID:Immune regulation by rapamycin: moving beyond T cells. 1938 76

The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin-2 (IL-2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group. Additional studies have begun to identify molecular features that might predict response to IL-2 therapy. In contrast, clinical trial data suggest that temsirolimus was relatively more active than interferon in patients with tumors containing non-clear cell features. Furthermore, pathologic examination showed no correlation of response with CAIX expression, but an apparent association with high expression of either phospho-AKT or phospho-S6, proteins either upstream or downstream of mammalian target of rapamycin. Preliminary investigations of tumor specimens from patients receiving vascular endothelial growth factor-targeted therapy suggested that high hypoxia-inducible factor expression might predict response. In addition, response appeared more likely in tumors with mutated or methylated VHL genes; however, substantial antitumor activity was still observed in patients with VHL wild-type tumors, particularly in patients treated with either sunitinib or axitinib, rather than bevacizumab or sorafenib. Although these data provide some guidance in treatment selection, considerably more research is needed to identify and validate selection models for particular treatment approaches, and to enable rational and optimal utilization of the available treatment options.
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PMID:Treatment selection for patients with metastatic renal cell carcinoma. 1940 69


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