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)

Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian target of rapamycin (mTOR). To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1beta, interferon-gamma, interleukin-2, or tumor necrosis factor-alpha mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 +/- 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating mononuclear cells in vehicle-treated myosin-immunized rats. Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.
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PMID:Rapamycin ameliorates experimental autoimmune myocarditis. 1604 46

The difficult separation of clinical graft-versus-tumor (GVT) effects from graft-versus-host disease (GVHD) reflects their shared biology. Experimental approaches to mediate GVT effects while limiting GVHD include: (1) allograft T cell depletion followed by immune enhancement; (2) modulation of T cell dose or T cell subset composition; (3) donor lymphocyte infusion; (4) reduced-intensity host preparation; (5) modulation of Th1/Th2 and Tc1/Tc2 cell balance; (6) cytokine therapy or neutralization; (7) T regulatory cell therapy; (8) co-stimulatory pathway modulation; (9) chemokine pathway modulation; (10) induction of antigen-specific T cells; (11) alloreactive NK cell therapy; and (12) targeted pharmaceutical inhibition of proteosome, mammalian target of rapamycin, and histone deacetylase pathways. Clearly, a multitude of approaches exist that hold promise for separating GVT effects from GVHD. Future success in this endeavor will require a strong commitment towards translational research and continued advances in cell, vaccine, cytokine, monoclonal antibody, and targeted molecular therapy.
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PMID:Shared biology of GVHD and GVT effects: potential methods of separation. 1620 32

IL-4 signaling through the IL-4Ralpha chain regulates the development and proliferation of the Th2 lineage of effector CD4(+) T cells. Analyses of the IL-4R in factor-dependent cell lines led to the development of two apparently conflicting models of the primary structural determinants of IL-4R-mediated proliferative signaling. In one model, proliferation was dependent on the first conserved tyrosine in the cytoplasmic tail (Y1), while in the second, proliferation was independent of cytoplasmic tyrosines. We found that in activated primary T cells, mutation of only the Y1 residue resulted in a modest decrease in IL-4-induced S phase entry, a further decrease in cell-cycle completion, and a complete failure of IL-4 to induce p70S6 kinase phosphorylation. Consistent with a role for the PI3K/mammalian target of rapamycin pathway in mediating cytokine acceleration of G(2)/M transit, pretreatment of activated T cells with rapamycin resulted in only a modest decrease in IL-4-induced S phase entry, but a total block of cell-cycle completion. Strikingly, IL-4Ralpha chains that lacked all cytoplasmic tyrosines were competent to signal for STAT5 phosphorylation, mediated efficient S phase entry, and promoted cell-cycle progression. The ability of tyrosine-deficient IL-4Rs to mediate proliferative signaling and STAT phosphorylation was absolutely dependent on the presence of an intact ID-1 region. These findings show that IL-4Ralpha lacking cytoplasmic tyrosine residues is competent to induce ID-1-dependent proliferation, and indicate that IL-4 can promote G(2)/M progression via activation of the mammalian target of rapamycin pathway initiated at the Y1 residue.
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PMID:Sequence motifs in IL-4R alpha mediating cell-cycle progression of primary lymphocytes. 1621 Jun 22

The standard treatment for renal cell carcinoma (RCC) is surgery. Partial nephrectomy is often performed for treatment of small RCC. Radiofrequency ablation (RFA) offers another nephron-sparing minimally invasive approach. It is most successful for tumors not larger than 3 cm in diameter. The rate of severe complications of RFA is low. Further studies are necessary to determine the long-term efficacy of RFA in RCC. Metastatic RCC is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients. New therapies such as targeted molecular therapies are being developed to improve efficacy and treat those patients who are resistant to systemic immunotherapy. Targeted molecular therapies include inhibition of the Raf kinase pathway, inhibition of its receptor kinases, anti-vascular endothelial growth factor monoclonal antibody or the mammalian target of rapamycin pathway. Further clinical research will be required to develop a more effective therapy and the application of combined treatment modalities.
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PMID:[Progress in therapeutic strategy for renal cell carcinoma]. 1648 51

Cytokine-based immunotherapy was the only viable option in metastatic, nonresectable renal cell carcinoma (RCC) for many years. Systemic immunotherapy has become increasingly established as a standard therapy during the last 15 years. In this context, interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) turned out to be the most effective single agents in RCC. Subsequently, the approved subcutaneous application of these compounds was the preferred administration route in Germany. Response rates with cytokine combination therapy were almost similar to those of more aggressive concepts using additional chemotherapeutic agents.Currently, new compounds targeting specific signaling pathways are readily available and have passed clinical testing. Such small molecules like tyrosine kinase inhibitors, monoclonal antibodies, or the mTOR inhibitor CCI-779 may dramatically change the established concepts of systemic RCC treatment. This paper gives an overview of established, current, and evolving concepts of systemic therapy in RCC.
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PMID:[Systemic therapy of metastatic renal cell carcinoma]. 1662 45

Erythropoietin (Epo) is used commonly to treat cancer and/or therapy-related anemia. Until recently, Epo was considered to be a specific stimulator of erythropoiesis, acting via its receptor, EpoR. It becomes clear, however, that EpoR is expressed in a variety of cell types other than hematopoietic cells, and that Epo is a potent cytoprotective cytokine increasing cell survival under hypoxic conditions. Epo and EpoR are also expressed in various malignant tumors, and EpoR expression shows association with tumor invasion and progression. Recently, a functional Epo autocrine signaling mechanism was also detected in human melanoma cells. In this study, we examined the hypothesis that Epo activates the Akt signaling pathway in human melanoma cells and thus promotes the survival of tumor cells. The Akt signaling pathway in response to Epo was examined in melanoma. Similar to Epo, the expression of EpoR was up-regulated in response to hypoxia and Epo stimulation in melanoma cells. Melanoma cells constitutively expressed Akt with variable expression of mammalian target of rapamycin, and Epo dose-dependently induced their activity. Epo increased Akt kinase activity, which was abrogated by co-treatment with LY294002, a specific blocker of phosphoinositide 3-kinase. LY294002 also inhibited the cytoprotective effects of Epo in melanoma cells under both normoxic and hypoxic conditions. Our results suggest that Epo promotes melanoma cell survival by activating an Akt-dependent signaling pathway.
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PMID:Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells. 1684 23

Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon-gamma (IFN-gamma) is another potential therapeutic agent for TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN-gamma reduces the severity of TSC-related disease in mouse models. Here, we examine the effects of treating tumor-bearing nude mice with a combination of a rapamycin analog (CCI-779) and IFN-gamma. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI-779 plus IFN-gamma had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI-779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC-related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC.
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PMID:Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. 1684 61

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.
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PMID:Targeted approaches for treating advanced clear cell renal carcinoma. 1697 18

Autophagy is a tightly regulated catabolic mechanism that degrades proteins and organelles. Autophagy mediates programmed cell death under certain conditions. To determine the role of autophagy in T cells, we examined, in mouse CD4+ T cells, conditions under which autophagy is induced and alterations of the cell fate when autophagy is blocked. We have found that resting naive CD4+ T cells do not contain detectable autophagosomes. Autophagy can be observed in activated CD4+ T cells upon TCR stimulation, cytokine culturing, and prolonged serum starvation. Induction of autophagy in T cells requires JNK and the class III PI3K. Autophagy is inhibited by caspases and mammalian target of rapamycin in T cells. Interestingly, more Th2 cells than Th1 cells undergo autophagy. Th2 cells become more resistant to growth factor-withdrawal cell death when autophagy is blocked using either chemical inhibitors 3-methyladenine, or by RNA interference knockdown of beclin 1 and Atg7. Therefore, autophagy is an important mechanism that controls homeostasis of CD4+ T cells.
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PMID:Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. 1701 1

Vascular endothelial growth factor (VEGF) could play a relevant role in angiogenesis associated with chronic allograft nephropathy. Interleukin-1beta (IL-1beta) has a key role in inflammatory response. It induces prostaglandin (PG) E2, which is involved in VEGF release by some normal and tumor cells. In the present work, we studied the effect of IL-1beta on VEGF release by rat mesangial cells, the transduction signal, and whether or not PGE2 is involved in this effect. IL-1beta induced a time-dependent formation of VEGF (analyzed by enzyme-linked immunosorbent assay) and PGE2 (analyzed by enzyme immunoassay). The latter correlated with microsomal-PGE-synthase (mPGES)-1 expression rather than with cyclooxygenase (COX)-2 in terms of protein, determined by Western blotting. No effect of IL-1beta on COX-1, cytosolic PGES, or mPGES-2 expression was observed. Indomethacin exerted a nonsignificant effect on IL-1beta-induced VEGF, and exogenously added PGE2 exhibited a nonsignificant stimulatory effect on VEGF formation. SB 203580, a p38 mitogen-activated protein kinase inhibitor, weakly inhibited the induction of VEGF by IL-1beta in a concentration-dependent manner, whereas LY 294002, a phosphoinoside 3-kinase (PI3-K) inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, strongly inhibited both IL-1beta- and tumor necrosis factor-alpha-induced VEGF formation in a concentration-dependent manner. Rapamycin also decreased glomerular VEGF levels in the anti-Thy1.1 model of experimental glomerulonephritis. In conclusion, the PI3-K-mTOR pathway seems to be essential in cytokine-induced release of VEGF in mesangial cells.
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PMID:IL-1beta induces VEGF, independently of PGE2 induction, mainly through the PI3-K/mTOR pathway in renal mesangial cells. 1703 41


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