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)

Advanced renal cell carcinoma remains resistant to drug-, hormone-, and cytokine-based therapies. Promising new immunotherapeutic approaches include monoclonal antibodies, kinase inhibitors, mammalian target of rapamycin inhibition, dendritic cell, and tumor antigen vaccines. Most of these approaches have yet to produce clinical responses significantly superior to those of previous standard therapies, although most are well tolerated and elicit relatively high rates of stable disease. Two recently approved agents, a kinase inhibitor and a mTOR inhibitor, are recommended for use as first-line therapies against renal cell carcinoma. An additional approved tyrosine kinase inhibitor, sorafenib, is recommended as second-line therapy. More clinical research on these agents and their use in combination, especially sequentially, is warranted.
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PMID:Current immunotherapeutic strategies in renal cell carcinoma. 1802 54

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Lipid bodies (lipid droplets) are emerging as dynamic organelles with roles in lipid metabolism and inflammation. Here we investigated the roles of leptin in signaling pathways involved in cytoplasmic lipid body biogenesis and leukotriene B(4) synthesis in macrophages. Our results demonstrated that leptin directly activated macrophages and induced the formation of adipose differentiation-related protein-enriched lipid bodies. Newly formed lipid bodies were sites of 5-lipoxygenase localization and correlated with an enhanced capacity of leukotriene B(4) production. We demonstrated that leptin-induced macrophage activation was dependent on phosphatidylinositol 3-kinase (PI3K) activity, since the lipid body formation was inhibited by LY294002 and was absent in the PI3K knock-out mice. Leptin induces phosphorylation of p70(S6K) and 4EBP1 key downstream signaling intermediates of the mammalian target of rapamycin (mTOR) pathway in a rapamycin-sensitive mechanism. The mTOR inhibitor, rapamycin, inhibited leptin-induced lipid body formation, both in vivo and in vitro. In addition, rapamycin inhibited leptin-induced adipose differentiation-related protein accumulation in macrophages and lipid body-dependent leukotriene synthesis, demonstrating a key role for mTOR in lipid body biogenesis and function. Our results establish PI3K/mTOR as an important signaling pathway for leptin-induced cytoplasmic lipid body biogenesis and adipose differentiation-related protein accumulation. Furthermore, we demonstrate a previously unrecognized link between intracellular (mTOR) and systemic (leptin) nutrient sensors in macrophage lipid metabolism. Leptin-induced increased formation of cytoplasmic lipid bodies and enhanced inflammatory mediator production in macrophages may have implications for obesity-related cardiovascular diseases.
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PMID:Leptin induces macrophage lipid body formation by a phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent mechanism. 1803 69

Ras is a key regulator of the MAP kinase-signaling cascade and may cause morphologic change of Ras-transformed cells. Signal transducer and activator of transcription 3 (Stat3) can be activated by cytokine stimulation. In this study, we unravel that Ha-ras(V12) overexpression can downregulate the expression of Stat3 protein at a posttranslational level in NIH3T3 cells. Furthermore, we demonstrate that Stat3 expression downregulated by Ha-ras(V12) overexpression is through proteosome degradation and not through a mTOR/p70S6K-related signaling pathway. The suppression of Stat3 accompanied by the morphologic change induced by Ha-ras(V12) was through mitogen extracellular kinase (MEK)/extracellular-regulated kinase (ERK) signaling pathway. Microtubule disruption is involved in Ha-ras(V12)-induced morphologic change, which could be reversed by overexpression of Stat3. Taken together, we are the first to demonstrate that Stat3 protein plays a critical role in Ha-ras(V12)-induced morphologic change. Oncogenic Ras-triggered morphologic change is through the activation of MEK/ERK to posttranslationally downregulate Stat3 expression. Our finding may shed light on developing novel therapeutic strategies against Ras-related tumorigenesis.
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PMID:Oncogenic Ras-induced morphologic change is through MEK/ERK signaling pathway to downregulate Stat3 at a posttranslational level in NIH3T3 cells. 1823 38

Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-beta superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1alpha protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.
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PMID:Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells. 1825 6

In this review, pathogenesis and genetic alterations of urologic malignancies and their therapeutic target molecule are summarized briefly. In bladder cancer, only a little has been revealed. Loss of heterozygosity of 9p/q is frequently observed in low grade, low stage tumors. In invasive or carcinoma in situ tumors, alteration of p53 and Rb tumor suppressor gene is frequently found. In prostate cancer, the process of carcinogenesis from normal epithelium to cancer hypothesized by Nelson et al. (N Engl J Med 24; 349 : 366-381) seems to be logic. Androgen independency of tumor cells is associated with androgen receptor gene mutation and amplification, however, the mechanism is not well clarified. It is a turning point, therapeutic strategy is changing from cytokine immunotherapy to molecular targeting therapy in metastatic renal cell carcinoma. The pathway from growth factors such as vascular endothelial growth factor and platelet derived growth factor, and their receptors to mTOR is a central controller of tumor angiogenesis and proliferation.
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PMID:[Tumor inhibitory factors in urologic malignancies]. 1826 Mar 61

The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.
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PMID:Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. 1833 66

Little is known about the signals downstream of PI3K which regulate mast cell homeostasis and function following FcepsilonRI aggregation and Kit ligation. In this study, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1) pathway in these responses. In human and mouse mast cells, stimulation via FcepsilonRI or Kit resulted in a marked PI3K-dependent activation of the mTORC1 pathway, as revealed by the wortmannin-sensitive sequential phosphorylation of tuberin, mTOR, p70S6 kinase (p70S6K), and 4E-BP1. In contrast, in human tumor mast cells, the mTORC1 pathway was constitutively activated and this was associated with markedly elevated levels of mTORC1 pathway components. Rapamycin, a specific inhibitor of mTORC1, selectively and completely blocked the FcepsilonRI- and Kit-induced mTORC1-dependent p70S6K phosphorylation and partially blocked the 4E-BP1 phosphorylation. In parallel, although rapamycin had no effect on FcepsilonRI-mediated degranulation or Kit-mediated cell adhesion, it inhibited cytokine production, and kit-mediated chemotaxis and cell survival. Furthermore, Rapamycin also blocked the constitutive activation of the mTORC1 pathway and inhibited cell survival of tumor mast cells. These data provide evidence that mTORC1 is a point of divergency for the PI3K-regulated downstream events of FcepsilonRI and Kit for the selective regulation of mast cell functions. Specifically, the mTORC1 pathway may play a critical role in normal and dysregulated control of mast cell homeostasis.
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PMID:Activation and function of the mTORC1 pathway in mast cells. 1835 81

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

The multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-alpha-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-alpha signaling cascades has not been examined in primary human keratinocytes used as a model of inflammatory skin disease and psoriasis. Employing a series of in vitro and in cellulo approaches, we have demonstrated that in primary human keratinocytes (i) TNF-alpha rapidly induces ROS generation, IkappaB degradation, NF-kappaB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-alpha-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-kappaB activation and by ROS; (iii) TNF-alpha-dependent NF-kappaB activation (that is, IkappaB degradation and NF-kappaB p65 nuclear translocation) is not mediated by ROS; and (iv) a cell-penetrating derivative of the antioxidant enzyme, catalase, as well as taurine and N-acetyl-cysteine attenuate the TNF-alpha-induced production of cytokines. These latter results suggest that catalase and perhaps other antioxidants should be considered as part of a more specific and effective therapy for the treatment of inflammatory skin diseases, including psoriasis.
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PMID:Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. 1846 78

The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solid-organ transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.
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PMID:Differential effects of rapamycin in anti-GBM glomerulonephritis. 1848 Mar 12


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