UNIPROT:P42345 - FACTA Search

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)

A stable supramolecular cluster in T cells at the contact site of APCs, the immunological synapse (IS), is essential for full T cell activation. Failure of IS maturation, as determined by defective relocalization of the TCR/CD3 complex at the T cell/APC contact site, is linked with T cell hyporesponsiveness. The effects of clinically used immunosuppressants on these critical events, however, are undefined. Here, we show that treatment of T cells with cyclosporin A, FK506, and dexamethasone, which are known to inhibit calcineurin and NF-kappaB, respectively, but not rapamycin, the inhibitor of mammalian target of rapamycin, selectively prevented TCR/CD3 relocalization into the IS, while relocalization of adhesion and cytoskeletal proteins as well as T cell/APC conjugate formation remained unaltered. The involvement of calcineurin and NF-kappaB in IS maturation was confirmed by using specific inhibitors of these molecules (FR901725, gossypol, SN50). FK778, as an inhibitor of DNA replication and also TCR/CD3-activated tyrosine kinases, globally abrogated cytoskeletal, adhesion, and signaling molecule relocalization, thereby preventing formation of an IS at an earlier, immature stage along with impaired, antigen-specific T cell/APC conjugate formation. Collectively, blocking IS formation at distinct stages may mediate effects on T cell activation of currently used immunosuppressants, apart from their capacity to block gene transcription, cytokine signaling, and DNA replication. Furthermore, these data imply novel functions of calcineurin and NF-kappaB for successful IS maturation.
...
PMID:Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-kappaB in immunological synapse formation. 1703 82

Inhibition of translational efficiency is responsible at least in part for the sepsis-induced decrease in protein synthesis observed in skeletal muscle. Moreover, infusion of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) into naive rats produces a comparable decrement. Therefore, the purpose of the present study was to determine whether inhibition of TNF action under in vivo conditions could prevent the sepsis-induced decrease in translation initiation observed in the postabsorptive state. To address this aim, sepsis was produced by cecal ligation and puncture (CLP) and rats were studied in the fasted condition 20 to 24 hours thereafter. Both septic and time-matched nonseptic control rats were pretreated with TNF-binding protein (TNF(BP)) before CLP or sham surgery to neutralize endogenously produced TNF. Sepsis altered the distribution of eukaryotic initiation factor 4E (eIF4E) in the gastrocnemius by increasing the amount associated with 4E-BP1 (inactive complex) and decreasing the amount bound to eIF4G (active complex). This change in eIF4E availability was associated with a decreased phosphorylation of 4E-BP1. Furthermore, the phosphorylation of ribosomal protein S6 and mammalian target of rapamycin (mTOR) was also decreased in the gastrocnemius from septic rats. Pretreatment of septic rats with TNF(BP) largely ameliorated the altered distribution of eIF4E as well as the reduced phosphorylation of 4E-BP1, S6, and mTOR. In contrast, sepsis did not change either the total amount or the phosphorylation state of eIF2alpha or eIF2Bepsilon. Furthermore, no sepsis-induced change in eIFs was detected in the slow-twitch soleus muscle. The ability of TNF(BP) to prevent the sepsis-induced alterations in translation initiation was independent of change in plasma insulin and proportional to the insulinlike growth factor I content in blood and muscle but was associated with a reduction in plasma corticosterone. Hence, the decreased constitutive protein synthesis observed in fast-twitch skeletal muscle in response to peritonitis is mediated by a TNF-dependent mechanism affecting mTOR regulation of translation initiation.
...
PMID:Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor alpha. 1716 Dec 26

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.
...
PMID:TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. 1731 37

A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10-/-) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10-/- mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4+ T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10-/- mice ameliorated the colitis, probably as a result of decreasing the number of CD4+ T cells in the colonic mucosa and an associated reduction in IFN-gamma production.
...
PMID:Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis. 1743 23

Management of renal cell carcinoma (RCC) has made considerable progress in recent years, and new emerging strategies are being developed. On the basis of the results of two randomised studies in the early 2000s, nephrectomy has now become the standard as cytoreductive surgery before embarking on systemic treatment with cytokines. Interleukin (IL)-2 and interferon were the standard treatment in metastatic RCC (MRCC) until 2006. The efficacy of these two drugs, which have now been used for >20 years in MRCC, is still controversial. On the basis of many studies, these drugs should not be given to patients with a poor prognosis. In patients with good prognostic factors, a cytokine-based regimen should remain the standard as either a high-dose IL-2 or subcutaneous regimen. In patients with intermediate risk, the results of the French Percy Quattro study encourage the use of new targeted therapies as first-line therapy. Development of targeted therapies in RCC has been necessary largely because the Von Hippel-Lindau (VHL) gene is often mutated in sporadic RCC. VHL protein abnormalities lead to accumulation of hypoxia-inducible factor (HIF)-alpha and activation of a series of genes, including vascular endothelial growth factor (VEGF), thus inducing angiogenesis. Results from many recent studies with new agents that block the VEGF pathway have been reported and offer new strategic options for patients with MRCC. Sunitinib and sorafenib, two tyrosine kinase inhibitors, improve progression-free survival in RCC compared with standard treatment and have been recently approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating HIF-alpha, improves survival in RCC patients with poor risk features. Bevacizumab, a monoclonal antibody against VEGF, has shown very promising efficacy. Overall, treatment of MRCC is currently moving from the cytokine era to the targeted agent era. However, many questions still remain regarding the efficacy of combination treatments and on the best way to achieve complete remission, which is probably the best hope of curing MRCC.
...
PMID:Advanced renal cell carcinoma: current and emerging management strategies. 1754 70

Transplantation of mesenchymal stem cells (MSCs) has been used to treat a wide range of diseases, and the mechanism of action is postulated to be mediated by either differentiation into functional reparative cells that replace injured tissues or secretion of paracrine factors that promote tissue repair. To complement earlier studies that identified some of the paracrine factors, we profiled the paracrine proteome to better assess the relevance of MSC paracrine factors to the wide spectrum of MSC-mediated therapeutic effects. To evaluate the therapeutic potential of the MSC paracrine proteome, a chemically defined serum-free culture medium was conditioned by MSCs derived from human embryonic stem cells using a clinically compliant protocol. The conditioned medium was analyzed by multidimensional protein identification technology and cytokine antibody array analysis and revealed the presence of 201 unique gene products. 86-88% of these gene products had detectable transcript levels by microarray or quantitative RT-PCR assays. Computational analysis predicted that these gene products will significantly drive three major groups of biological processes: metabolism, defense response, and tissue differentiation including vascularization, hematopoiesis, and skeletal development. It also predicted that the 201 gene products activate important signaling pathways in cardiovascular biology, bone development, and hematopoiesis such as Jak-STAT, MAPK, Toll-like receptor, transforming growth factor-beta, and mTOR (mammalian target of rapamycin) signaling pathways. This study identified a large number of MSC secretory products that have the potential to act as paracrine modulators of tissue repair and replacement in diseases of the cardiovascular, hematopoietic, and skeletal tissues. Moreover our results suggest that human embryonic stem cell-derived MSC-conditioned medium has the potency to treat a variety of diseases in humans without cell transplantation.
...
PMID:Elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells. 1756 74

TC21(R-Ras2), a Ras-related GTPase with transforming potential similar to H-, K- and N-Ras, is implicated in the pathogenesis of human cancers. Transforming growth factor beta (TGF-beta), a cytokine that plays a significant role in modulating tumorigenesis, normally prevents uncontrolled cell proliferation but paradoxically induces proliferation in H-Ras-transformed cancer cells. Although TC21 activates some pathways that mediate cellular transformation by the classical Ras proteins, the mechanisms through which TC21 induces tumor formation and how TGF-beta regulates TC21 transformed cells is not known. To better understand the role of TC21 in cancer progression, we overexpressed an activated G23V mutant of TC21 in a nontumorigenic murine mammary epithelial (EpH4) cell line. Mutant TC21-expressing cells were significantly more oncogenic than cells expressing activated G12V H-Ras both in vivo and in vitro. TC21-induced transformation and proliferation required activation of p38 MAPK, mTOR (the mammalian target of rapamycin), and phosphoinositide 3-kinase but not Akt/PKB. Transformation by TC21 rendered EpH4 cells insensitive to the growth inhibitory effects of TGF-beta, and the soft agar growth of these cells was increased upon TGF-beta stimulation. Despite losing responsiveness to TGF-beta-mediated growth inhibition, both Smad-dependent and independent pathways remained intact in TC21-transformed cells. Thus, overexpression of active TC21 in EpH4 cells induces tumorigenicity through the phosphoinositide 3-kinase, p38 MAPK, and mTOR pathways, and these cells lose their sensitivity to the normal growth inhibitory role of TGF-beta.
...
PMID:Signaling pathways regulating TC21-induced tumorigenesis. 1765 62

Interferon (IFN)-gamma, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.
...
PMID:Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation. 1787 72

The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance. Signaling through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1). However, an involvement of mTOR in IL-6-induced insulin resistance has not yet been reported. Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1. Interestingly, we find that the phosphorylation of STAT3 on Ser(727) and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling. Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Taken together, we propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.
...
PMID:Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. 1799 46

The management of advanced renal cell carcinoma (RCC) is undergoing a revolution, with the introduction of new agents and surgical paradigms. Thoughtful integration of diagnostic, surgical and medical approaches to the patient is paramount for disease control. Methods of risk stratifying kidney cancers are reviewed, as well as mechanisms of action of newer drugs approved in advanced metastatic kidney cancer. These drugs present opportunities for application to patients in an earlier stage of disease, and adjuvant RCC trials designs are discussed. Improvements have been made in the understanding of the molecular and genetic basis of RCC, both for causative and prognostic markers, with models addressing prediction of tumor behavior and therapeutic targets. Practice patterns have shifted from cytokine therapies to targeted molecular approaches, particularly emphasizing the VEGF pathway, related intracellular kinases and the mammalian target of rapamycin. Autologous vaccine adjuvant studies are maturing. In conclusion, elucidation of specific genes, proteins and aberrant molecular pathways associated with kidney cancer are ongoing. These new agents may lead to opportunities to improvement of disease-free survival through therapy in the adjuvant setting.
...
PMID:Growing opportunities for adjuvant therapy of renal cell carcinoma: targeted drugs and vaccines. 1800 Dec 57

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>