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)

T cell responses are determined by the environment in which antigen is encountered. In the absence of proper costimulation, anergizing stimuli induce the activation of a specific program of gene expression. Proteins encoded by these genes impose a state of functional unresponsiveness in anergic T cells through the activation of different mechanisms that include dampening of the T cell receptor signaling and direct inhibition of cytokine expression. Anergy can be reversed by stimulating T cells in the presence of interleukin (IL-)2. Signaling through the IL-2 receptor has been shown to activate mTOR, which plays an important role in the integration of signals that determine the fate of T cells. The mechanisms underlying the IL-2-dependent regulation of T cell tolerance are still not fully elucidated. In this study we show that IL-2 receptor signaling mediated through JAK3 and mTOR inhibits the expression of anergy-inducing genes independently of any effect on cell cycle progression. Interestingly, we also show that this effect is likely due to changes on the levels of AP-1 activation induced by IL-2 receptor signaling in T cells. Our data identifies a mechanism that can explain how IL-2 may prevent or reverse the establishment of anergy in T cells and, therefore, helps to understand how the cytokine environment can be determinant to shape the outcome of T cell responses - tolerance or activation - when antigen is encountered.
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PMID:IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genes. 1899 Apr 50

Malignant renal tumors constitute 3% of human cancers, although their frequency differs greatly in various areas. Since the fifties, the incidence of renal cancers has been increasing, but at the some time the prognosis has been improving. In particular, in the last years, several new treatment modalities have been introduced, relying on the understanding of renal cancer biology. The identified etiological factors include smoking, increased body mass, dietary factors and chronic renal disease. There are several renal tumor types differing in morphology, molecular genetics and biology. Inactivation of the VHL gene leads to formation of the most frequent form in adults, namely clear cell carcinoma. The VHL gene product, a component of an ubiquitin-ligase complex, regulates expression of several genes. Papillary carcinomas depend mainly on the HGF receptor gene (c-Met) activating mutations. At least two types of papillary carcinomas exist, which have different morphology and prognosis. The molecular biology of chromophobe carcinoma and oncocytoma is poorly understood. Differential diagnosis of these tumors is particularly difficult and may require extensive immunohistochemical and molecular studies. Collecting duct carcinoma and medullary carcinoma are extremely aggressive but rare tumors. Some renal tumors have been described or recognized only relatively recently; these newer entities include multilocular cystic clear cell carcinoma, spindle cell papillary mucinous carcinoma, tubulocystic carcinoma, renal epithelial and stromal tumor, epithelioid and oncocytic angiomyolipoma. Besides histological typing, the prognostic factors include tumor stage, grade and several immunohistochemical and molecular markers that are currently under elaboration. The improved prognosis in renal cancer depends on earlier detection, but also on refinement of therapeutic methods. Small tumors may currently be treated by partial nephrectomy or radiofrequency ablation and larger ones by a laparoscopic approach. All these methods seem to give satisfactory results with low morbidity and mortality rates. Renal carcinoma is notorious for its low sensitivity to chemotherapy and radiotherapy. For several years, immunological treatment with IL-2 and INF-alpha was the only adjuvant therapy method. However, recently several new drugs have been introduced; they act on tyrosine-kinase receptors, VEGF, c-Met or mTOR pathway. With this progress, perfect understanding of renal tumor biology and exact histological diagnosis have become of prime practical importance.
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PMID:Pathology of renal tumors in adults. Molecular biology, histopathological diagnosis and prognosis. 1909 56

The calcineurin inhibitors cyclosporin A and tacrolimus and the inhibitors of the mTOR, sirolimus and everolimus bind immunophilins that are required for their immunosuppressive action. In contrast to cyclosporin A, tacrolimus and the mTOR inhibitors (MTIs) share common immunophilins, the FK506-binding proteins (FKBPs). We investigated the immunosuppressive interactions of MTIs on tacrolimus based immune suppression, since insights in immunological drug-drug interactions can be very relevant for optimization of immunosuppressive regimens in allograft transplantation medicine. Isolated peripheral blood mononuclear cells from healthy volunteers were incubated with combinations of MTIs and calcineurin inhibitors and when monitored for calcineurin activity and IL-2 excretion after mitogen stimulation, tacrolimus IC(50) concentrations shifted to higher concentrations in the presence of MTIs. This antagonism was absent for cyclosporin A, reproducible for 10 healthy volunteers (p<0.001) and stronger for sirolimus than for everolimus. When cell lysate was treated with and without MTI, tacrolimus and FKBP12, FKBP12 could increase calcineurin inhibition by tacrolimus and reverse the MTI antagonism for both MTIs. These results demonstrate that FKBP12 can be rate limiting for calcineurin inhibition at high tacrolimus concentrations and that the antagonism of sirolimus and everolimus on tacrolimus based immune suppression is mediated via saturation of FKBP12.
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PMID:Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12. 1915 28

The availability of approved agents with distinct mechanisms of action (immunotherapy, vascular endothelial growth factor pathway, and mTOR inhibitors) has complicated treatment decisions for patients with advanced kidney cancer. High-dose IL-2 therapy is the only treatment that can produce durable complete responses; however, it has significant side effects and the vast majority of patients do not benefit. Thus, identifying the optimal patients to receive first-line IL-2 therapy is a priority. Past studies have identified some clinical features that might be associated with benefit from IL-2-based immunotherapy. Subsequent investigations of tumors from patients treated with IL-2 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 two groups of roughly equal size, with 96% of long-term responding patients being in the favorable prognostic group. This model is currently undergoing prospective validation. More recent studies involving gene expression profiling and array CGH have begun to identify additional features that might predict response to IL-2 therapy. Taken together, these data offer the possibility to limit the use of this toxic therapy to those most likely to benefit.
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PMID:Treatment selection for patients with metastatic renal cell carcinoma: identification of features favoring upfront IL-2-based immunotherapy. 1916 38

In this study, we demonstrate that the E3 ubiquitin ligase gene related to anergy in lymphocytes (GRAIL) is expressed in quiescent naive mouse and human CD4 T cells and has a functional role in inhibiting naive T cell proliferation. Following TCR engagement, CD28 costimulation results in the expression of IL-2 whose signaling through its receptor activates the Akt-mammalian target of rapamycin (mTOR) pathway. Activation of mTOR allows selective mRNA translation, including the epistatic regulator of GRAIL, Otubain-1 (Otub1), whose expression results in the degradation of GRAIL and allows T cell proliferation. The activation of mTOR appears to be the critical component of IL-2R signaling regulating GRAIL expression. CTLA4-Ig treatment blocks CD28 costimulation and resultant IL-2 expression, whereas rapamycin and anti-IL-2 treatment block mTOR activation downstream of IL-2R signaling. Thus, all three of these biotherapeutics inhibit mTOR-dependent translation of mRNA transcripts, resulting in blockade of Otub1 expression, maintenance of GRAIL, and inhibition of CD4 T cell proliferation. These observations provide a mechanistic pathway sequentially linking CD28 costimulation, IL-2R signaling, and mTOR activation as important requirements for naive CD4 T cell proliferation through the regulation of Otub1 and GRAIL expression. Our findings also extend the role of GRAIL beyond anergy induction and maintenance, suggesting that endogenous GRAIL regulates general cell cycle and proliferation of primary naive CD4 T cells.
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PMID:Naive CD4 t cell proliferation is controlled by mammalian target of rapamycin regulation of GRAIL expression. 1941 43

Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
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PMID:The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. 1953 25

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

Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.
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PMID:CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. 1981 30

Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy. Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against VEGF-VEGFR and mTOR. Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival. At the moment, six molecules have been approves in advanced RCC: cytokines (IL-2 and IFN), antiangiogenic therapies (sunitinib, sorafenib, bevacizumab) and mTOR inhibitors (Temsirolimus, everolimus). Nephrectomy is an important component of the multimodality treatment of mRCC. Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies. Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting.
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PMID:[Renal cell carcinoma management and therapies in 2010]. 2041 1

Treatment options for patients with metastatic renal cell carcinoma (RCC) have changed dramatically, and a new paradigm has evolved. IFN-alpha and IL-2 were previously mainstays of therapy, but since December 2005, six new agents have been approved in the USA for the treatment of advanced RCC. Three of these new agents are multitargeted kinase inhibitors, including sunitinib, sorafenib, and recently pazopanib, two target the mTOR (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with IFN-alpha) that targets VEGF. Sunitinib has emerged as the standard of care for treatment-naive RCC patients, with the recently approved bevacizumab and IFN-alpha combination providing an additional option for this population. The recent approval of pazopanib, based on the results from sequential Phase II and III clinical trials demonstrating improved overall response rates and progression-free survival, provides yet another option for front-line therapy. The current article examines the pazopanib preclinical and clinical data, provides an overview of the development of this tyrosine kinase inhibitor, and provides some speculation concerning its role in RCC therapy.
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PMID:Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma. 2046 94


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