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)

Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-1 from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine/threonine kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin-promoted IRS-1 tyrosine phosphorylation. Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-1 tyrosine phosphorylation by TNF was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstream target of Akt. mTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase/Akt/mTOR pathway, which is antagonized by PTEN.
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PMID:A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. 1128 30

Sirolimus (Rapamune), Wyeth-Ayerst, Madison, NJ) is a new, potent, immunosuppressant that is emerging as a foundation for long-term immunosuppressive therapy in renal transplantation. The drug acts during both co-stimulatory activation and cytokine-driven pathways via a unique mechanism: inhibition of a multifunctional serine-threonine kinase, mammalian target of rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus displays a synergistic interaction to enhance the efficacy of cyclosporin A (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly controlled, rates of acute rejection episodes were < 10%, despite markedly reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled trials, the rates of acute rejection episodes within 12 months following administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids were reduced to 19 and 14%, respectively. Since the inhibitory effect of sirolimus disables virtually all responses to cytokine mediators due to the widespread involvement of mTOR in multiple signalling pathways, the agent is likely also to retard proliferation of endothelial and vascular smooth muscle cells, an important component of the immuno-obliterative processes associated with chronic rejection. The advantages of this unique therapeutic action combined with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive and hyperlipidaemic side effects. Ongoing studies are assessing whether the long-term benefits of sirolimus to permit reduction in exposure to or elimination of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the condition that erodes long-term renal transplant survival.
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PMID:Sirolimus: a comprehensive review. 1182 25

Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a lipid phosphatase with putative tumor suppressing abilities, which is frequently mutated in prostate cancer. Loss of PTEN leads to constitutive activation of the phosphatidylinositol 3'-kinase/serine-threonine kinase (Akt) signal transduction pathway and has been associated with resistance to chemotherapy. This study aimed to determine the effects of PTEN status and treatment with rapamycin, an inhibitor of mTOR, in the response of prostate cancer cell lines to doxorubicin. The DU-145 PTEN-positive cell line was significantly more susceptible to the antiproliferative effects of doxorubicin as compared with the PTEN-negative PC-3 cell line. Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR-regulated 70-kDa S6 (p70(s6k)) kinase and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status/Akt activation modulate the cellular response to doxorubicin. Treatment of PC-3 PTEN-negative cells with rapamycin inhibited 70-kDa S6 kinase and increased the proliferative response of these cells to doxorubicin, so that it was comparable with the responses of PTEN-positive DU-145 cells and the PC-3-transfected cells. Furthermore, treatment of mice bearing the PTEN-negative PC-3 prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical development combined with doxorubicin, inhibited the growth of the doxorubicin-resistant PC-3 tumors confirming the observations in vitro. Thus, rapamycin and CCI-779, by interacting with downstream intermediates in the phosphatidylinositol 3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred by PTEN mutation/Akt activation. These results provide the rationale to explore in clinical trials whether these agents increase the response to chemotherapy of patients with PTEN-negative/Akt active cancers.
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PMID:Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. 1241 39

Recent therapeutic strategies to combat organ allograft rejection have focused on T-cell signaling pathways and the molecules that comprise them. The macrolide antibiotic produced by the bacterium Streptomyces hygroscopicus, known as sirolimus or rapamycin, has shown great therapeutic potential in the transplant setting. Sirolimus alone or in combination with other immunosuppressive agents can block acute rejection, chronic graft destruction, and promote permanent allograft acceptance. Sirolimus targets a unique serine-threonine kinase, mammalian target of rapamycin (mTor), which plays a key role in mitogenic and nutritional cells signals. Within T cells, mTor regulates a number of proteins likely dependent on T cell growth factors such as interleukin 2. This review is focused on the molecular mechanisms by which mTor may regulate T-cell signaling cascades and affect T-cell responsiveness, and how sirolimus likely uncouples this activity.
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PMID:Molecular actions of sirolimus: sirolimus and mTor. 1274

The ability of stem cells to generate distinct fates is critical for the generation of cellular diversity during development. Central nervous system (CNS) stem cells respond to bone morphogenetic protein (BMP) 4 by differentiating into a wide variety of dorsal CNS and neural crest cell types. We show that distinct mechanisms are responsible for the generation of two of these cell types, smooth muscle and glia. Smooth muscle differentiation requires BMP-mediated Smad1/5/8 activation and predominates where local cell density is low. In contrast, glial differentiation predominates at high local densities in response to BMP4 and is specifically blocked by a dominant-negative mutant Stat3. Upon BMP4 treatment, the serine-threonine kinase FKBP12/rapamycin-associated protein (FRAP), mammalian target of rapamycin (mTOR), associates with Stat3 and facilitates STAT activation. Inhibition of FRAP prevents STAT activation and glial differentiation. Thus, glial differentiation by BMP4 occurs by a novel pathway mediated by FRAP and STAT proteins. These results suggest that a single ligand can regulate cell fate by activating distinct cytoplasmic signals.
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PMID:BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. 1279 77

An intact VEGF receptor/PI3K/PKB/Akt signaling cascade protects endothelial cells from apoptotic stress-stimuli and mediates the formation of new blood vessels in pathological conditions such as cancer. Therefore, downregulation of this signaling cascade is of clinical interest for antiangiogenic cancer therapy. In this report, we demonstrate that VEGF controls the protein stability of the serine-threonine kinase PKB/Akt via inhibition of PKB/Akt protein degradation. VEGF deprivation or blockage of the VEGF signal transduction cascade with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 resulted in a specific decrease of the PKB/Akt protein level and subsequent cellular restimulation with VEGF rescued its stability. Real-time quantitative RT-PCR analysis demonstrated that VEGF does not regulate PKB/Akt gene expression. On the other hand, broad range inhibitors of caspases and the proteasome complex prevented VEGF-dependent downregulation of the PKB/Akt protein level indicating that PKB/Akt protein stability is regulated by VEGF-controlled proteolysis. Inhibition of the VEGF receptor and PKB/Akt-downstream PIK-related mTOR-kinase by rapamycin also neutralized the VEGF-protective effect in an PKB/Akt gene expression-independent way but results in proteolysis-dependent reduction of PKB/Akt protein stability. These results demonstrate a novel regulatory mechanism of the activated VEGF receptor/mTOR-signal transduction pathway to control the protein stability of PKB/Akt and survival threshold in endothelial cells.
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PMID:Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells. 1506 12

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G1 phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy.
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PMID:New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists. 1531 29

Although most cells in the embryonic mouse cortex express the serine-threonine kinase Akt-1, a small population of progenitors expresses Akt-1 protein at a higher level. To determine the functional significance of this difference, we used a retrovirus to increase Akt-1 expression in cortical progenitors. Increased Akt expression enhanced Akt activation after growth factor stimulation of progenitors. In vivo, it promoted retention in progenitor layers, the ventricular zone and subventricular zone. In vitro, it enhanced proliferation and survival, but did not impair migration. Moreover, it increased the proportion of stem cells, defined by a self-renewal assay. These effects did not depend on the Akt substrate p21(Cip1). In contrast, rapamycin, an inhibitor of mTOR (mammalian target of rapamycin), altered effects of elevated Akt-1 selectively: it eliminated the increase in stem cells and reduced the proliferative response, but had no effect on survival. The ability of elevated Akt-1 to increase the self-renewing population therefore depends on a rapamycin-sensitive mechanism (presumably inhibition of mTOR activity) but not on p21(Cip1), and can be distinguished from its effects on the proliferation and survival of other types of progenitors. Our findings suggest that expression of a high level of Akt-1 by a subpopulation of cortical progenitors biases their responses to extrinsic signals to increase their survival, proliferation, and/or self-renewal. Heterogeneity in Akt-1 level among progenitors could therefore allow cells that share a microenvironment to respond differently to the same extrinsic signals.
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PMID:Akt-1 expression level regulates CNS precursors. 1545 27

Highly specific signal transduction inhibitors are being developed as anti-cancer agents against an array of molecular targets, with the promise of increased selectivity and lower toxicity than classic cytotoxic chemotherapy agents. Rapamycin and its analogues are a promising class of novel therapeutics that specifically inhibit signaling from the serine-threonine kinase, mammalian target of rapamycin (mTOR). mTOR is a key intermediary in multiple mitogenic signaling pathways and plays a central role in modulating proliferation and angiogenesis in normal tissues and neoplastic processes. Rapamycin potently inhibits T-cell proliferation, and is approved for clinical use as an immuno-suppressant following kidney transplantation. Hyperactivation of mTOR signaling has been implicated in tumorigenesis, and promising pre-clinical studies in several tumor types suggest that the anti-proliferative and anti-angiogenic properties of rapamycin may be useful in cancer therapy. These studies have led to several clinical trials evaluating the safety and efficacy of rapamycin analogs in cancer therapy. The goal of this article is to review the mechanism of action of rapamycin as an anti-cancer agent, and to review the clinical experience with rapamycin and rapamycin analogs as immunosuppressive and anti-neoplastic therapeutic agents.
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PMID:Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. 1557 19

The mammalian target of rapamycin is a serine-threonine kinase that regulates cell cycle progression. Rapamycin and its analogues inhibit the mammalian target of rapamycin and are being actively investigated in clinical trials as novel targeted anticancer agents. Although cyclin D1 is down-regulated by rapamycin, the role of this down-regulation in rapamycin-mediated growth inhibition and the mechanism of cyclin D1 down-regulation are not well understood. Here, we show that overexpression of cyclin D1 partially overcomes rapamycin-induced cell cycle arrest and inhibition of anchorage-dependent growth in breast cancer cells. Rapamycin not only decreases endogenous cyclin D1 levels but also decreases the expression of transfected cyclin D1, suggesting that this is at least in part caused by accelerated proteolysis. Indeed, rapamycin decreases the half-life of cyclin D1 protein, and the rapamycin-induced decrease in cyclin D1 levels is partially abrogated by proteasome inhibitor N-acetyl-leucyl-leucyl-norleucinal. Rapamycin treatment leads to an increase in the kinase activity of glycogen synthase kinase 3beta (GSK3beta), a known regulator of cyclin D1 proteolysis. Rapamycin-induced down-regulation of cyclin D1 is inhibited by the GSK3beta inhibitors lithium chloride, SB216763, and SB415286. Rapamycin-induced G1 arrest is abrogated by nonspecific GSK3beta inhibitor lithium chloride but not by selective inhibitor SB216763, suggesting that GSK3beta is not essential for rapamycin-mediated G1 arrest. However, rapamycin inhibits cell growth significantly more in GSK3beta wild-type cells than in GSK3beta-null cells, suggesting that GSK3beta enhances rapamycin-mediated growth inhibition. In addition, rapamycin enhances paclitaxel-induced apoptosis through the mitochondrial death pathway; this is inhibited by selective GSK3beta inhibitors SB216763 and SB415286. Furthermore, rapamycin significantly enhances paclitaxel-induced cytotoxicity in GSK3beta wild-type but not in GSK3beta-null cells, suggesting a critical role for GSK3beta in rapamycin-mediated paclitaxel-sensitization. Taken together, these results show that GSK3beta plays an important role in rapamycin-mediated cell cycle regulation and chemosensitivity and thus significantly potentiates the antitumor effects of rapamycin.
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PMID:Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. 1575 96


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