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)

At the late blastocyst stage, the epithelial trophectoderm cells of the mammalian embryo undergo a phenotypic change that allows them to invade into the uterine stroma and make contact with the maternal circulation. This step can be regulated in vitro by the availability of amino acids. Embryos cultured in defined medium lacking amino acids cannot form trophoblast cell outgrowths on fibronectin, an in vitro model of implantation, but remain viable for up to 3 days in culture and will form outgrowths when transferred into complete medium. The amino acid requirement is a developmentally regulated permissive event that occurs during a 4- to 8-h period at the early blastocyst stage. Amino acids affect spreading competence specifically by regulating the onset of protrusive activity and not the onset of integrin activation. Rapamycin, a specific inhibitor of the kinase mTOR/FRAP/RAFT1, blocks amino acid stimulation of embryo outgrowth, demonstrating that mTOR is required for the initiation of trophectoderm protrusive activity. Inhibition of global protein translation with cycloheximide also inhibits amino acid-dependent signals, suggesting that mTOR regulates the translation of proteins required for trophoblast differentiation. Our data suggest that mTOR activity has a developmental regulatory function in trophectoderm differentiation that may serve to coordinate embryo and uterus at the time of implantation.
 ...
PMID:Exogenous amino acids regulate trophectoderm differentiation in the mouse blastocyst through an mTOR-dependent pathway. 1178 55

Insulin inhibits the expression of the hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) and glucose-6-phosphatase (G6Pase) genes. The signaling pathway that mediates these events requires the activation of phosphatidylinositol 3-kinase, whereas transfection studies have suggested an involvement of Akt (protein kinase B) and FKHR, a transcription factor regulated by Akt. We now demonstrate that insulin repression of endogenous IGFBP-1 gene transcription was blocked by rapamycin or by amino acid starvation. Rapamycin inhibited the mammalian target of rapamycin (mTOR) and the subsequent activation of p70/p85 S6 protein kinase-1 (S6K1) by insulin, whereas amino acid depletion prevented insulin induction of these signaling molecules. Importantly, we demonstrate that insulin regulation of the thymine-rich insulin response element of the IGFBP-1 promoter was also inhibited by rapamycin. However, sustained activation of S6K1 did not repress this promoter. In addition, rapamycin did not affect insulin regulation of G6Pase expression or Akt activation. We propose that these observations indicate that an mTOR-dependent, but S6K-independent mechanism regulates the suppression of IGFBP-1 (but not G6Pase) gene expression by insulin. Therefore, although the insulin-responsive sequence of the G6Pase gene promoter is related to that of the IGFBP-1 promoter, the signaling pathways that mediate suppression of these genes are distinct.
 ...
PMID:Insulin regulation of insulin-like growth factor-binding protein-1 gene expression is dependent on the mammalian target of rapamycin, but independent of ribosomal S6 kinase activity. 1178 21

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.
 ...
PMID:Sirolimus: a comprehensive review. 1182 25

One of the least-understood areas in biology is the determination of the size of animals and their organs. In Drosophila, components of the insulin receptor phosphoinositide 3-kinase (PI3K) pathway determine body, organ, and cell size. Several biochemical studies have suggested that Akt/protein kinase B is one of the important downstream targets of PI3K. To examine the role of Akt in the regulation of organ size in mammals, we have generated and characterized transgenic mice expressing constitutively active Akt (caAkt) or kinase-deficient Akt (kdAkt) specifically in the heart. The heart weight of caAkt transgenic mice was increased 2.0-fold compared with that of nontransgenic mice. The increase in heart size was associated with a comparable increase in myocyte cell size in caAkt mice. The kdAkt mutant protein attenuated the constitutively active PI3K-induced overgrowth of the heart, and the caAkt mutant protein circumvented cardiac growth retardation induced by a kinase-deficient PI3K mutant protein. Rapamycin attenuated caAkt-induced overgrowth of the heart, suggesting that the mammalian target of rapamycin (mTOR) or effectors of mTOR mediated caAkt-induced heart growth. In conclusion, Akt is sufficient to induce a marked increase in heart size and is likely to be one of the effectors of the PI3K pathway in mediating heart growth.
 ...
PMID:Akt/protein kinase B promotes organ growth in transgenic mice. 1190 72

Rapamycin and its derivatives, CCI-779 and RAD-001, inhibit the mammalian target of rapamycin (mTOR), downregulating translation of specific mRNAs required for cell cycle progression from G1 to S phase. Preclinically, mTOR inhibitors potently suppress growth and proliferation of numerous tumor cell lines in culture or when grown in mice as xenografts. CCI-779 and RAD-001 are being developed as antitumor drugs and are undergoing clinical trials. Clinically, CCI-779 has shown evidence of antitumor activity but induced relatively mild side effects in patients. Here we discuss potential antitumor mechanisms and resistance mechanisms of mTOR inhibitors, and summarize the current status of these compounds as novel antitumor agents.
 ...
PMID:Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. 1202 63

Chronic insulin exposure induces serine/threonine phosphorylation and degradation of IRS-1 through a rapamycin-sensitive pathway, which results in a down-regulation of insulin action. In this study, to investigate whether rapamycin (an mTOR inhibitor) could prevent insulin resistance induced by hyperinsulinemia, 3T3-L1 adipocytes were incubated chronically in the presence of insulin with or without the addition of rapamycin. Subsequently, the cells were washed and re-stimulated acutely with insulin. Chronic insulin stimulation caused a reduction of GLUT-4 and IRS-1 proteins with a correlated decrease in acute insulin-induced PKB and MAPK phosphorylations as well as a reduction in insulin-stimulated glucose transport. Rapamycin prevented the reduction of IRS-1 protein levels and insulin-induced PKB Ser-473 phosphorylation with a partial normalization of insulin-induced glucose transport. In contrast, rapamycin had no effect on the decrease in insulin-induced MAPK phosphorylation or GLUT-4 protein levels. These results suggest that chronic insulin exposure leads to a down-regulation of PKB and MAPK pathways through different mechanisms in adipocytes.
 ...
PMID:Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. 1205 62

RAFT1/FRAP/mTOR is a key regulator of cell growth and division and the mammalian target of rapamycin, an immunosuppressive and anticancer drug. Rapamycin deprivation and nutrient deprivation have similar effects on the activity of S6 kinase 1 (S6K1) and 4E-BP1, two downstream effectors of RAFT1, but the relationship between nutrient- and rapamycin-sensitive pathways is unknown. Using transcriptional profiling, we show that, in human BJAB B-lymphoma cells and murine CTLL-2 T lymphocytes, rapamycin treatment affects the expression of many genes involved in nutrient and protein metabolism. The rapamycin-induced transcriptional profile is distinct from those induced by glucose, glutamine, or leucine deprivation but is most similar to that induced by amino acid deprivation. In particular, rapamycin treatment and amino acid deprivation up-regulate genes involved in nutrient catabolism and energy production and down-regulate genes participating in lipid and nucleotide synthesis and in protein synthesis, turnover, and folding. Surprisingly, however, rapamycin had effects opposite from those of amino acid starvation on the expression of a large group of genes involved in the synthesis, transport, and use of amino acids. Supported by measurements of nutrient use, the data suggest that RAFT1 is an energy and nutrient sensor and that rapamycin mimics a signal generated by the starvation of amino acids but that the signal is unlikely to be the absence of amino acids themselves. These observations underscore the importance of metabolism in controlling lymphocyte proliferation and offer a novel explanation for immunosuppression by rapamycin.
 ...
PMID:The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. 1210 Dec 49

mTOR controls cell growth, in part by regulating p70 S6 kinase alpha (p70alpha) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). Raptor is a 150 kDa mTOR binding protein that also binds 4EBP1 and p70alpha. The binding of raptor to mTOR is necessary for the mTOR-catalyzed phosphorylation of 4EBP1 in vitro, and it strongly enhances the mTOR kinase activity toward p70alpha. Rapamycin or amino acid withdrawal increases, whereas insulin strongly inhibits, the recovery of 4EBP1 and raptor on 7-methyl-GTP Sepharose. Partial inhibition of raptor expression by RNA interference (RNAi) reduces mTOR-catalyzed 4EBP1 phosphorylation in vitro. RNAi of C. elegans raptor yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR. Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo.
 ...
PMID:Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. 1215 Sep 26

Mammalian target of rapamycin (mTOR) is a serine and threonine protein kinase that regulates numerous cellular functions, in particular, the initiation of protein translation. mTOR-mediated phosphorylation of both the translational repressor eukaryotic initiation factor 4E binding protein-1 and p70 S6 kinase are early events that control the translation initiation process. Rapamycin, an inhibitor of mTOR, is a potent immunosuppressant due, in part, to its ability to interfere with T-cell activation at the level of translation, and it has gained a prominent role in preventing the development and progression of rejection in pancreatic islet transplant recipients. The characterization of the insulin signaling cascade that modulates mTOR in insulin-sensitive tissues has been a major focus of investigation. Recently, the ability of nutrients, in particular the branched-chain amino acid leucine, to activate mTOR independent of insulin by a process designated as nutrient signaling has been identified. The beta-cell expresses components of the insulin signaling cascade and utilizes the metabolism of nutrients to affect insulin secretion. These combined transduction processes make the beta-cell an unique cell to study metabolic and autocrine regulation of mTOR signaling. Our studies have described the ability of insulin and IGFs in concert with the nutrients leucine, glutamine, and glucose to modulate protein translation through mTOR in beta-cells. These findings suggest that mitochondria-derived factors, ATP in particular, may be responsible for nutrient signaling. The significance of these findings is that the optimization of mitochondrial function is not only important for insulin secretion but may significantly impact the growth and proliferation of beta-cells through these mTOR signaling pathways.
 ...
PMID:Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. 1235 22

The mammalian target of rapamycin (mTOR) is a Ser/Thr (S/T) protein kinase, which controls mRNA translation initiation by modulating phosphorylation of the translational regulators PHAS-I and p70(S6K). Here we show that in vitro mTOR is able to phosphorylate these two regulators at comparable rates. Both (S/T)P sites, such as Thr36, Thr45, and Thr69 in PHAS-I and the h(S/T)h site (where h is a hydrophobic amino acid) Thr389 in p70(S6K), were phosphorylated. Rapamycin-FKBP12 inhibited mTOR activity. Surprisingly, the extent of inhibition depended on the substrate. Moreover, mutating Ser2035 in the rapamycin-binding domain (FRB) not only decreased rapamycin sensitivity as expected but also dramatically affected the sites phosphorylated by mTOR. The results demonstrate that mutations in Ser2035 are not silent with respect to mTOR activity and implicate the FRB in substrate recognition. The findings also impose new limitations on interpreting results from experiments in which rapamycin and/or rapamycin-resistant forms of mTOR are used to investigate mTOR function in cells.
 ...
PMID:The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. 1237 Feb 90


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