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)

Metformin is a biguanide derivative that is widely used in the treatment of diabetes mellitus. One of the pharmacological targets of metformin is adenosine monophosphate-activated protein kinase (AMPK). We investigated the effect of metformin on the suppression of intestinal polyp formation in Apc(Min/+) mice. Administration of metformin (250 mg/kg) did not reduce the total number of intestinal polyp formations, but significantly reduced the number of intestinal polyp formations larger than 2 mm in diameter in Apc(Min/+) mice. To examine the indirect effect of metformin, the index of insulin resistance and serum lipid levels in Apc(Min/+) mice were assessed. These factors were not significantly attenuated by the treatment with metformin, indicating that the suppression of polyp growth is not due to the indirect drug action. The levels of tumor cell proliferation as determined by 5-bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemical staining, and apoptosis, via transferase deoxytidyl uridine end labeling staining, in the polyps of metformin-treated mice were not significantly different in comparison to those of control mice. Gene expression of cyclin D1 and c-myc in intestinal polyps were also not significantly different between those two groups. In contrast, metformin activated AMPK in the intestinal polyps, resulting in the inhibition of the activation of mammalian target of rapamycin, which play important roles in the protein synthesis machinery. Metformin suppressed the polyp growth in Apc(Min/+) mice, suggesting that it may be a novel candidate as a chemopreventive agent for colorectal cancer.
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PMID:Metformin suppresses intestinal polyp growth in ApcMin/+ mice. 1880 38

Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.
Diabetes Obes Metab 2008 Nov
PMID:The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. 1883 43

Factors that promote pancreatic beta cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate beta cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in beta cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.
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PMID:Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. 1884 52

TSC-mTOR signaling plays a crucial role in the regulation of cell growth and survival control. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that forms two distinct functional complexes, termed TOR complex 1 (TORC1) and TORC2, respectively. TORC1 is a rapamycin-sensitive complex and regulates a wide array of cellular processes including translation, transcription, and autophagy. Tuberous sclerosis complex (TSC) gene products, TSC1 and TSC2 are tumor suppressors and specifically suppress TORC1 activity. Mutation of either TSC1 or TSC2 causes TSC disease, which is characterized by formation of hamartomas in multiple organs. Although the role of TSC-mTOR pathway in tumor and cancer development has been extensively studied, more recent studies have indicated a role for mTOR function in appetite, memory, aging, and energy metabolism. Dysregulation of the TSC-mTOR pathway may cause not only tumor development but also metabolic disorders such as diabetes and its complications.
Diabetes Res Clin Pract 2008 Nov 13
PMID:Role of TSC-mTOR pathway in diabetic nephropathy. 1892 85

Despite the use of the sirolimus (rapamycin) drug-eluting coronary stent, diabetics are at increased risk of developing in-stent restenosis for unclear reasons. Hyperleptinemia, which often coexists with diabetes and metabolic syndrome, is an independent risk factor for progression of coronary artery disease. It has not been determined whether elevated circulating leptin decreases the efficacy of the sirolimus drug-eluting stent in inhibiting neointimal hyperplasia, the process underlying restenosis after stenting. Here we show that leptin activates the mammalian target of rapamycin (mTOR) signaling pathway in primary murine vascular smooth muscle cells (VSMC) and stimulates VSMC proliferation in a PI3K-dependent fashion. Exogenous leptin, administered at levels comparable to those found in obese humans, promotes neointimal VSMC hyperplasia in a murine femoral artery wire injury model. Leptin significantly increases the dose of the mTOR inhibitor sirolimus that is required for effective inhibition of neointimal formation. Combination therapy with LY294002, a PI3K inhibitor, and sirolimus effectively inhibits leptin-enhanced neointimal hyperplasia. These data show that, in the setting of hyperleptinemia, higher doses of an mTOR inhibitor, or combination therapy with mTOR and PI3K inhibitors, inhibits neointimal hyperplasia after arterial injury. These studies may explain the higher rates of restenosis observed in diabetics treated with a sirolimus-eluting coronary stent and suggest a potential novel therapeutic approach for inhibiting in-stent restenosis in such patients.
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PMID:Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors. 1902 99

Patients with metastatic renal cell carcinoma (RCC) generally show a poor prognosis; treatment approaches have not significantly improved patient survival. Temsirolimus inhibits the mammalian target of rapamycin kinase. Clinical studies have shown positive results when the drug is administered to patients with this disease. The clinical benefit of temsirolimus for poor-risk, advanced RCC patients was demonstrated in a Phase III study comparing temsirolimus with interferon alpha (IFN-alpha) or combined temsirolimus plus IFN-alpha as first-line treatment of advanced RCC, showed that treatment with temsirolimus alone significantly increased median overall survival in poor-risk, advanced RCC patients (10.9 vs 7.3 vs 8.4 months). This was the first Phase III trial to demonstrate an overall improvement in survival using an agent as "targeted therapy" for patients with advanced RCC. By November 2007, 200 patients with advanced RCC had been treated with temsirolimus before its approval by the European Medicines Agency (EMEA) within a compassionate use program. The single-center treatment experiences using temsirolimus in patients for compassionate use are described herein. The treatment was generally well tolerated; side effects (mucositis, diabetes, and peripheral edema) were within the range expected from the pivotal trials and manageable with supportive care. Further development strategies for temsirolimus in patients with RCC include its evaluation with bevacizumab and also as second-line therapy in patients who have failed first-line therapy with sunitinib.
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PMID:Temsirolimus in renal cell carcinoma. 1910 Sep 5

Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth and metabolism in response to nutrients, growth factors, cellular energy, and stress. TOR, which was originally discovered in yeast, is conserved in all eukaryotes including plants, worms, flies, and mammals. The discovery of TOR led to a fundamental change in how we think about cell growth. It is not a spontaneous process that just happens when building blocks (nutrients) are available, but rather a highly regulated, plastic process controlled by TOR-dependent signaling pathways. TOR is found in 2 structurally and functionally distinct multiprotein complexes, TORC1 and TORC2. The 2 TOR complexes, like TOR itself, are highly conserved. Mammalian TORC1 (mTORC1) is rapamycin sensitive and contains mTOR, raptor, and mLST8. TORC1 in yeast and mammals mediates temporal control of cell growth by regulating several cellular processes, including translation, transcription, ribosome biogenesis, nutrient transport, and autophagy. mTORC2 is rapamycin insensitive and contains mTOR, rictor, mSIN1, PRR5, and mLST8. TORC2 in yeast and mammals mediates spatial control of cell growth by regulating the actin cytoskeleton. Thus, the 2 TOR complexes constitute an ancestral signaling network conserved throughout eukaryotic evolution to control the fundamental process of cell growth. As a central controller of cell growth, TOR plays a key role in development and aging and has been implicated in disorders such as cancer, cardiovascular disease, obesity, and diabetes. The challenge now is to understand the role of mTOR signaling to coordinate and integrate overall body growth in multicellular organisms.
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PMID:mTOR-what does it do? 1910 Sep 9

Clinical studies of drug-eluting stents delivering the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (Sirolimus), have demonstrated a reduced efficacy for these devices in patients with diabetes, which suggests that the mTOR pathway may cease to be dominant in mediating the vascular response to injury under diabetic conditions. We hypothesized that changes in serum composition accompanying diabetes may reduce the role of mTOR in mediating the vascular response to injury. We measured the ability of a median dose of rapamycin (10 nM) to inhibit the proliferation of human coronary artery smooth muscle cells (huCASMCs) stimulated with serum obtained from donors with diabetes (n = 14) and without diabetes (n = 16). In an additional analysis, we compared the effects of rapamycin on huCASMCs stimulated with the serum of donors with metabolic syndrome (n = 15) versus those without (n = 7). There was no difference in the effect of rapamycin on huCASMC proliferation after stimulation with serum from either donors with diabetes or donors with metabolic syndrome compared with the respective controls. We conclude that the changes in the serum composition common to diabetes and metabolic syndrome are insufficient to diminish the role of mTOR in the progression of cardiovascular disease.
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PMID:Sera from patients with diabetes do not alter the effect of mammalian target of rapamycin inhibition on smooth muscle cell proliferation. 1912 35

mTOR (mammalian target of rapamycin) is a highly conserved serine/threonine protein kinase that has roles in cell metabolism, cell growth and cell survival. Although it has been known for some years that mTOR acts as a hub for inputs from growth factors (in particular insulin and insulin-like growth factors), nutrients and cellular stresses, some of the mechanisms involved are still poorly understood. Recent work has implicated mTOR in a variety of important human pathologies, including cancer, Type 2 diabetes and neurodegenerative disorders, heightening interest and accelerating progress in dissecting out the control and functions of mTOR.
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PMID:mTOR: dissecting regulation and mechanism of action to understand human disease. 1914 34

The mammalian target of rapamycin (mTOR) plays an important role in cell growth. Dysfunction of mTOR has been linked to many human diseases, such as cancers, obesity, diabetes, cardiovascular diseases and neurological disorders. Currently, the mTOR inhibitor rapamycin and its analogs have been vigorously evaluated and developed as anticancer drugs. Here, we will review the most recent patents and patent applications relating to mTOR pathway. Moreover, we will discuss the patents and patent applications on the treatment of mTOR-associated metabolic diseases and cancers.
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PMID:Recent patents and patent applications relating to mTOR pathway. 1914 38


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