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)

The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, oncocytomas, renal cell carcinomas, and both benign and malignant angiomyolipomas. All of these occur in children as well as adults with TSC. Benign angiomyolipomas, which can cause spontaneous life-threatening hemorrhage, are by far the most prevalent and the greatest source of morbidity. What is particularly unusual about TSC, setting it apart from virtually all other inherited forms of renal disease, is the abnormalities of both mesenchymal cells (angiomyolipomas) and epithelial cells (cysts, oncocytomas, and carcinomas). Recently, the TSC1/TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin). This places TSC1/TSC2 at center stage in signaling pathways that regulate cell growth. Furthermore, recent advances in TSC1/TSC2 signaling open the door for targeted therapy for TSC patients. Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.
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PMID:Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. 1585 27

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.
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PMID:The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. 1656 52

Sirolimus is a potent immunosuppressant drug with a novel mechanism of action. It inhibits the mammalian target of rapamycin (mTOR) and blocks the cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus is widely used as a maintenance immunosuppressive agent in organ transplantation. Also, a potentially benefit of this valuable drug in some immunologic and malignant diseases is currently under scrutiny.Classical side effects: hematological (anaemia, leucopenia, thrombocytopenia), hypercholesterolemia, arthralgias, extremity oedema and impaired wound healing have been frequently associated with the use of sirolimus. Additionally with its increased use, transplant professionals are encountering a variety of previously unreported and potentially more severe side effects.Here, we review the most recent data on sirolimus unexpected side effects (with an emphasis on pulmonary and renal toxicity), its use in renal transplantation and its new potential therapeutic indications (chronic glomerulopathies, polycystic kidney disease, different types of cancer). A brief description of the current knowledge of sirolimus therapeutic drug monitoring, methods of analysis, pharmacokinetics and drug interactions with calcineurin inhibitors is also included.
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PMID:Sirolimus--challenging current perspectives. 1703 68

Studies of rapamycin properties in yeast led to the discovery of TOR (target of rapamycin) and its mammalian analogue, mTOR. mTOR is a central regulator of cell growth and proliferation in response to environmental stimuli such as growth factors and nutrients. mTOR regulates several pathways, particularly translation process by controlling the activity of two proteins in response to a broad range of mitogenic stimuli, S6K1 and 4E-BP1. Inhibition of cell growth by rapamycine and analogues have been demonstrated in numerous cell types, explaining the broad development of these drugs in clinical practice. Rapamycine is a potent immunosuppressive drug used in solid organ transplantation for the prevention of allograft rejection. In oncology, mTOR inhibitors are currently evaluated in several types of cancers. They are now widely used for coating stents to reduce post-stenting restenosis after coronary angioplasty. Finally, rapamycine is now evaluated in various diseases characterized by cell growth disorders such as phacomatosis and autosomal dominant polycystic kidney disease.
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PMID:[mTOR inhibitors: pleiotropic antiproliferative drugs]. 1710 Oct 96

Recent work has uncovered a functional link between polycystin-1 (PC1), the protein affected in autosomal-dominant polycystic kidney disease (ADPKD) and tuberin, the protein affected in tuberous sclerosis complex (TSC). These data suggest that PC1 functions by inducing the formation of a complex with tuberin and the Ser/Thr kinase mTOR thereby inhibiting mTOR activity. In normal, adult kidney, mTOR is inactive. However, it is activated in response to insults and required for proliferative and hyperthrophic repair processes. We propose a model in which the PC1-tuberin-mTOR complex functions to sense renal insults, possibly by ciliary mechanotransduction, and regulates the activity of mTOR to trigger a formal repair program. In ADPKD, defects in PC1 would lead to constitutive activation of mTOR, and the affected cells would be engaged in a permanent state of futile repair leading to the formation and growth of renal cysts. The mTOR inhibitor rapamycin has proven highly effective in preventing and even reversing cyst growth in rodent models of polycystic kidney disease resulting in preservation of renal function. mTOR inhibitors, already in clinical use as immunosuppressants, may therefore be promising for future therapeutic approaches for ADPKD.
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PMID:Regulation of mTOR by polycystin-1: is polycystic kidney disease a case of futile repair? 1710 41

Diagnosis and treatment of autosomal dominant polycystic kidney disease (ADPKD) is rapidly changing. Cellular pathways that involve the polycystins are being mapped and involve the primary cilium, intracellular calcium and cAMP regulation, and the mammalian target of rapamycin (mTOR) pathway. With the use of new imaging approaches, earlier diagnosis of hepatic cystic disease is possible, and measurement of kidney and cystic growth as well as kidney blood flow is possible over relatively short periods. PKD gene type, gender, proteinuria, and the presence of hypertension relate to the rate of kidney growth in ADPKD. On the basis of risk factors for progression to ESRD and the pathogenic roles that intracellular cAMP and mTOR play in cystogenesis, novel therapies are now being tested, including maximal inhibition of the renin-angiotensin system, inhibition of renal intracellular cAMP using vasopressin V2 receptor antagonists, and somatostatin analogues, as well as inhibitors of mTOR. This review addresses the current understanding of the pathogenesis and the natural history of ADPKD; accuracy and reliability of diagnostic approaches in utero, childhood, and adulthood; the value of reliable magnetic resonance imaging to measure disease progression early in the course of ADPKD; and novel therapeutic approaches that are being evaluated in ADPKD.
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PMID:Autosomal dominant polycystic kidney disease: time for a change? 1742 47

The root cause for most cases of autosomal-dominant polycystic kidney disease (ADPKD) is mutations in the polycystin-1 (PC1) gene. While PC1 has been implicated in a perplexing variety of protein interactions and signaling pathways, what its normal function is and why its disruption leads to the proliferation of renal epithelial cells are unknown. Recent results suggest that PC1 is involved in mechanotransduction by primary cilia measuring the degree of luminal fluid flow. PC1 has also recently been shown to regulate the mTOR and signal transducers and activators of transcription (STAT) 6 pathways. These two pathways are normally dormant in the healthy kidney but are activated in response to injury and appear to drive a proliferative repair response. This review develops the idea that a critical function of PC1 and primary cilia in the adult kidney may be to sense renal injury by detecting changes in luminal fluid flow and to trigger proliferation. Constitutive activation of these pathways in ADPKD would lead to the futile attempt to repair a nonexisting injury, resulting in cyst growth. The existence of many known cellular and molecular similarities between renal repair and ADPKD supports this model.
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PMID:Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. 1771 62

G protein-coupled receptor (GPCR) agonists, including neurotransmitters, hormones, chemokines, and bioactive lipids, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. Typically, the binding of an agonistic ligand to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the activity of phospholipases C, D, and A2 leading to the synthesis of lipid-derived second messengers, Ca2+ fluxes and subsequent activation of protein phosphorylation cascades, including PKC/PKD, Raf/MEK/ERK, and Akt/mTOR/p70S6K is an important early response to mitogenic GPCR agonists. The EGF receptor (EGFR) tyrosine kinase has emerged as a transducer in the signaling by GPCRs, a process termed transactivation. GPCR signal transduction also induces striking morphological changes and rapid tyrosine phosphorylation of multiple cellular proteins, including the non-receptor tyrosine kinases Src, focal adhesion kinase (FAK), and the adaptor proteins CAS and paxillin. The pathways stimulated by GPCRs are extensively interconnected by synergistic and antagonistic crosstalks that play a critical role in signal transmission, integration, and dissemination. The purpose of this article is to review recent advances in defining the pathways that play a role in transducing mitogenic responses induced by GPCR agonists.
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PMID:Mitogenic signaling pathways induced by G protein-coupled receptors. 1778 53

Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.
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PMID:Potential pharmacological interventions in polycystic kidney disease. 1803 88

The immunosuppressive agent sirolimus exerts an antiproliferative effect by inhibiting mammalian target of rapamycin (mTOR). Because excessive proliferation of the biliary epithelium is a prominent feature of the polycystic liver that accompanies autosomal dominant polycystic kidney disease (ADPKD), we hypothesized that sirolimus may benefit patients with this disorder. We retrospectively measured the volumes of polycystic livers and kidneys in ADPKD patients who had received kidney transplants and had participated in a prospective randomized trial that compared a sirolimus-containing immunosuppression regimen to a tacrolimus-containing regimen. Sixteen subjects (seven with sirolimus, nine with tacrolimus) had received abdominal imaging studies within 11 mo before and at least 7 mo after transplantation, making them suitable for our analysis. Treatment with the sirolimus regimen for an average of 19.4 mo was associated with an 11.9 +/- 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 +/- 0.09% increase. A trend toward a greater reduction in native kidney volume was also noted in the sirolimus group compared with the nonsirolimus group. Regarding mechanism, the epithelium that lines hepatic cysts exhibited markedly higher levels of phospho-AKT, phospho-ERK, phospho-mTOR, and the downstream effector phospho-S6rp compared with control biliary epithelium. In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts.
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PMID:Sirolimus reduces polycystic liver volume in ADPKD patients. 1819 97


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