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)

Rapamycin inhibits the FK506-binding protein 12 (FKBP12)/mammalian target of rapamycin (mTOR) complex and causes cell cycle arrest in G1. The precise mechanism of growth inhibition by rapamycin is only partly understood. Rapamycin led to growth inhibition in the human prostate cancer cell lines LNCaP and PC3 cells after 72 h, ID50: 93 and 50 nM, respectively. Filter cDNA array analysis showed down-regulation by more than 0.75x by rapamycin in PC3 cells and LNCaP cells of the following genes: follistatin, eukaryotic initiation factor-4E (eIF4E), glucose-6-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH)-A, ATP synthase, heat shock protein (HSP)-1. Upregulation by more than 1.5x was found for: bone morphogenetic protein (BMP)-4, FKBP12, carcinoma embryonic antigen (CEA) precursor, eukaryotic initiation factor (eIF)-3 p36 subunit, latent transforming growth factor (TGF) beta binding protein (LTBP)1. Rapamycin induced BMP4 and reduced follistatin expression in PC3 cells. This resulted in a dose-dependent nuclear expression of Smad4 and activated the SBE4 Smad-reporter, indicating activation of TGFbeta/BMP signaling. Combining rapamycin with PI3K inhibition (LY294002) increased growth inhibition. These findings illustrate that Smad signaling plays a role in the anticancer effects of rapamycin and show that combination with PI3K inhibition improves growth inhibition.
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PMID:Rapamycin induces Smad activity in prostate cancer cell lines. 1259 18

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the Gq family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca2+. This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism which requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kappaB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.
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PMID:Cholecystokinin activates a variety of intracellular signal transduction mechanisms in rodent pancreatic acinar cells. 1268 72

Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
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PMID:Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. 1282 Sep 60

To understand the role of arachidonic acid (AA) in regulating vascular smooth muscle cell (VSMC) growth, its effects on phosphorylation of Akt, S6K1, ribosomal protein S6, 4EBP1, and eIF4E were studied. Arachidonic acid stimulated phosphorylation of Akt, S6K1, ribosomal protein S6, 4EBP1, and eIF4E in a time-dependent manner in VSMC. Arachidonic acid stimulation of phosphorylation of the above signaling molecules is specific, as these events were not affected by other unsaturated or saturated fatty acids. Metabolic conversion of AA via the LOX/MOX and/or COX pathways, to some extent, was required for its effects on the phosphorylation of Akt, S6K1, ribosomal protein S6, 4EBP1, and eIF4E. In addition, AA increased PI3K activity in a time-dependent manner in VSMC. LY294002, an inhibitor of PI3K, completely blocked AA-induced phosphorylation of Akt, S6K1, ribosomal protein S6, 4EBP1, and eIF4E, suggesting a role for PI3K in these effects. Consistent with its effects on translation initiation signaling events, AA induced global protein synthesis in VSMC and this response was dependent, to some extent, on its metabolism via the LOX/MOX and/or COX pathways, and mediated by the PI3K/Akt/mTOR pathway. Thus, the above observations provide the first biochemical evidence for the role of AA in the activation of translation initiation signaling in VSMC.
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PMID:Arachidonic acid activation of translation initiation signaling in vascular smooth muscle cells. 1367 36

Prostate cancer is one of the most common cancers among men. Recent studies demonstrated that PI3K signaling is an important intracellular mediator which is involved in multiple cellular functions including proliferation, differentiation, anti-apoptosis, tumorigenesis, and angiogenesis. In the present study, we demonstrate that the inhibition of PI3K activity by LY294002, inhibited prostate cancer cell proliferation and induced the G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins including cyclin D1, CDK4, and Rb phosphorylation at Ser780, Ser795, and Ser807/811, whereas expression of CDK6 and beta-actin was not affected by LY294002. The expression of cyclin kinase inhibitor, p21(CIP1/WAF1), was induced by LY294002, while levels of p16(INK4) were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation and p70(S6K), but not MAPK. PI3K regulates cell cycle through AKT, mTOR to p70(S6K). The mTOR inhibitor rapamycin has similar inhibitory effects on G(1) cell cycle progression and expression of cyclin D1, CDK4, and Rb phosphorylation. These results suggest that PI3K mediates G(1) cell cycle progression and cyclin expression through the activation of AKT/mTOR/p70(S6K) signaling pathway in the prostate cancer cells.
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PMID:Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. 1455 32

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
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PMID:Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. 1456 7

Tuberous sclerosis is an autosomal dominant human genetic disorder in which distinctive tumors called hamartomas develop. Germline mutations in either TSC1 or TSC2 cause this syndrome, and hamartomas typically display second hit events with loss of the remaining normal allele. Studies initiated in Drosophila have identified a role for the Tsc1 and Tsc2 genes in the regulation of cell and organ size, and genetic interaction studies have placed them in the PI3K-Akt-mTOR-S6K pathway. Biochemical studies have shown that activated Akt phosphorylates TSC2 in the TSC1/TSC2 protein complex, inactivating it; while TSC1/TSC2 has GAP activity for the Rheb GTPase (a member of the ras family), and activated Rheb-GTP activates mTOR. Thus, in cells lacking TSC1 or TSC2 there are increased levels of Rheb-GTP which leads to activation of mTOR, leading to cell size increase and growth. These developments provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches.
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PMID:Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. 1461 11

The purpose of this study was to examine the role of the ribosomal protein S6 protein kinase (p70S6K), a protein synthesis regulator, in promoting retinal neuronal cell survival. Differentiated R28 rat retinal neuronal cells were used as an experimental model. Cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% newborn calf serum, and during the period of experimentation were exposed either to the absence or presence of 10 nm insulin. Insulin treatment induced p70S6K, mTOR, and Akt phosphorylation, effects that were completely prevented by the PI3K inhibitor, LY294002. Insulin-induced phosphorylation of p70S6K and mTOR was prevented by the mTOR inhibitor, rapamycin. Apoptosis, induced by serum deprivation and evaluated by Hoechst staining, was inhibited by insulin treatment in R28 cells, but not in L6 muscle cells. This effect of insulin was also largely prevented by rapamycin. Inhibition of p70S6K activity by exogenous expression of a dominant negative mutant of p70S6K prevented insulin-induced cell survival, whereas, overexpression of wild type p70S6K or expression of a rapamycin resistant form of the kinase enhanced the effect of insulin on survival. Enhanced cell survival under the latter condition was accompanied by increased p70S6K activity and phosphorylation. Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin-resistant mutant. Together, these results suggest that p70S6K plays a key role in insulin stimulated retinal neuronal cell survival.
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PMID:Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. 1466 May 91

Insulin-like growth factors (IGFs) are essential for skeletal muscle development, regeneration, and hypertrophy. Although autocrine actions of IGF-II are known to initiate myoblast differentiation, the regulatory elements and upstream signaling pathways for myogenic expression of IGF-II remain elusive. Here, we report the regulation of IGF-II transcription by mTOR, as well as by amino acid sufficiency, through the IGF-II promoter 3 and a downstream enhancer during C2C12 myoblast differentiation. Furthermore, we present evidence that IGF production, and not IGF signaling, is the primary target for mTOR's function in the initiation of differentiation. Moreover, myogenic signaling by mTOR is independent of its kinase activity and mediated by the PI3K-Akt pathway. Our findings represent the first identification of a signaling pathway that regulates IGF-II expression in myogenesis and implicate the mTOR-IGF axis as a molecular link between nutritional levels and skeletal muscle development.
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PMID:IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients. 1466 39

In 1321N1 astrocytoma cells, stimulation of the IGF-1 (insulin-like growth factor-1) receptor increased the association of PI3K [phosphoinositide (PI) 3-kinase] activity with IRS-1 (insulin re-ceptor substrate 1), and increased the cellular concentration of PtdIns(3,4,5)P3. Carbachol, acting on M3 muscarinic receptors, inhibited insulin-, but not PDGF (platelet-derived growth factor)-, stimulated responses by approximately 50%. The inhibition of IRS-1-associated PI3K activity by carbachol (i) was rapid (<1 min), persistent (> or =60 min) and potent (half-maximal concentration approximately 1 microM); (ii) was reproduced by stimuli for several phospholipase-C-coupled receptors; (iii) was prevented by the inhibition of protein kinase C, but not by chelation of intracellular Ca2+; and (iv) was not blocked or reproduced by inhibitors or stimuli respectively of mitogen-activated protein kinase, PI3K, protein kinase B or the mammalian target of rapamycin. However, the effects of carbachol were prevented by sodium vanadate, a protein tyrosine phosphatase inhibitor, and were accompanied by reduced insulin-stimulated IRS-1 tyrosine phosphorylation and recruitment of the 85 kDa regulatory subunit of PI3K to IRS-1, but not by reduced IGF-1 receptor kinase activity. The inhibitory effect of carbachol was reproduced by okadaic acid, a protein serine/threonine phosphatase inhibitor, but not by PDGF, yet all three agents stimulated the serine phosphorylation of IRS-1 at residues Ser312, Ser616 and Ser636/639, albeit to different extents. Thus muscarinic receptors may inhibit insulin signalling by promoting IRS-1 tyrosine dephosphorylation and/or by uncoupling IRS-1 from the stimulated IGF-1 receptor by stimulating IRS-1 serine phosphorylation. However, the proportion of IRS-1 molecules phosphorylated at a particular site or the phosphorylation of additional IRS-1 serine residues other than those noted above must be important.
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PMID:Muscarinic-receptor-mediated inhibition of insulin-like growth factor-1 receptor-stimulated phosphoinositide 3-kinase signalling in 1321N1 astrocytoma cells. 1476 30


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