Disease relevance of Frap1

• Energy depletion and hypoxia result in mTOR inhibition [1].
• Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity [2].
• Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines [3].
• Negative regulation of melanogenesis by phospholipase D1 through mTOR/p70 S6 kinase 1 signaling in mouse B16 melanoma cells [4].
• We, therefore, studied AKT activation in multiple myeloma cells treated with mTOR inhibitors [5].

Psychiatry related information on Frap1

• Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease [6].

High impact information on Frap1

• Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells [7].
• High ABI in all cell lines was suppressed by mTOR inhibitors LY294002 and rapamycin [7].
• Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice [7].
• Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer [8].
• Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition [9].

Chemical compound and disease context of Frap1

• This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved [10].
• Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity [11].
• We also found that LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy [12].
• In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer [13].
• Likewise, activation of molecules associated with hypertrophy (AKT, mTOR, and p70(S6k)) was diminished in mice overexpressing integrin [14].

Biological context of Frap1

• While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known [1].
• Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia [1].
• Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene [1].
• Translational up-regulation is blocked by inactivation of FRAP signaling by rapamycin, resulting in G(1) cell cycle arrest [15].
• The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process [16].

Anatomical context of Frap1

• The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors [3].
• Although the role of FRAP has been extensively studied in vitro, characterization of mammalian FRAP function in vivo has been limited to the immune system and tumor models [15].
• Using the mTOR inhibitor rapamycin, we show that mTOR is required for the rapid and sustained serum-induced activation of 45S ribosomal gene transcription (rDNA transcription), a major rate-limiting step in ribosome biogenesis and cellular growth [17].
• Based on our cell-free kinase and small interference RNA results, we conclude that mTOR complexed to RICTOR is the Ser-473 kinase in 3T3-L1 adipocytes [18].
• Our results show that Delta10mTORrr signals 4E-BP1 and permits rapamycin-treated myoblasts to differentiate, confirming the mTOR dependence of the inhibition of myogenesis by rapamycin [19].

Associations of Frap1 with chemical compounds

• In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein [16].
• Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST [20].
• The FKBP-12-rapamycin associated protein (FRAP, also known as mTOR and RAFT-1) is a member of the phosphoinositide kinase related kinase family [15].
• Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639 [21].
• The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase known to control initiation of translation through two downstream pathways: eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic initiation factor 4E and ribosomal p70 S6 kinase (S6K1) [19].
• The reduction in 4E-BP1 phosphorylation was associated with a reduction in the abundance of Raptor and mTOR proteins, Raptor-associated mTOR, reduced phosphorylation of the downstream protein p70S6 kinase, and attenuated incorporation of [(14)C]phenylalanine into protein [22].
• Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone [23].

Physical interactions of Frap1

• Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801 [1].
• The effects of insulin on the mammalian target of rapamycin, mTOR, were investigated in 3T3-L1 adipocytes. mTOR protein kinase activity was measured in immune complex assays with recombinant PHAS-I as substrate [24].

Enzymatic interactions of Frap1

• Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K [25].
• Conversely, loss of mTOR protein induced apoptosis due to up-regulation of cleaved caspase-3 activity [26].
• Recent data indicate that a mTOR complex phosphorylates Akt, and this complex is insensitive to rapamycin [27].

Regulatory relationships of Frap1

• However, the mechanism by which Akt activates mTOR is not fully understood [28].
• Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307 [29].
• mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma [30].
• The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease [31].
• These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR [32].
• In vivo inhibition of mTOR downregulates Mdm2 protein levels and induces p53-dependent apoptosis [33].

Other interactions of Frap1

• Recent studies have identified TSC1 and TSC2, two tumor suppressor genes involved in tuberous sclerosis complex, as regulators of the mammalian target of rapamycin (mTOR) pathway [34].
• This selective synaptic activation of mTOR-S6K is also resistant to APV and inhibited by Ca(2+) channel blockers and higher concentrations of glutamate [35].
• Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle [36].
• Overall, the data are consistent with exercise-induced repression of mTOR signalling and global rates of mRNA translation, accompanied perhaps by up-regulated translation of selected mRNAs through regulatory mechanisms such as eIF4E and rpS6 phosphorylation, mediated by activation of the ERK1/2 pathway [36].
• Thus, there is an mTOR-dependent survival signal required downstream of Akt [9].

Analytical, diagnostic and therapeutic context of Frap1

• The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials [37].
• Insulin affected neither the amount of mTOR immunoprecipitated nor the amount of mTOR detected by immunoblotting with mTAb2 [24].
• Insulin-stimulated kinase activity was clearly observed when immunoprecipitations were conducted with the mTOR antibody, mTAb2 [24].
• In vivo effects of RAD001 on Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed by immunohistochemistry and Western blot analysis [38].
• VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner [8].

References