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 translation of mRNA in eukaryotic cells is regulated by amino acids through multiple mechanisms. One such mechanism involves activation of mTOR (Fig. 1). mTOR controls a myriad of downstream effectors, including RNA polymerase I, S6K1, 4E-BP1, and eEF2 kinase. In yeast, and probably in higher eukaryotes, mTOR signals through Tap42p/alpha 4 to regulate protein phosphatases. Through phosphorylation of Tap42p/alpha 4, mTOR abrogates dephosphorylation of the downstream effectors by PP2 A and/or PP6, resulting in their increased phosphorylation. Although at this time still speculative, in vitro results using mTOR immunoprecipitates suggest that mTOR, or an associated kinase, may also be directly involved in phosphorylating some effectors. Enhanced RNA polymerase I activity results in increased transcription of rDNA genes, whereas increased S6K1 activity promotes preferential translation of TOP mRNAs, such as those encoding ribosomal proteins. Together, stimulated RNA polymerase I and S6K1 activities enhance ribosome biogenesis, increasing the translational capacity of the cell. Phosphorylation of 4E-BP1 prohibits its association with eIF4E, allowing eIF4E to bind to eIF4G and form the active eIF4F complex. Increased eIF4F formation preferentially stimulates translation of mRNAs containing long, highly-structured 5' UTRs. Finally, amino acids cause inhibition of the eEF2 kinase, resulting in an increase in the proportion of eEF2 in the active, dephosphorylated form. By inhibiting eEF2 phosphorylation, amino acids may not only stimulate translation elongation, but may also prevent activation of GCN2 by enhancing the rate of removal of deacylated tRNA from the P-site on the ribosome; a potential activator of GCN2. GCN2 may also be regulated directly by the accumulation of deacylated-tRNA caused by treatment with inhibitors of tRNA synthetases or in cells incubated in the absence of essential amino acids. However, because the Km of the tRNA synthetases for amino acids is well above the amino acid concentrations found in plasma of fasted animals, such a mechanism may not be operative in mammals in vivo. Activation of GCN2 results in increased phosphorylation of the alpha-subunit of eIF2, which in turn causes inhibition of eIF2B. Thus, by preventing activation of GCN2, amino acids preserve eIF2B activity, which promotes translation of all mRNAs, i.e., global protein synthesis is enhanced.
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PMID:Regulation of translation initiation by amino acids in eukaryotic cells. 1157 65

Regulation of ribosomal RNA gene transcription by RNA polymerase I (Pol I) is fundamental to ribosome biogenesis and therefore protein translation capacity and cell growth, yet little is known of the key signaling cascades involved. We show here that insulin-like growth factor-1 (IGF-1)-induced Pol I transcription in HEK293 cells is entirely dependent on phosphatidylinositol 3-kinase (PI3K) activity and, additionally, is modulated by the mammalian target of rapamycin (mTOR), which coordinates Pol I transcription with the availability of amino acids. The mitogen-activated protein kinase (MAPK) pathway is weakly stimulated by IGF-1 in these cells and partly contributes to Pol I transcription regulation. Activation of Pol I transcription by IGF-1 results from enhancement of the activity of the Pol I transcription machinery and increased occupancy by SL1 of the endogenous tandemly repeated ribosomal promoters in vivo. The inputs from PI3K, mTOR, and MAPK pathways converge to direct appropriate rRNA gene expression by Pol I in the nucleolus of mammalian cells in response to environmental cues, such as growth factors and nutrients.
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PMID:Phosphatidylinositol 3-kinase and mTOR signaling pathways regulate RNA polymerase I transcription in response to IGF-1 and nutrients. 3241 13

In cycling cells, transcription of ribosomal RNA genes by RNA polymerase I (Pol I) is tightly coordinated with cell growth. Here, we show that the mammalian target of rapamycin (mTOR) regulates Pol I transcription by modulating the activity of TIF-IA, a regulatory factor that senses nutrient and growth-factor availability. Inhibition of mTOR signaling by rapamycin inactivates TIF-IA and impairs transcription-initiation complex formation. Moreover, rapamycin treatment leads to translocation of TIF-IA into the cytoplasm. Rapamycin-mediated inactivation of TIF-IA is caused by hypophosphorylation of Se 44 (S44) and hyperphosphorylation of Se 199 (S199). Phosphorylation at these sites affects TIF-IA activity in opposite ways, for example, phosphorylation of S44 activates and S199 inactivates TIF-IA. The results identify a new target formTOR-signaling pathways and elucidate the molecular mechanism underlying mTOR-dependent regulation of RNA synthesis.
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PMID:mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. 1500 9

PTEN is a tumor suppressor whose function is frequently lost in human cancer. It possesses a lipid phosphatase activity that represses the activation of PI3 kinase/Akt signaling, leading to decreased cell growth, proliferation, and survival. The potential for PTEN to regulate transcription of the large rRNAs by RNA polymerase I (RNA Pol I) was investigated. As increased synthesis of rRNAs is a hallmark of neoplastic transformation, the ability of PTEN to control the transcription of rRNAs might be crucial for its tumor suppressor function. The expression of PTEN in PTEN-deficient cells represses RNA Pol I transcription, while decreasing PTEN expression enhances transcription. PTEN-mediated repression requires its lipid phosphatase activity and is independent of the p53 status of the cell. This event can be uncoupled from PTEN's ability to regulate the cell cycle. RNA Pol I is regulated through PI3 kinase/Akt/mammalian target of rapamycin/S6 kinase, and the expression of constitutively activated S6 kinase is able to abrogate transcription repression by PTEN. No change in the expression of the RNA Pol I transcription components, upstream binding factor or SL1, was observed upon PTEN expression. However, chromatin immunoprecipitation assays demonstrate that PTEN differentially reduces the occupancy of the SL1 subunits on the rRNA gene promoter. Furthermore, PTEN induces dissociation of the SL1 subunits. Together, these results demonstrate that PTEN represses RNA Pol I transcription through a novel mechanism that involves disruption of the SL1 complex.
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PMID:PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex. 1605 4

The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2alpha plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2alpha phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting approximately 90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2alpha, suggesting that this pathway may be broadly utilized by stresses that activate eIF2alpha kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.
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PMID:Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. 1947 Jul 60

Target of rapamycin (TOR) is a conserved regulator of gene expression from yeast to humans. In budding yeast, TOR is associated with ribosomal DNA (rDNA) promoter, which is critical for ribosome biogenesis and transfer RNA (tRNA) synthesis. Whether mTOR behaves similarly in mammalian cells is unknown. Here, we report that mTOR is detected at several different promoters in human and murine cells, including that of rDNA and tRNA genes. The association of mTOR with these promoters is regulated by growth signals and sensitive to rapamycin. Together, our observations suggest that mTOR is closely involved in gene regulation at the promoters, which is a conserved mechanism to control RNA polymerase I- and III-dependent genes that are critical for protein synthesis and cell growth.
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PMID:mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. 2034 49

The mammalian target of rapamycin (mTOR) regulates growth via promoting translation and transcription. Here, employing an mTOR active-site inhibitor WYE-125132 (WYE-132), we have performed quantitative phospho-proteomics and identified a Ser-75-containing phosphopeptide from Maf1, a known repressor of RNA polymerase III (Pol III) transcription. Treatment of cancer cells with WYE-132 or the rapamycin analog CCI-779 led to a rapid loss of the phosphorylation at Ser-75, whereas this effect was not seen in cells treated with cytotoxic agents or unrelated inhibitors. WYE-132-induced Maf1 dephosphorylation correlated with its accumulation in the nucleus and a marked decline in the cellular levels of pre-tRNAs. Depletion of cellular Maf1 via small interfering RNA increased basal pre-tRNA and rendered tRNA synthesis refractory to mTOR inhibitors. Maf1 mutant proteins carrying S75A alone or with S60A, T64A, and S68A (Maf1-S75A, Maf1-4A) progressively enhanced basal repression of tRNA in actively proliferating cells and attenuated amino acid-induced tRNA transcription. Gene alignment revealed conservation of all four Ser/Thr sites in high eukaryotes, further supporting a critical role of these residues in Maf1 function. Interestingly, mTOR inhibition led to an increase in the occupancy of Maf1 on a set of Pol III-dependent genes, with concomitant reduction in the binding of Pol III and Brf1. Unexpectedly, mTORC1 itself was also enriched at the same set of Pol III templates, but this association was not influenced by mTOR inhibitor treatment. Our results highlight a new and unique mode of regulation of Pol III transcription by mTOR and suggest that normalization of Pol III activity may contribute to the therapeutic efficacy of mTOR inhibitors.
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PMID:Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells. 2023 13

Yeast and mammalian MAF1 are both regulated by the TOR (target of rapamycin) pathway. However, the exact mechanisms of regulation diverge at TOR, with yeast Maf1 phosphorylated mainly by the TORC1 (TOR complex 1) substrate Sch9 kinase and mammalian MAF1 by mTORC1 (mammalian target of rapamycin complex 1) itself. Sch9 phosphorylation of yeast Maf1 regulates Maf1 localization, but it is less clear whether phosphorylation of human MAF1 regulates its localization. Replacement of phosphosites with alanine decreases Pol III (RNA polymerase III) transcription, but the effect is much more pronounced for human MAF1 than for the yeast protein. In both cases, Pol III repression can be further increased by rapamycin treatment or, in mammalian cells, serum starvation, suggesting that the TOR pathway controls another aspect of Pol III transcription that is closely linked to MAF1, as it depends on the presence of MAF1.
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PMID:MAF1: a new target of mTORC1. 2142 25

Precise regulation of ribosome biogenesis is fundamental to maintain normal cell growth and proliferation, and accelerated ribosome biogenesis is associated with malignant transformation. Here, we show that the kinase AKT regulates ribosome biogenesis at multiple levels to promote ribosomal RNA (rRNA) synthesis. Transcription elongation by RNA polymerase I, which synthesizes rRNA, required continuous AKT-dependent signaling, an effect independent of AKT's role in activating the translation-promoting complex mTORC1 (mammalian target of rapamycin complex 1). Sustained inhibition of AKT and mTORC1 cooperated to reduce rRNA synthesis and ribosome biogenesis by additionally limiting RNA polymerase I loading and pre-rRNA processing. In the absence of growth factors, constitutively active AKT increased synthesis of rRNA, ribosome biogenesis, and cell growth. Furthermore, AKT cooperated with the transcription factor c-MYC to synergistically activate rRNA synthesis and ribosome biogenesis, defining a network involving AKT, mTORC1, and c-MYC as a master controller of cell growth. Maximal activation of c-MYC-dependent rRNA synthesis in lymphoma cells required AKT activity. Moreover, inhibition of AKT-dependent rRNA transcription was associated with increased lymphoma cell death by apoptosis. These data indicate that decreased ribosome biogenesis is likely to be a fundamental component of the therapeutic response to AKT inhibitors in cancer.
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PMID:AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. 2187 79

Raptor is the key scaffolding protein that recruits mTOR substrates to rapamycin-sensitive mTOR complex 1 (mTORC1), a molecular integrator of mitogenic and nutrient/energy environmental inputs into protein translation and cell growth. Although Raptor phosphorylation on various sites is pivotal in the regulation of mTORC1 activity, it remains to be elucidated whether site-specific phosphorylation differentially distributes Raptor to unique subcellular compartments. When exploring the spatiotemporal cell cycle dynamics of six different phospho (P)-Raptor isoforms (Thr ( 706) , Ser ( 722) , Ser ( 863) , Ser ( 792) and Ser ( 877) ), a number of remarkable events differentially defined a topological resetting of P-RaptorThr706 on interphasic and mitotic chromosomes. In interphase nuclei, P-Raptor (Thr706) co-localized with fibrillarin, a component of the nucleolar small nuclear ribonucleoprotein particle, as well as with RNA polymerase I, the enzyme that transcribes nucleolar rRNA. Upon Actinomycin D-induced nucleolar segregation and disaggregation, P-RaptorThr706 was excluded from the nucleolus to accumulate at discrete nucleoplasmic bodies. During mitosis, CDK1 inhibition-induced premature assembly of nucleoli relocated fibrillarin to the surrounding regions of chromosomal-associated P-Raptor (Thr706) , suggesting that a subpopulation of mitotic P-Raptor (Thr706) remained targeted at chromosomal loops of rDNA or nuclear organizer regions (NORs). At the end of mitosis and cytokinesis, when reassembly of incipient nucleoli begins upon NORs activation of rDNA transcription, fibrillarin spatially reorganized with P-Raptor (Thr706) to give rise to daughter nucleoli. Treatment with IGF1 exclusively hyperactivated nuclear P-Raptor (Ser706) and concomitantly promoted Ser ( 2481) autophosphorylation of mTOR, which monitors mTORC1-associated catalytic activity. Nucleolar- and NOR-associated P-Raptor (Ser706) may physically link mTORC1 signaling to ever-growing nucleolus plurifunctionality including ribosome biogenesis, cell stress sensor and cell cycle/aging control.
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PMID:Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs). 2190 Jul 51


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