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1.
Nucleic Acids Res ; 49(1): 458-478, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33332560

RESUMEN

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1.


Asunto(s)
Autoantígenos/fisiología , Proteína I de Unión a Poli(A)/fisiología , Polirribosomas/metabolismo , Biosíntesis de Proteínas/fisiología , ARN Mensajero/metabolismo , Ribonucleoproteínas/fisiología , Serina-Treonina Quinasas TOR/fisiología , Regiones no Traducidas 5'/genética , Autoantígenos/genética , Regulación de la Expresión Génica , Genes Reporteros , Células HeLa , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Mutagénesis Sitio-Dirigida , Mutación Missense , Naftiridinas/farmacología , Mutación Puntual , Biosíntesis de Proteínas/genética , Interferencia de ARN , ARN Mensajero/genética , Proteínas de Unión al ARN/aislamiento & purificación , Proteínas de Unión al ARN/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Ribonucleoproteínas/genética , Antígeno SS-B
2.
Nucleic Acids Res ; 49(6): 3461-3489, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33398329

RESUMEN

LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5'TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1's translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation, but only in conditions of mTORC1 inhibition.


Asunto(s)
Autoantígenos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Biosíntesis de Proteínas , Ribonucleoproteínas/metabolismo , Secuencias de Aminoácidos , Autoantígenos/química , Células HEK293 , Humanos , Naftiridinas/farmacología , Fosforilación/efectos de los fármacos , Unión Proteica , Ribonucleoproteínas/química , Serina/metabolismo , Sirolimus/farmacología , Treonina/metabolismo , Tirosina/metabolismo , Antígeno SS-B
3.
Semin Cell Dev Biol ; 36: 102-12, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25263010

RESUMEN

Control of translation allows for the production of stoichiometric levels of each protein in the cell. Attaining such a level of fine-tuned regulation of protein production requires the coordinated temporal and spatial control of numerous cellular signalling cascades impinging on the various components of the translational machinery. Foremost among these is the mTOR signalling pathway. The mTOR pathway regulates both the initiation and elongation steps of protein synthesis through the phosphorylation of numerous translation factors, while simultaneously ensuring adequate folding of nascent polypeptides through co-translational degradation of misfolded proteins. Perhaps most remarkably, mTOR is also a key regulator of the synthesis of ribosomal proteins and translation factors themselves. Two seminal studies have recently shown in translatome analysis that the mTOR pathway preferentially regulates the translation of mRNAs encoding ribosomal proteins and translation factors. Therefore, the role of the mTOR pathway in the control of protein synthesis extends far beyond immediate translational control. By controlling ribosome production (and ultimately ribosome availability), mTOR is a master long-term controller of protein synthesis. Herein, we review the literature spanning the early discoveries of mTOR on translation to the latest advances in our understanding of how the mTOR pathway controls the synthesis of ribosomal proteins.


Asunto(s)
Biosíntesis de Proteínas/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Humanos , Iniciación de la Cadena Peptídica Traduccional/genética , Fosforilación , Pliegue de Proteína , ARN Mensajero/genética , Proteínas Ribosómicas/biosíntesis , Proteínas Ribosómicas/genética , Transducción de Señal/genética
4.
J Biol Chem ; 290(26): 15996-6020, 2015 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-25940091

RESUMEN

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1.


Asunto(s)
Autoantígenos/metabolismo , Regulación hacia Abajo , Glicoproteínas de Membrana/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/genética , Ribonucleoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autoantígenos/genética , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Glicoproteínas de Membrana/genética , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Unión Proteica , ARN Largo no Codificante , ARN Mensajero/química , ARN Mensajero/metabolismo , Proteína Reguladora Asociada a mTOR , Ribonucleoproteínas/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Antígeno SS-B
5.
Biochem Soc Trans ; 42(4): 1135-40, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25110015

RESUMEN

miRNA strand selection is the process that determines which of the two strands in a miRNA duplex becomes the active strand that is incorporated into the RISC (RNA-induced silencing complex) (named the guide strand, leading strand or miR) and which one gets degraded (the passenger strand or miR*). Thermodynamic features of the duplex appear to play an important role in this decision; the strand with the weakest binding at its 5'-end is more likely to become the guide strand. Other key characteristics of human miRNA guide strands are a U-bias at the 5'-end and an excess of purines, whereas the passenger strands have a C-bias at the 5'-end and an excess of pyrimidines. Several proteins are known to play a role in strand selection [Ago (Argonaute), DICER, TRBP (trans-activation response RNA-binding protein), PACT (protein activator of dsRNA-dependent protein kinase) and Xrn-1/2]; however, the mechanisms by which these proteins act are largely unknown. For several miRNAs the miR/miR* ratio varies dependent on cell type, developmental stage and in different disease states, suggesting that strand selection is a tightly controlled process. The present review discusses our current knowledge regarding the factors and processes involved in strand selection and the many questions that still remain.


Asunto(s)
MicroARNs/metabolismo , Humanos , MicroARNs/química , Modelos Biológicos , Purinas/metabolismo , Termodinámica
6.
Biochem J ; 442(3): 681-92, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22216903

RESUMEN

eEF2K [eEF2 (eukaryotic elongation factor 2) kinase] phosphorylates and inactivates the translation elongation factor eEF2. eEF2K is not a member of the main eukaryotic protein kinase superfamily, but instead belongs to a small group of so-called α-kinases. The activity of eEF2K is normally dependent upon Ca(2+) and calmodulin. eEF2K has previously been shown to undergo autophosphorylation, the stoichiometry of which suggested the existence of multiple sites. In the present study we have identified several autophosphorylation sites, including Thr(348), Thr(353), Ser(366) and Ser(445), all of which are highly conserved among vertebrate eEF2Ks. We also identified a number of other sites, including Ser(78), a known site of phosphorylation, and others, some of which are less well conserved. None of the sites lies in the catalytic domain, but three affect eEF2K activity. Mutation of Ser(78), Thr(348) and Ser(366) to a non-phosphorylatable alanine residue decreased eEF2K activity. Phosphorylation of Thr(348) was detected by immunoblotting after transfecting wild-type eEF2K into HEK (human embryonic kidney)-293 cells, but not after transfection with a kinase-inactive construct, confirming that this is indeed a site of autophosphorylation. Thr(348) appears to be constitutively autophosphorylated in vitro. Interestingly, other recent data suggest that the corresponding residue in other α-kinases is also autophosphorylated and contributes to the activation of these enzymes [Crawley, Gharaei, Ye, Yang, Raveh, London, Schueler-Furman, Jia and Cote (2011) J. Biol. Chem. 286, 2607-2616]. Ser(366) phosphorylation was also detected in intact cells, but was still observed in the kinase-inactive construct, demonstrating that this site is phosphorylated not only autocatalytically but also in trans by other kinases.


Asunto(s)
Quinasa del Factor 2 de Elongación/metabolismo , Calmodulina/metabolismo , Dominio Catalítico , Quinasa del Factor 2 de Elongación/química , Quinasa del Factor 2 de Elongación/genética , Células HEK293 , Humanos , Fosforilación , Serina/genética , Treonina/genética
7.
EMBO J ; 27(7): 1005-16, 2008 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-18337751

RESUMEN

The calcium/calmodulin-dependent kinase that phosphorylates and inactivates eukaryotic elongation factor 2 (eEF2 kinase; eEF2K) is subject to multisite phosphorylation, which regulates its activity. Phosphorylation at Ser359 inhibits eEF2K activity even at high calcium concentrations. To identify the kinase that phosphorylates Ser359 in eEF2K, we developed an extensive purification protocol. Tryptic mass fingerprint analysis identified it as cdc2 (cyclin-dependent kinase 1). cdc2 co-purifies with Ser359 kinase activity and cdc2-cyclin B complexes phosphorylate eEF2K at Ser359. We demonstrate that cdc2 contributes to controlling eEF2 phosphorylation in cells. cdc2 is activated early in mitosis. Kinase activity against Ser359 in eEF2K also peaks at this stage of the cell cycle and eEF2 phosphorylation is low in mitotic cells. Inactivation of eEF2K by cdc2 may serve to keep eEF2 active during mitosis (where calcium levels rise) and thereby permit protein synthesis to proceed in mitotic cells. Amino-acid starvation decreases cdc2's activity against eEF2K, whereas loss of TSC2 (a negative regulator of mammalian target of rapamycin complex 1(mTORC1)) increases it. These data closely match the control of Ser359 phosphorylation and indicate that cdc2 may be regulated by mTORC1.


Asunto(s)
Aminoácidos/metabolismo , Proteína Quinasa CDC2/metabolismo , Ciclo Celular , Ciclina B/metabolismo , Quinasa del Factor 2 de Elongación/metabolismo , Animales , Bioensayo , Proteína Quinasa CDC2/antagonistas & inhibidores , Proteína Quinasa CDC2/aislamiento & purificación , Ciclo Celular/efectos de los fármacos , Ciclina B/aislamiento & purificación , Activación Enzimática/efectos de los fármacos , Fase G2/efectos de los fármacos , Células HeLa , Humanos , Leucina/metabolismo , Ratones , Proteína Quinasa 13 Activada por Mitógenos/metabolismo , Mitosis/efectos de los fármacos , Modelos Biológicos , Factor 2 de Elongación Peptídica/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Quinasas/metabolismo , Purinas/farmacología , Roscovitina , Serina/metabolismo , Especificidad por Sustrato/efectos de los fármacos , Serina-Treonina Quinasas TOR , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/metabolismo
8.
Cancer Discov ; 11(5): 1228-1247, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33328217

RESUMEN

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.


Asunto(s)
Neoplasias Colorrectales/genética , Factor 4E Eucariótico de Iniciación/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Inhibidores mTOR/farmacología , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Animales , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo
9.
Arterioscler Thromb Vasc Biol ; 29(1): 92-8, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18988891

RESUMEN

OBJECTIVE: Macrophage survival and proliferation is believed to be a contributing factor in the development of early atherosclerotic lesions. Oxidized low density lipoprotein (oxLDL), a key mediator in the pathogenesis of this disease, has been shown to block apoptosis in macrophages deprived of growth factor. In this report, we investigate the mechanism of oxLDL-mediated macrophage survival. METHODS AND RESULTS: OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca(2+)](i)). We also show that the calcium/calmodulin dependent kinase, eukaryotic elongation factor-2 kinase (eEF2 kinase), is activated in response to oxLDL, an effect that can be blocked by inhibiting calcium mobilization. Furthermore, selective inhibition of eEF2 kinase reverses the prosurvival effect of oxLDL and results in cellular apoptosis. p38 MAP kinase, a negative regulator of eEF2 kinase, is activated on growth factor withdrawal, a response that can be inhibited by oxLDL. Finally, we show that oxLDL, by activating eEF2 kinase, phosphorylates and therefore inhibits eEF2, resulting in an overall decrease in protein synthesis. CONCLUSIONS: These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase.


Asunto(s)
Quinasa del Factor 2 de Elongación/metabolismo , Lipoproteínas LDL/fisiología , Macrófagos/citología , Animales , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Calcio/fisiología , Supervivencia Celular/efectos de los fármacos , Ceramidas/farmacología , Quinasa del Factor 2 de Elongación/aislamiento & purificación , Femenino , Proteínas HSP90 de Choque Térmico/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Peroxidasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
10.
Nat Commun ; 9(1): 532, 2018 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-29416038

RESUMEN

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN/metabolismo , ARN/metabolismo , Ribonucleasa III/metabolismo , Células A549 , Línea Celular Tumoral , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ADN/genética , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Perfilación de la Expresión Génica , Recombinación Homóloga , Humanos , ARN/genética , Interferencia de ARN , Ribonucleasa III/genética
11.
J Biol Chem ; 282(34): 24514-24, 2007 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-17604271

RESUMEN

Signaling through the mammalian target of rapamycin complex 1 (mTORC1) is positively regulated by amino acids and insulin. PRAS40 associates with mTORC1 (which contains raptor) but not mTORC2. PRAS40 interacts with raptor, and this requires an intact TOR-signaling (TOS) motif in PRAS40. Like TOS motif-containing proteins such as eIF4E-binding protein 1 (4E-BP1), PRAS40 is a substrate for phosphorylation by mTORC1. Consistent with this, starvation of cells of amino acids or treatment with rapamycin alters the phosphorylation of PRAS40. PRAS40 binds 14-3-3 proteins, and this requires both amino acids and insulin. Binding of PRAS40 to 14-3-3 proteins is inhibited by TSC1/2 (negative regulators of mTORC1) and stimulated by Rheb in a rapamycin-sensitive manner. This confirms that PRAS40 is a target for regulation by mTORC1. Small interfering RNA-mediated knockdown of PRAS40 impairs both the amino acid- and insulin-stimulated phosphorylation of 4E-BP1 and the phosphorylation of S6. However, this has no effect on the phosphorylation of Akt or TSC2 (an Akt substrate). These data place PRAS40 downstream of mTORC1 but upstream of its effectors, such as S6K1 and 4E-BP1.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiología , Proteínas Quinasas S6 Ribosómicas/metabolismo , Factores de Transcripción/metabolismo , Proteínas 14-3-3/metabolismo , Proteínas de Ciclo Celular , Línea Celular , Células HeLa , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Modelos Biológicos , Complejos Multiproteicos , Mutación , Fosforilación , Unión Proteica , Proteínas , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Sirolimus/farmacología , Serina-Treonina Quinasas TOR
12.
J Biol Chem ; 280(19): 18717-27, 2005 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-15772076

RESUMEN

Amino acids positively regulate signaling through the mammalian target of rapamycin (mTOR). Recent work demonstrated the importance of the tuberous sclerosis protein TSC2 for regulation of mTOR by insulin. TSC2 contains a GTPase-activator domain that promotes hydrolysis of GTP bound to Rheb, which positively regulates mTOR signaling. Some studies have suggested that TSC2 also mediates the control of mTOR by amino acids. In cells lacking TSC2, amino acid withdrawal still results in dephosphorylation of S6K1, ribosomal protein S6, the eukaryotic initiation factor 4E-binding protein, and elongation factor-2 kinase. The effects of amino acid withdrawal are diminished by inhibiting protein synthesis or adding back amino acids. These studies demonstrate that amino acid signaling to mTOR occurs independently of TSC2 and involves additional unidentified inputs. Although TSC2 is not required for amino acid control of mTOR, amino acid withdrawal does decrease the proportion of Rheb in the active GTP-bound state. Here we also show that Rheb and mTOR form stable complexes, which are not, however, disrupted by amino acid withdrawal. Mutants of Rheb that cannot bind GTP or GDP can interact with mTOR complexes. We also show that the effects of hydrogen peroxide and sorbitol, cell stresses that impair mTOR signaling, are independent of TSC2. Finally, we show that the ability of energy depletion (which impairs mTOR signaling in TSC2+/+ cells) to increase the phosphorylation of eukaryotic elongation factor 2 is also independent of TSC2. This likely involves the phosphorylation of the elongation factor-2 kinase by the AMP-activated protein kinase.


Asunto(s)
Aminoácidos/metabolismo , Proteínas de Unión al GTP Monoméricas/fisiología , Neuropéptidos/fisiología , Proteínas Quinasas/metabolismo , Proteínas Represoras/fisiología , Proteínas Supresoras de Tumor/fisiología , Proteínas Quinasas Activadas por AMP , Proteínas Adaptadoras Transductoras de Señales , Adenosina Trifosfato/química , Aminoácidos/química , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Portadoras/química , Proteínas de Ciclo Celular , Línea Celular , Células Cultivadas , Cicloheximida/farmacología , Relación Dosis-Respuesta a Droga , Quinasa del Factor 2 de Elongación , Factores Eucarióticos de Iniciación , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Glucosa/química , Guanina/química , Guanosina Difosfato/química , Guanosina Trifosfato/química , Humanos , Peróxido de Hidrógeno/farmacología , Hidrólisis , Immunoblotting , Inmunoprecipitación , Ratones , Modelos Biológicos , Proteínas de Unión al GTP Monoméricas/química , Proteínas de Unión al GTP Monoméricas/metabolismo , Complejos Multienzimáticos/metabolismo , Mutación , Neuropéptidos/química , Neuropéptidos/metabolismo , Fosfoproteínas/química , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Inhibidores de la Síntesis de la Proteína/farmacología , Proteína Homóloga de Ras Enriquecida en el Cerebro , Proteínas Represoras/metabolismo , Proteína S6 Ribosómica/metabolismo , Transducción de Señal , Sorbitol/farmacología , Serina-Treonina Quinasas TOR , Factores de Tiempo , Transgenes , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/metabolismo
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