Base de dados : MEDLINE
Pesquisa : D08.811.682.047.820.150.415.250 [Categoria DeCS]
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[Au] Autor:Sorrentino G; Ruggeri N; Specchia V; Cordenonsi M; Mano M; Dupont S; Manfrin A; Ingallina E; Sommaggio R; Piazza S; Rosato A; Piccolo S; Del Sal G
[Ad] Endereço:1] Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy [2] Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
[Ti] Título:Metabolic control of YAP and TAZ by the mevalonate pathway.
[So] Source:Nat Cell Biol;16(4):357-66, 2014 Apr.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate-YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas de Drosophila/metabolismo
Ácido Mevalônico/metabolismo
Proteínas Nucleares/metabolismo
Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/fisiologia
Neoplasias da Mama/metabolismo
Proliferação Celular
Proteínas de Drosophila/genética
Drosophila melanogaster/metabolismo
Células HCT116
Células HEK293
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Hidroximetilglutaril-CoA Redutases NAD-Dependentes/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas Nucleares/genética
Fosfatos de Poli-Isoprenil/biossíntese
Fosfatos de Poli-Isoprenil/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Interferência de RNA
RNA Interferente Pequeno
Transdução de Sinais
Proteínas de Ligação a Elemento Regulador de Esterol/genética
Fatores de Transcrição/metabolismo
Transcrição Genética
Proteínas Supressoras de Tumor/genética
Proteínas rho de Ligação ao GTP/metabolismo
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Drosophila Proteins); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Intracellular Signaling Peptides and Proteins); 0 (Nuclear Proteins); 0 (Phosphoproteins); 0 (Polyisoprenyl Phosphates); 0 (Pyridines); 0 (RNA, Small Interfering); 0 (Sterol Regulatory Element Binding Proteins); 0 (TAZ protein, human); 0 (Trans-Activators); 0 (Transcription Factors); 0 (Tumor Suppressor Proteins); 0 (YAP1 (Yes-associated) protein, human); 0 (Yorkie protein, Drosophila); 0 (tazman protein, Drosophila); AM91H2KS67 (cerivastatin); EC (Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent); EC 2.7.1.- (LATS1 protein, human); EC (LATS2 protein, human); EC (Protein-Serine-Threonine Kinases); EC (hpo protein, Drosophila); EC (rho GTP-Binding Proteins); N21T0D88LX (geranylgeranyl pyrophosphate); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1406
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140325
[St] Status:MEDLINE
[do] DOI:10.1038/ncb2936

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[Au] Autor:Ma SM; Garcia DE; Redding-Johanson AM; Friedland GD; Chan R; Batth TS; Haliburton JR; Chivian D; Keasling JD; Petzold CJ; Lee TS; Chhabra SR
[Ad] Endereço:Joint BioEnergy Institute, Emeryville, CA, USA.
[Ti] Título:Optimization of a heterologous mevalonate pathway through the use of variant HMG-CoA reductases.
[So] Source:Metab Eng;13(5):588-97, 2011 Sep.
[Is] ISSN:1096-7184
[Cp] País de publicação:Belgium
[La] Idioma:eng
[Ab] Resumo:Expression of foreign pathways often results in suboptimal performance due to unintended factors such as introduction of toxic metabolites, cofactor imbalances or poor expression of pathway components. In this study we report a 120% improvement in the production of the isoprenoid-derived sesquiterpene, amorphadiene, produced by an engineered strain of Escherichia coli developed to express the native seven-gene mevalonate pathway from Saccharomyces cerevisiae (Martin et al. 2003). This substantial improvement was made by varying only a single component of the pathway (HMG-CoA reductase) and subsequent host optimization to improve cofactor availability. We characterized and tested five variant HMG-CoA reductases obtained from publicly available genome databases with differing kinetic properties and cofactor requirements. The results of our in vitro and in vivo analyses of these enzymes implicate substrate inhibition of mevalonate kinase as an important factor in optimization of the engineered mevalonate pathway. Consequently, the NADH-dependent HMG-CoA reductase from Delftia acidovorans, which appeared to have the optimal kinetic parameters to balance HMG-CoA levels below the cellular toxicity threshold of E. coli and those of mevalonate below inhibitory concentrations for mevalonate kinase, was identified as the best producer for amorphadiene (54% improvement over the native pathway enzyme, resulting in 2.5mM or 520 mg/L of amorphadiene after 48 h). We further enhanced performance of the strain bearing the D. acidovorans HMG-CoA reductase by increasing the intracellular levels of its preferred cofactor (NADH) using a NAD(+)-dependent formate dehydrogenase from Candida boidinii, along with formate supplementation. This resulted in an overall improvement of the system by 120% resulting in 3.5mM or 700 mg/L amorphadiene after 48 h of fermentation. This comprehensive study incorporated analysis of several key parameters for metabolic design such as in vitro and in vivo kinetic performance of variant enzymes, intracellular levels of protein expression, in-pathway substrate inhibition and cofactor management to enable the observed improvements. These metrics may be applied to a broad range of heterologous pathways for improving the production of biologically derived compounds.
[Mh] Termos MeSH primário: Proteínas de Bactérias
Delftia acidovorans
Escherichia coli
Hidroximetilglutaril-CoA Redutases NAD-Dependentes/biossíntese
Ácido Mevalônico/metabolismo
Organismos Geneticamente Modificados
[Mh] Termos MeSH secundário: Proteínas de Bactérias/biossíntese
Proteínas de Bactérias/genética
Delftia acidovorans/enzimologia
Delftia acidovorans/genética
Escherichia coli/genética
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/metabolismo
Formiato Desidrogenases/biossíntese
Formiato Desidrogenases/genética
Proteínas Fúngicas/biossíntese
Proteínas Fúngicas/genética
Hidroximetilglutaril-CoA Redutases NAD-Dependentes/genética
Organismos Geneticamente Modificados/genética
Organismos Geneticamente Modificados/crescimento & desenvolvimento
Organismos Geneticamente Modificados/metabolismo
Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese
Fosfotransferases (Aceptor do Grupo Álcool)/genética
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Formates); 0 (Fungal Proteins); 0 (Sesquiterpenes); 0 (amorpha-4,11-diene); 0YIW783RG1 (formic acid); EC (Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent); EC (Formate Dehydrogenases); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC (mevalonate kinase); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1111
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110804
[St] Status:MEDLINE
[do] DOI:10.1016/j.ymben.2011.07.001

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