1st Andrés Laguna Master Lecture. Metabolism of cell division: Discovery and perspectives

Moncada, S.S.

doi:10.1016/j.rceng.2013.07.008

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Metabolism of cell division: Discovery and perspectives" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1440 "Ancho" => 1208 "Tamanyo" => 110788 ] ] "descripcion" => array:1 [ "es" => "Metabolismo de la glucosa en los astrocitos. Tras la inhibición de la respiración mitocondrial por medio de óxido nítrico se produce una disminución de la concentración de ATP y la consiguiente fosforilación de la proteincinasa activada por AMP (AMPK). Esto da lugar a la activación de la 6-fosfofructo-2-cinasa/fructosa-2,6-bisfosfatasa (PFKFB) y a una mayor generación de fructosa-2-6-bifosfato que da como resultado la sobrerregulación de la glucólisis mediada por 6-fosfofructo-1-cinasa (PFK1)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sir Salvador Moncada" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Sir Salvador" "apellidos" => "Moncada" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2254887413001100" "doi" => "10.1016/j.rceng.2013.07.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887413001100?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256513002233?idApp=WRCEE" "url" => "/00142565/0000021300000008/v1_201310250818/S0014256513002233/v1_201310250818/es/main.assets" ] ] "itemAnterior" => array:19 [ "pii" => "S2254887413001069" "issn" => "22548874" "doi" => "10.1016/j.rceng.2013.07.005" "estado" => "S300" "fechaPublicacion" => "2013-11-01" "aid" => "781" "copyright" => "Elsevier España, S.L." 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"apellidos" => "de la Sierra" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256513001690" "doi" => "10.1016/j.rce.2013.05.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256513001690?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887413001069?idApp=WRCEE" "url" => "/22548874/0000021300000008/v1_201310250817/S2254887413001069/v1_201310250817/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "1st Andrés Laguna Master Lecture. Metabolism of cell division: Discovery and perspectives" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "399" "paginaFinal" => "402" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "S.S. Moncada" "autores" => array:1 [ 0 => array:3 [ "nombre" => "S.S." "apellidos" => "Moncada" "email" => array:1 [ 0 => "j_a_gutierrez@network.lilly.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "University College of London, London, UK" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "I Lección Magistral Andrés Laguna. Metabolismo de la división celular: descubrimiento y perspectivas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1721 "Ancho" => 1659 "Tamanyo" => 175355 ] ] "descripcion" => array:1 [ "en" => "Metabolic control of cell proliferation. Both 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) and glutaminase 1 (GLS1) are regulated by the anaphase-promoting complex (APC/C), an ubiquitin ligase, when coupled to its Cdh1 activator. A reduction in the APC/C-Cdh1 activity releases both enzymes, so that PFKFB3 can over-regulate glycolysis and GLS1 can activate glutaminolysis. Thus, both metabolic pathways are coordinated with the cell cycle." ] ] ] "textoCompleto" => "Andrés Laguna Master LessonIt is a great honor and pleasure for me to have been invited to give this first Andrés Lagoon Master Lecture as part of the celebration of the life and work of this distinguished Spanish physician and scholar who lived during the first half of the 16th century. In addition to being a physician, this traveler and poet also trained and graduated as a botanist, politician, diplomat, humanist and linguist, as so elegantly described in the book “Vida y obra del doctor Andrés Laguna” (Life and Work of Dr. Andrés Lagoon).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Over the years, my research interests have focused on drugs similar to aspirin, prostacyclins, nitric oxide and, more recently, cell proliferation, which is the topic of this conference.As a continuation of our work on the inhibitory effect of nitric oxide on mitochondrial respiration, and in collaboration with Juan Bolaños and Ángeles Almeida, we have observed that astrocytes, but not neurons, respond to respiration inhibition with an increase in their glycolytic metabolism. In addition, they use the ATP (adenosine 5′-triphosphate) generated by the glycolytic pathway to maintain their mitochondrial membrane potential and, thereby, their viability.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Subsequent studies have demonstrated that, in contrast to neurons, astrocytes have increased activity of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) after respiration inhibition. This enzyme generates fructose-2,6-bisphosphate (Fru-2,6-P2), a potent allosteric activator of 6-phosphofructo-1-kinase (PFK1), which is a key regulator of glycolysis. PFKFB silencing suppressed the astrocytes’ ability to over-regulate glycolysis in response to respiration inhibition. By using the small interfering RNA (siRNA) strategy, we showed that respiration inhibition results in a change in the AMP (adenosine 5′-monophoshate) to ATP ratio and in the resulting phosphorylation (activation) of the AMP-activated protein kinase (AMPK). This results in the activation of PFKFB, increased glycolysis regulation and increased protection of the cells against apoptosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0015">3</a> As a result, the virtual absence of PFKFB in the neurons could explain their extreme susceptibility to energy depletion and degeneration.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Following these findings, we found that PFKFB3 (the specific isoform present in astrocytes), unlike other PFKFB isoforms, contains a KEN box that begins at position 142.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> This fact identifies the proteins for their ubiquitination by the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase, when this binds to its activator Cdh1.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> We have shown that the PFKFB3 of neurons is constantly subjected to proteasomal degradation by the APC/C-Cdh1 action. This explains why the PFKFB3 protein is absent in neurons despite the fact that the neurons express their messenger ribonucleic acid (mRNA). It also explains why glycolysis over-regulation is not produced in these cells.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> We found that neurons use glucose to produce the antioxidant glutathione using the pentose phosphate pathway. Therefore, through the active reduction of glycolysis regulation by APC/C-Cdh1, the neurons use glucose to maintain their antioxidant state at the expense of the use of glucose for bioenergetic purposes.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>APC/C plays an essential role in cell proliferation through cell cycle protein degradation. When combined with its Cdc20 activator, APC/C regulates the proteins responsible for the transition between the metaphase and the anaphase. When combined with Cdh1, APC/C is responsible for the destruction of cyclins in the early G1 phase of the cycle. To start phase S, during which chromosomal replication takes place, APC/C-Cdh1 inactivation must take place at a critical point in the G1 phase, known as the restriction point (R). The restriction point is known to be sensitive both to growth factors and to nutrients.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> The fact that PFKFB3 is an APC/C-Cdh1 substrate has led us to demonstrate that its degradation by means of the ubiquitin ligase could be an integral part of the G1 phase of the cell cycle and that an increase in PFKFB3 after the reduction of APC/C-Cdh1 that is produced in the mid to late G1 phase could be the mechanism coordinating the glucose supply with all the other necessary steps for the progression to phase S.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Our research subsequently showed in 2 different cell types (neoplastic and non-neoplastic cells) that, through Cdh1 over-expression, both cell proliferation and glycolysis are inhibited, while the same are enhanced by means of their silencing. Using a form of PFKFB3 with a mutation in its KEN box (which makes it resistant to APC/C-Cdh1 ubiquitination), we demonstrated that even though glycolysis is essential for cellular proliferation, glycolysis by itself does not result in cell proliferation in the presence of high concentrations of Cdh1.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> These results were confirmed in human T lymphocyte proliferation studies,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> thereby demonstrating that the mechanism involved in this process is the same for the proliferation of recently isolated normal cells and is not a phenomenon limited to certain cell lines, either cancerous or normal. These studies also established that, as with cyclins, PFKFB3 activity during the cell cycle depends on 2 stages. The first stage requires gene expression and the subsequent protein synthesis, both of which take place in early phases. The enzyme generated in this manner is continuously ubiquitinated until it is activated when APC/C-Cdh1 levels decrease during the mid to late G1 phase.Glutamine, through its conversion to glutamate and subsequent processing in the tricarboxylic acid (TCA) cycle, is a key contributor of glucose in cell proliferation.<a class="elsevierStyleCrossRefs" href="#bib0050">10,11</a> The first stage of glutaminolysis (the conversion of glutamine to glutamate and the generation of ammonia from the amide substrate group) has glutaminase (GLS) as the catalytic enzyme, whose 2 isoforms contain KEN boxes. This fact led us to search for and identify GLS as the target for APC/C-Cdh1.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> We found that the most abundant form in human lymphocyte proliferation is GLS1, the isoenzyme that is most frequently associated with cancer cell proliferation.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Our experiments with lymphocyte proliferation showed that GLS1 accumulation occurred as APC/C-Cdh1 levels decreased and coincided with increased use of glutamine and with increased glycolysis. Therefore, decreased APC/C-Cdh1 activity releases not only PFKFB3 to activate glycolysis allosterically through the synthesis of fructose 2,6-biphosphate but also GLS1 to activate glutaminolysis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). This explains the simultaneous increase in the use of both substrates during cell proliferation, as reported many years ago.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Cdh1 overexpression decreased both the proliferative response and the use of glutamine. The concomitant overexpression of a mutated form of GLS1, which was no longer a APC/C-Cdh1 substrate, restored the production of ammonia, but not the proliferative response.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> We also found that even though GLS1 is ubiquitinated by APC/C-Cdh1, GLS1 differs from PFKFB3 in that, in order for it to be recognized by this ubiquitin ligase, the presence of a KEN box and a D box is necessary, instead of just a KEN box.<a class="elsevierStyleCrossRef" href="#bib0065">13</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>In order to correlate more precisely the emergence of these metabolic enzymes with a specific cell proliferation stage, we decided to use cells that had been synchronized using standardized procedures. Thus, we correlated the presence of PFKFB3 and GLS1 with the cell cycle progression in HeLa cells treated with either double thymidine block (DTB) or DTB and nocodazole for its synchronization at the G1/S or G2/M limit, respectively. We found that the protein PFKFB3 levels, which were initially below the limits of detection, increased abruptly in the mid to late G1 phase after the disappearance of Cdh1. This PFKFB3 peak had a brief duration (only 2–4h) and was correlated with the transient increased generation of lactate.<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a> We showed that the disappearance of PFKFB3 after the transition from G1 to S, when APC/C-Cdh1 was no longer active, was due to the action of the SCF-β-TrCP complex.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> We found that PFKFB3 also contains a consensus site for the recognition of the β-TrCP protein (the DSGXXS motif) and that Ser273 is the specific residue whose phosphorylation is necessary for the recognition of the protein by ubiquitin ligase<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a> at the start of phase S. As a result, the presence of PFKFB3 is firmly controlled to ensure over-regulation by increased glycolysis at a specific point in phase G1. In contrast, the use of synchronized HeLa cells showed that GLS1 is not a substrate for SCF-β-TrCP and is not degraded until the end of mitosis, at which point APC/C-Cdh1 reactivates. The use of glutamine in these experiments was correlated with increased protein GLS1 levels in the mid to late G1 phase, which remained high until GLS1 was degraded by APC/C-Cdh1.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> The opposite posttranslational regulation of PFKFB3 and GLS1, which we verified by means of ubiquitination and protein stability studies,<a class="elsevierStyleCrossRef" href="#bib0065">13</a> suggests that glycolysis and glutaminolysis play different roles during different stages of the cell cycle.Our studies demonstrated that the activity of a number of crucial metabolic enzymes “fluctuates” during the cell cycle in a manner similar to that of cyclins.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> It remains to be seen whether other proteins with consensus recognition motifs for APC/C-Cdh1 and SCF-β-TrCP fluctuate in a similar manner. The elucidation of the stages subsequent to the decrease in APC/C-Cdh1 activity is now of considerable importance, given that the progression through G1 is not only a central point for the coordination of cell cycle progression with the metabolism, but also a site where a high degree of deregulation occurs during neoplastic transformation.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Careful comparison between normal cells and proliferating cancer cells will indicate whether there are relevant differences that justify a “selective cancer” approach to therapy.Authorship<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Concept and design of the manuscript: S. Moncada.</li><li class="elsevierStyleListItem" id="lsti0010">2.Data collection: S. Moncada.</li><li class="elsevierStyleListItem" id="lsti0015">3.Data analysis and interpretation: S. Moncada.</li><li class="elsevierStyleListItem" id="lsti0020">4.Drafting, review and approval of the submitted manuscript: S. Moncada.</li></ul>Conflicts of interestThe author declares that he has no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Andrés Laguna Master Lesson" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Authorship" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflicts of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-06-04" "fechaAceptado" => "2013-06-05" "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Moncada SS. I Lección Magistral Andrés Laguna. Metabolismo de la división celular: descubrimiento y perspectivas. Rev Clin Esp. 2013;213:399–402." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "As part of the 1st Andrés Laguna Master Lecture, Auditorium of the University of Alcala. 18th of October, 2012." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2116 "Ancho" => 1666 "Tamanyo" => 101322 ] ] "descripcion" => array:1 [ "en" => "Glucose metabolism in the astrocytes. After mitochondrial respiration inhibition by means of nitric oxide, a reduction in ATP concentration is produced, with subsequent phosphorylation of the AMP-activated protein kinase (AMPK). This results in the activation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) and increased generation of fructose-2-6-biphosphate, which results in over-regulation of 6-phosphofructo-1-kinase (PFK1)-mediated glycolysis." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1721 "Ancho" => 1659 "Tamanyo" => 175355 ] ] "descripcion" => array:1 [ "en" => "Metabolic control of cell proliferation. Both 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) and glutaminase 1 (GLS1) are regulated by the anaphase-promoting complex (APC/C), an ubiquitin ligase, when coupled to its Cdh1 activator. A reduction in the APC/C-Cdh1 activity releases both enzymes, so that PFKFB3 can over-regulate glycolysis and GLS1 can activate glutaminolysis. Thus, both metabolic pathways are coordinated with the cell cycle." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Junta de Castilla y León. Consejería de Cultura y Bienestar Social. Gráficas Varona, Salamanca" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Vida y obra del doctor Andrés Laguna" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "1990" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A transient inhibition of mitochondrial ATP synthesis by nitric oxide synthase activation triggered apoptosis in primary cortical neurons" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Almeida" 1 => "J.P. Bolaños" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Neurochem" "fecha" => "2001" "volumen" => "77" "paginaInicial" => "676" "paginaFinal" => "690" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11299330" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0091674901716259" "estado" => "S300" "issn" => "00916749" ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Almeida" 1 => "S. Moncada" 2 => "J.P. Bolaños" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ncb1080" "Revista" => array:6 [ "tituloSerie" => "Nat Cell Biol" "fecha" => "2004" "volumen" => "6" "paginaInicial" => "45" "paginaFinal" => "51" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14688792" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Herrero-Méndez" 1 => "A. Almeida" 2 => "E. Fernández" 3 => "C. Maestre" 4 => "S. Moncada" 5 => "J.P. 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Hunt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Semin Cell Biol" "fecha" => "1991" "volumen" => "2" "paginaInicial" => "213" "paginaFinal" => "222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1842340" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genomic stability and tumour suppression by the APC/C cofactor Cdh1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. García-Higuera" 1 => "E. Manchado" 2 => "P. Dubus" 3 => "M. Canamero" 4 => "J. Méndez" 5 => "S. 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prostacyclins&#44; nitric oxide and&#44; more recently&#44; cell proliferation&#44; which is the topic of this conference&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">As a continuation of our work on the inhibitory effect of nitric oxide on mitochondrial respiration&#44; and in collaboration with Juan Bola&#241;os and &#193;ngeles Almeida&#44; we have observed that astrocytes&#44; but not neurons&#44; respond to respiration inhibition with an increase in their glycolytic metabolism&#46; In addition&#44; they use the ATP &#40;adenosine 5&#8242;-triphosphate&#41; generated by the glycolytic pathway to maintain their mitochondrial membrane potential and&#44; thereby&#44; their viability&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Subsequent studies have demonstrated that&#44; in contrast to neurons&#44; astrocytes have increased activity of 6-phosphofructo-2-kinase&#47;fructose-2&#44;6-bisphosphatase &#40;PFKFB&#41; after respiration inhibition&#46; This enzyme generates fructose-2&#44;6-bisphosphate &#40;Fru-2&#44;6-P2&#41;&#44; a potent allosteric activator of 6-phosphofructo-1-kinase &#40;PFK1&#41;&#44; which is a key regulator of glycolysis&#46; PFKFB silencing suppressed the astrocytes&#8217; ability to over-regulate glycolysis in response to respiration inhibition&#46; By using the small interfering RNA &#40;siRNA&#41; strategy&#44; we showed that respiration inhibition results in a change in the AMP &#40;adenosine 5&#8242;-monophoshate&#41; to ATP ratio and in the resulting phosphorylation &#40;activation&#41; of the AMP-activated protein kinase &#40;AMPK&#41;&#46; This results in the activation of PFKFB&#44; increased glycolysis regulation and increased protection of the cells against apoptosis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> As a result&#44; the virtual absence of PFKFB in the neurons could explain their extreme susceptibility to energy depletion and degeneration&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Following these findings&#44; we found that PFKFB3 &#40;the specific isoform present in astrocytes&#41;&#44; unlike other PFKFB isoforms&#44; contains a KEN box that begins at position 142&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This fact identifies the proteins for their ubiquitination by the anaphase-promoting complex&#47;cyclosome &#40;APC&#47;C&#41;&#44; the E3 ubiquitin ligase&#44; when this binds to its activator Cdh1&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> We have shown that the PFKFB3 of neurons is constantly subjected to proteasomal degradation by the APC&#47;C-Cdh1 action&#46; This explains why the PFKFB3 protein is absent in neurons despite the fact that the neurons express their messenger ribonucleic acid &#40;mRNA&#41;&#46; It also explains why glycolysis over-regulation is not produced in these cells&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> We found that neurons use glucose to produce the antioxidant glutathione using the pentose phosphate pathway&#46; Therefore&#44; through the active reduction of glycolysis regulation by APC&#47;C-Cdh1&#44; the neurons use glucose to maintain their antioxidant state at the expense of the use of glucose for bioenergetic purposes&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">APC&#47;C plays an essential role in cell proliferation through cell cycle protein degradation&#46; When combined with its Cdc20 activator&#44; APC&#47;C regulates the proteins responsible for the transition between the metaphase and the anaphase&#46; When combined with Cdh1&#44; APC&#47;C is responsible for the destruction of cyclins in the early G1 phase of the cycle&#46; To start phase S&#44; during which chromosomal replication takes place&#44; APC&#47;C-Cdh1 inactivation must take place at a critical point in the G1 phase&#44; known as the restriction point &#40;R&#41;&#46; The restriction point is known to be sensitive both to growth factors and to nutrients&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The fact that PFKFB3 is an APC&#47;C-Cdh1 substrate has led us to demonstrate that its degradation by means of the ubiquitin ligase could be an integral part of the G1 phase of the cell cycle and that an increase in PFKFB3 after the reduction of APC&#47;C-Cdh1 that is produced in the mid to late G1 phase could be the mechanism coordinating the glucose supply with all the other necessary steps for the progression to phase S&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Our research subsequently showed in 2 different cell types &#40;neoplastic and non-neoplastic cells&#41; that&#44; through Cdh1 over-expression&#44; both cell proliferation and glycolysis are inhibited&#44; while the same are enhanced by means of their silencing&#46; Using a form of PFKFB3 with a mutation in its KEN box &#40;which makes it resistant to APC&#47;C-Cdh1 ubiquitination&#41;&#44; we demonstrated that even though glycolysis is essential for cellular proliferation&#44; glycolysis by itself does not result in cell proliferation in the presence of high concentrations of Cdh1&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> These results were confirmed in human T lymphocyte proliferation studies&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> thereby demonstrating that the mechanism involved in this process is the same for the proliferation of recently isolated normal cells and is not a phenomenon limited to certain cell lines&#44; either cancerous or normal&#46; These studies also established that&#44; as with cyclins&#44; PFKFB3 activity during the cell cycle depends on 2 stages&#46; The first stage requires gene expression and the subsequent protein synthesis&#44; both of which take place in early phases&#46; The enzyme generated in this manner is continuously ubiquitinated until it is activated when APC&#47;C-Cdh1 levels decrease during the mid to late G1 phase&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Glutamine&#44; through its conversion to glutamate and subsequent processing in the tricarboxylic acid &#40;TCA&#41; cycle&#44; is a key contributor of glucose in cell proliferation&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> The first stage of glutaminolysis &#40;the conversion of glutamine to glutamate and the generation of ammonia from the amide substrate group&#41; has glutaminase &#40;GLS&#41; as the catalytic enzyme&#44; whose 2 isoforms contain KEN boxes&#46; This fact led us to search for and identify GLS as the target for APC&#47;C-Cdh1&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> We found that the most abundant form in human lymphocyte proliferation is GLS1&#44; the isoenzyme that is most frequently associated with cancer cell proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Our experiments with lymphocyte proliferation showed that GLS1 accumulation occurred as APC&#47;C-Cdh1 levels decreased and coincided with increased use of glutamine and with increased glycolysis&#46; Therefore&#44; decreased APC&#47;C-Cdh1 activity releases not only PFKFB3 to activate glycolysis allosterically through the synthesis of fructose 2&#44;6-biphosphate but also GLS1 to activate glutaminolysis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; This explains the simultaneous increase in the use of both substrates during cell proliferation&#44; as reported many years ago&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Cdh1 overexpression decreased both the proliferative response and the use of glutamine&#46; The concomitant overexpression of a mutated form of GLS1&#44; which was no longer a APC&#47;C-Cdh1 substrate&#44; restored the production of ammonia&#44; but not the proliferative response&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> We also found that even though GLS1 is ubiquitinated by APC&#47;C-Cdh1&#44; GLS1 differs from PFKFB3 in that&#44; in order for it to be recognized by this ubiquitin ligase&#44; the presence of a KEN box and a D box is necessary&#44; instead of just a KEN box&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">In order to correlate more precisely the emergence of these metabolic enzymes with a specific cell proliferation stage&#44; we decided to use cells that had been synchronized using standardized procedures&#46; Thus&#44; we correlated the presence of PFKFB3 and GLS1 with the cell cycle progression in HeLa cells treated with either double thymidine block &#40;DTB&#41; or DTB and nocodazole for its synchronization at the G1&#47;S or G2&#47;M limit&#44; respectively&#46; We found that the protein PFKFB3 levels&#44; which were initially below the limits of detection&#44; increased abruptly in the mid to late G1 phase after the disappearance of Cdh1&#46; This PFKFB3 peak had a brief duration &#40;only 2&#8211;4<span class="elsevierStyleHsp" style=""></span>h&#41; and was correlated with the transient increased generation of lactate&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> We showed that the disappearance of PFKFB3 after the transition from G1 to S&#44; when APC&#47;C-Cdh1 was no longer active&#44; was due to the action of the SCF-&#946;-TrCP complex&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> We found that PFKFB3 also contains a consensus site for the recognition of the &#946;-TrCP protein &#40;the DSGXXS motif&#41; and that Ser<span class="elsevierStyleSup">273</span> is the specific residue whose phosphorylation is necessary for the recognition of the protein by ubiquitin ligase<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> at the start of phase S&#46; As a result&#44; the presence of PFKFB3 is firmly controlled to ensure over-regulation by increased glycolysis at a specific point in phase G1&#46; In contrast&#44; the use of synchronized HeLa cells showed that GLS1 is not a substrate for SCF-&#946;-TrCP and is not degraded until the end of mitosis&#44; at which point APC&#47;C-Cdh1 reactivates&#46; The use of glutamine in these experiments was correlated with increased protein GLS1 levels in the mid to late G1 phase&#44; which remained high until GLS1 was degraded by APC&#47;C-Cdh1&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The opposite posttranslational regulation of PFKFB3 and GLS1&#44; which we verified by means of ubiquitination and protein stability studies&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> suggests that glycolysis and glutaminolysis play different roles during different stages of the cell cycle&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Our studies demonstrated that the activity of a number of crucial metabolic enzymes &#8220;fluctuates&#8221; during the cell cycle in a manner similar to that of cyclins&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> It remains to be seen whether other proteins with consensus recognition motifs for APC&#47;C-Cdh1 and SCF-&#946;-TrCP fluctuate in a similar manner&#46; The elucidation of the stages subsequent to the decrease in APC&#47;C-Cdh1 activity is now of considerable importance&#44; given that the progression through G1 is not only a central point for the coordination of cell cycle progression with the metabolism&#44; but also a site where a high degree of deregulation occurs during neoplastic transformation&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Careful comparison between normal cells and proliferating cancer cells will indicate whether there are relevant differences that justify a &#8220;selective cancer&#8221; approach to therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authorship</span><p id="par0045" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Concept and design of the manuscript&#58; S&#46; Moncada&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Data collection&#58; S&#46; Moncada&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Data analysis and interpretation&#58; S&#46; Moncada&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Drafting&#44; review and approval of the submitted manuscript&#58; S&#46; Moncada&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Moncada SS&#46; I Lecci&#243;n Magistral Andr&#233;s Laguna&#46; Metabolismo de la divisi&#243;n celular&#58; descubrimiento y perspectivas&#46; Rev Clin Esp&#46; 2013&#59;213&#58;399&#8211;402&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">As part of the <span class="elsevierStyleSmallCaps">1</span>st Andr&#233;s Laguna Master Lecture&#44; Auditorium of the University of Alcala&#46; 18th of October&#44; 2012&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Glucose metabolism in the astrocytes&#46; After mitochondrial respiration inhibition by means of nitric oxide&#44; a reduction in ATP concentration is produced&#44; with subsequent phosphorylation of the AMP-activated protein kinase &#40;AMPK&#41;&#46; This results in the activation of 6-phosphofructo-2-kinase&#47;fructose-2&#44;6-bisphosphatase &#40;PFKFB&#41; and increased generation of fructose-2-6-biphosphate&#44; which results in over-regulation of 6-phosphofructo-1-kinase &#40;PFK1&#41;-mediated glycolysis&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Metabolic control of cell proliferation&#46; Both 6-phosphofructo-2-kinase&#47;fructose-2&#44;6-bisphosphatase &#40;PFKFB&#41; and glutaminase 1 &#40;GLS1&#41; are regulated by the anaphase-promoting complex &#40;APC&#47;C&#41;&#44; an ubiquitin ligase&#44; when coupled to its Cdh1 activator&#46; A reduction in the APC&#47;C-Cdh1 activity releases both enzymes&#44; so that PFKFB3 can over-regulate glycolysis and GLS1 can activate glutaminolysis&#46; Thus&#44; both metabolic pathways are coordinated with the cell cycle&#46;</p>"
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                      "titulo" => "A transient inhibition of mitochondrial ATP synthesis by nitric oxide synthase activation triggered apoptosis in primary cortical neurons"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Almeida"
                            1 => "J&#46;P&#46; Bola&#241;os"
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                        "tituloSerie" => "J Neurochem"
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                        "paginaInicial" => "676"
                        "paginaFinal" => "690"
                        "link" => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            1 => "S&#46; Moncada"
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                      "doi" => "10.1038/ncb1080"
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                      "titulo" => "The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC&#47;C-Cdh1"
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                          "autores" => array:6 [
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                            1 => "A&#46; Almeida"
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                        "tituloSerie" => "Nat Cell Biol"
                        "fecha" => "2009"
                        "volumen" => "11"
                        "paginaInicial" => "747"
                        "paginaFinal" => "752"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19448625"
                            "web" => "Medline"
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                      "titulo" => "The function of APC&#47;CCdh1 in cell cycle and beyond"
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                        0 => array:2 [
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                          "autores" => array:2 [
                            0 => "M&#46; Li"
                            1 => "P&#46; Zhang"
                          ]
                        ]
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                    ]
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                      "doi" => "10.1186/1747-1028-4-2"
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                        "tituloSerie" => "Cell Div"
                        "fecha" => "2009"
                        "volumen" => "4"
                        "paginaInicial" => "2"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19152694"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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              "etiqueta" => "6"
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                0 => array:2 [
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                      "titulo" => "A restriction point for control of normal animal cell proliferation"
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                        "tituloSerie" => "Proc Natl Acad Sci USA"
                        "fecha" => "1974"
                        "volumen" => "71"
                        "paginaInicial" => "1286"
                        "paginaFinal" => "1290"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4524638"
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                      "titulo" => "Glycolysis&#58; A bioenergetic or a survival pathway&#63;"
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                          "autores" => array:3 [
                            0 => "J&#46;P&#46; Bola&#241;os"
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                        "tituloSerie" => "Trends Biochem Sci"
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                        "volumen" => "35"
                        "paginaInicial" => "145"
                        "paginaFinal" => "149"
                        "link" => array:1 [
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                      "titulo" => "E3 ubiquitin ligase APC&#47;C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation"
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                          "etal" => false
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                      ]
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                        "paginaFinal" => "741"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20080744"
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                ]
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                0 => array:2 [
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                      "titulo" => "Anaphase-promoting complex&#47;cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes"
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                          "etal" => true
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                            1 => "M&#46; Palacios-Callender"
                            2 => "N&#46; Frakich"
                            3 => "J&#46; de Le&#243;n"
                            4 => "C&#46;A&#46; Schmitt"
                            5 => "L&#46; Boorn"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
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                        "tituloSerie" => "Proc Natl Acad Sci USA"
                        "fecha" => "2010"
                        "volumen" => "107"
                        "paginaInicial" => "18868"
                        "paginaFinal" => "18873"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20921411"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glutamine metabolism in the animal body"
                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "H&#46;A&#46; Krebs"
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                        "serieFecha" => "1980"
                      ]
                    ]
                  ]
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                      "titulo" => "Glutamine metabolism in lymphocytes&#58; Its biochemical&#44; physiological and clinical importance"
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                          "etal" => false
                          "autores" => array:3 [
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                          ]
                        ]
                      ]
                    ]
                  ]
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                      "Revista" => array:7 [
                        "tituloSerie" => "Q J Exp Physiol"
                        "fecha" => "1985"
                        "volumen" => "70"
                        "paginaInicial" => "473"
                        "paginaFinal" => "489"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3909197"
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                    0 => array:2 [
                      "titulo" => "Co-expression of glutaminase K and L isoenzymes in human tumour cells"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "J&#46;A&#46; Campos-Sandoval"
                            2 => "F&#46;J&#46; Alonso"
                            3 => "J&#46;A&#46; Segura"
                            4 => "E&#46; Manzanares"
                            5 => "P&#46; Ruiz-S&#225;nchez"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1042/BJ20040996"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biochem J"
                        "fecha" => "2005"
                        "volumen" => "386"
                        "paginaInicial" => "535"
                        "paginaFinal" => "542"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15496140"
                            "web" => "Medline"
                          ]
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              "etiqueta" => "13"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells"
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "M&#46; Palacios-Callender"
                            2 => "N&#46; Frakich"
                            3 => "S&#46; Carcamo"
                            4 => "I&#46; Kovacs"
                            5 => "S&#46; Tudzarova"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.1117500108"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci USA"
                        "fecha" => "2011"
                        "volumen" => "108"
                        "paginaInicial" => "21069"
                        "paginaFinal" => "21074"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22106309"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Two ubiquitin ligases&#44; APC&#47;C-Cdh1 and SKP1-CUL1-F &#40;SCF&#41;-&#946;-TrCP&#44; sequentially regulate glycolysis during the cell cycle"
                      "autores" => array:1 [
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                            1 => "S&#46;L&#46; Colombo"
                            2 => "K&#46; Stoeber"
                            3 => "S&#46; Carcamo"
                            4 => "G&#46;H&#46; Williams"
                            5 => "S&#46; Moncada"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.1102247108"
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                        "tituloSerie" => "Proc Natl Acad Sci USA"
                        "fecha" => "2011"
                        "volumen" => "108"
                        "paginaInicial" => "5278"
                        "paginaFinal" => "5283"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21402913"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cyclins and their partners&#58; from a simple idea to complicated reality"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46; Hunt"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Cell Biol"
                        "fecha" => "1991"
                        "volumen" => "2"
                        "paginaInicial" => "213"
                        "paginaFinal" => "222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1842340"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Genomic stability and tumour suppression by the APC&#47;C cofactor Cdh1"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46; Garc&#237;a-Higuera"
                            1 => "E&#46; Manchado"
                            2 => "P&#46; Dubus"
                            3 => "M&#46; Canamero"
                            4 => "J&#46; M&#233;ndez"
                            5 => "S&#46; Moreno"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ncb1742"
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                        "tituloSerie" => "Nat Cell Biol"
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                        "volumen" => "10"
                        "paginaInicial" => "802"
                        "paginaFinal" => "811"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18552834"
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              ]
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