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1.
Genes Dev ; 25(10): 1041-51, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21576264

RESUMEN

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.


Asunto(s)
Carnitina O-Palmitoiltransferasa/metabolismo , Estrés Fisiológico/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Apoptosis/fisiología , Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Células Cultivadas , Resistencia a Antineoplásicos/genética , Células Madre Embrionarias/enzimología , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Hipoxia/patología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Estrés Fisiológico/genética , Serina-Treonina Quinasas TOR/metabolismo , Trasplante Heterólogo , Regulación hacia Arriba
2.
J Neurosci ; 30(50): 16938-48, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21159964

RESUMEN

An increasing body of evidence points to a key role of endoplasmic reticulum (ER) stress in acute and chronic neurodegenerative conditions. Extensive ER stress can trigger neuronal apoptosis, but the signaling pathways that regulate this cell death remain unclear. In the present study, we demonstrate that PUMA, a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family, is transcriptionally activated in cortical neurons by ER stress and is essential for ER-stress-induced cell death. PUMA is known to be a key transcriptional target of p53, but we have found that ER stress triggers PUMA induction and cell death through a p53-independent mechanism mediated by the ER-stress-inducible transcription factor ATF4 (activating transcription factor 4). Specifically, we demonstrate that ectopic expression of ATF4 sensitizes mouse cortical neurons to ER-stress-induced apoptosis and that ATF4-deficient neurons exhibit markedly reduced levels of PUMA expression and cell death. However, chromatin immunoprecipitation experiments suggest that ATF4 does not directly regulate the PUMA promoter. Rather, we found that ATF4 induces expression of the transcription factor CHOP (C/EBP homologous protein) and that CHOP in turn activates PUMA induction. Specifically, we demonstrate that CHOP binds to the PUMA promoter during ER stress and that CHOP knockdown attenuates PUMA induction and neuronal apoptosis. In summary, we have identified a key signaling pathway in ER-stress-induced neuronal death involving ATF4-CHOP-mediated transactivation of the proapoptotic Bcl-2 family member PUMA. We propose that this pathway may be an important therapeutic target relevant to a number of neurodegenerative conditions.


Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/genética , Retículo Endoplásmico/metabolismo , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Estrés Fisiológico/genética , Factor de Transcripción CHOP/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Factor de Transcripción Activador 4/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/genética , Técnicas de Cultivo de Célula , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Ratones , Ratones Noqueados , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estrés Fisiológico/fisiología , Tapsigargina/farmacología , Factor de Transcripción CHOP/genética , Transfección/métodos , Proteínas Supresoras de Tumor/genética , Tunicamicina/farmacología
3.
Cell Metab ; 17(1): 113-24, 2013 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-23274086

RESUMEN

AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Animales , Linfocitos B/metabolismo , Línea Celular , Glucólisis , Células HCT116 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Estimación de Kaplan-Meier , Ratones , Ratones Transgénicos , Neoplasias/metabolismo , Neoplasias/mortalidad , Neoplasias/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal
4.
Science ; 329(5996): 1201-5, 2010 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-20647423

RESUMEN

The mammalian adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Cromatina/metabolismo , Histonas/metabolismo , Estrés Fisiológico , Transcripción Genética , Proteínas Quinasas Activadas por AMP/química , Adaptación Fisiológica , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular , Células Cultivadas , Inmunoprecipitación de Cromatina , Activación Enzimática , Regulación de la Expresión Génica , Histonas/química , Humanos , Ratones , Fosforilación , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Serina/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo
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