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1.
EMBO Rep ; 25(1): 45-67, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38177900

RESUMEN

Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.


Asunto(s)
GTP Fosfohidrolasas , Lisofosfolípidos , Mitocondrias , Mitocondrias/genética , Mitocondrias/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Dinámicas Mitocondriales , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo
2.
Cell Rep ; 33(11): 108511, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33326786

RESUMEN

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.


Asunto(s)
Hipocampo/inmunología , Trastornos de la Memoria/inmunología , Neuronas/metabolismo , Factores de Transcripción/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Ratas
3.
Cell ; 174(1): 59-71.e14, 2018 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-29804835

RESUMEN

Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.


Asunto(s)
Potenciación a Largo Plazo , Memoria , Neuronas/metabolismo , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Calcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Hipocampo/citología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , N-Metilaspartato/farmacología , Neuronas/efectos de los fármacos , Optogenética , Técnicas de Placa-Clamp , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico , Potenciales Sinápticos/efectos de los fármacos
4.
Biol Psychiatry ; 83(2): 137-147, 2018 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-29033027

RESUMEN

BACKGROUND: Anhedonia, the diminished ability to experience pleasure, is an important dimensional entity linked to depression, schizophrenia, and other emotional disorders, but its origins and mechanisms are poorly understood. We have previously identified anhedonia, manifest as decreased sucrose preference and social play, in adolescent male rats that experienced chronic early-life adversity/stress (CES). Here we probed the molecular, cellular, and circuit processes underlying CES-induced anhedonia and tested them mechanistically. METHODS: We examined functional brain circuits and neuronal populations activated by social play in adolescent CES and control rats. Structural connectivity between stress- and reward-related networks was probed using high-resolution diffusion tensor imaging, and cellular/regional activation was probed using c-Fos. We employed viral-genetic approaches to reduce corticotropin-releasing hormone (Crh) expression in the central nucleus of the amygdala in anhedonic rats, and tested for anhedonia reversal in the same animals. RESULTS: Sucrose preference was reduced in adolescent CES rats. Social play, generally considered an independent measure of pleasure, activated brain regions involved in reward circuitry in both control and CES groups. In CES rats, social play activated Crh-expressing neurons in the central nucleus of the amygdala, typically involved in anxiety/fear, indicating aberrant functional connectivity of pleasure/reward and fear circuits. Diffusion tensor imaging tractography revealed increased structural connectivity of the amygdala to the medial prefrontal cortex in CES rats. Crh-short hairpin RNA, but not control short hairpin RNA, given into the central nucleus of the amygdala reversed CES-induced anhedonia without influencing other emotional measures. CONCLUSIONS: These findings robustly demonstrate aberrant interactions of stress and reward networks after early-life adversity and suggest mechanistic roles for Crh-expressing amygdala neurons in emotional deficits portending major neuropsychiatric disorders.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Anhedonia/fisiología , Ansiedad/metabolismo , Hormona Liberadora de Corticotropina/genética , Recompensa , Estrés Psicológico/metabolismo , Amígdala del Cerebelo/fisiopatología , Animales , Ansiedad/genética , Ansiedad/fisiopatología , Conducta Animal/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Imagen de Difusión Tensora , Silenciador del Gen , Masculino , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Neuronas/metabolismo , Juego e Implementos de Juego , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Conducta Social , Estrés Psicológico/fisiopatología
5.
Cereb Cortex ; 27(6): 3457-3470, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28407141

RESUMEN

Hippocampus, a temporal lobe structure involved in learning and memory, receives information from all sensory modalities. Despite extensive research on the role of sensory experience in cortical map plasticity, little is known about whether and how sensory experience regulates functioning of the hippocampal circuits. Here, we show that 9 ± 2 days of whisker deprivation during early mouse development depresses activity of CA3 pyramidal neurons by several principal mechanisms: decrease in release probability, increase in the fraction of silent synapses, and reduction in intrinsic excitability. As a result of deprivation-induced presynaptic inhibition, CA3-CA1 synaptic facilitation was augmented at high frequencies, shifting filtering properties of synapses. The changes in the AMPA-mediated synaptic transmission were accompanied by an increase in NR2B-containing NMDA receptors and a reduction in the AMPA/NMDA ratio. The observed reconfiguration of the CA3-CA1 connections may represent a homeostatic adaptation to augmentation in synaptic activity during the initial deprivation phase. In adult mice, tactile disuse diminished intrinsic excitability without altering synaptic facilitation. We suggest that sensory experience regulates computations performed by the hippocampus by tuning its synaptic and intrinsic characteristics.


Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Privación Sensorial/fisiología , Transmisión Sináptica/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Corticosterona/sangre , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Conducta Exploratoria/fisiología , Técnicas In Vitro , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , N-Metilaspartato/metabolismo , Red Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Neurotransmisores/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/efectos de los fármacos , Vibrisas/inervación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo
6.
Stress ; 17(1): 39-50, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23768074

RESUMEN

Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of the crh gene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ∼100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly on crh or indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.


Asunto(s)
Hormona Liberadora de Corticotropina/biosíntesis , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipotálamo/metabolismo , Envejecimiento , Animales , Animales Recién Nacidos , Corticosterona/sangre , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Restricción Física , Estrés Fisiológico , Estrés Psicológico
7.
Front Neuroendocrinol ; 35(2): 171-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24145148

RESUMEN

Stress is among the strongest signals promoting neuroplasticity: Stress signals, indicating real or perceived danger, lead to alterations of neuronal function and often structure, designed to adapt to the changed conditions and promote survival. Corticotropin releasing factor (CRF) is expressed and released in several types of neuronal populations that are involved in cognition, emotion and the regulation of autonomic and endocrine function. CRF expressing neurons undergo functional and structural plasticity during stress and, in addition, the peptide acts via specific receptors to promote plasticity of target neurons.


Asunto(s)
Hormona Liberadora de Corticotropina/fisiología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Animales , Humanos , Memoria/fisiología , Estrés Fisiológico/fisiología
8.
J Neurosci ; 33(43): 16945-60, 2013 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-24155300

RESUMEN

The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time- and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calcium-dependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co-opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress.


Asunto(s)
Calpaína/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Espinas Dendríticas/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Calpaína/antagonistas & inhibidores , Células Cultivadas , Espinas Dendríticas/metabolismo , Dipéptidos/farmacología , Hipocampo/citología , Hipocampo/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de Hormona Liberadora de Corticotropina/agonistas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Espectrina/genética , Espectrina/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo
9.
Biol Psychiatry ; 71(4): 317-26, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21783178

RESUMEN

BACKGROUND: Faulty regulation of the central extrahypothalamic corticotropin-releasing factor (CRF) expression is associated with stress-related psychopathologies including anxiety disorders and depression. Extensive pharmacological literature describes the effects of CRF agonists or antagonists' administration on anxiety-like behavior. However, the relevance of the endogenous agonist, presumed to be CRF, has never been explicitly demonstrated. Several genetic models have been used to study the role of CRF in the physiological response to stress and in stress-related disorders. Nevertheless, developmental compensatory mechanisms and lack of spatial and temporal specificity limited the interpretations of these studies. METHODS: Two lentiviral-based systems were designed, generated, and used to knockdown (KD) or conditionally overexpress (OE) CRF in the central amygdala (CeA) of adult mice. Behavioral responses associated with the CeA, such as anxiety, depression and fear memory, and the plasma corticosterone levels were evaluated under both basal and stressful conditions. RESULTS: Changing the CeA-CRF levels mildly affected anxiety-like behaviors under basal conditions. However, following exposure to an acute stressor, CeA-CRF-KD strongly attenuated stress-induced anxiety-like behaviors, whereas a short-term CeA-CRF-overexpression enhanced the stress-induced effects on these behaviors. Interestingly, a significant increase in basal corticosterone levels in the CeA-CRF-KD mice was observed, demonstrating the importance of endogenous CeA-CRF levels for basal, but not stress-induced, corticosterone levels. CONCLUSIONS: These results highlight the pivotal role of CeA CRF expression regulation in mediating adequate behavioral responses to stress and introduce these novel viral tools as a useful approach for dissecting the role of central CRF in mediating behavioral and neuroendocrine responses to stress.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/genética , Hormona Liberadora de Corticotropina , Depresión/genética , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Conducta Animal/fisiología , Corticosterona/metabolismo , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Depresión/etiología , Depresión/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Vectores Genéticos , Lentivirus , Ratones , Ratones Transgénicos , Estrés Fisiológico/genética , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo
10.
Nat Neurosci ; 13(11): 1351-3, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20890295

RESUMEN

DNA methylation regulates gene transcription and has been suggested to encode psychopathologies derived from early life stress. We found that methylation regulated the expression of the Crf (also known as Crh) gene and that chronic social stress in adult mice induced long-term demethylation of this genomic region. Demethylation was observed only in the subset of defeated mice that displayed social avoidance and site-specific knockdown of Crf attenuated the stress-induced social avoidance.


Asunto(s)
Hormona Liberadora de Corticotropina/genética , Metilación de ADN , Regulación de la Expresión Génica/fisiología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/genética , Análisis de Varianza , Animales , Antidepresivos Tricíclicos/uso terapéutico , Reacción de Prevención , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Hormona Liberadora de Corticotropina/deficiencia , Hormona Liberadora de Corticotropina/metabolismo , AMP Cíclico/farmacología , Metilación de ADN/efectos de los fármacos , Decitabina , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/fisiología , Proteínas Fluorescentes Verdes/genética , Imipramina/uso terapéutico , Inyecciones Intraventriculares/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Microdisección/métodos , Naftalenos , Neuroblastoma , Neuronas/efectos de los fármacos , Oxepinas , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Interferencia de ARN/fisiología , ARN Mensajero/metabolismo
11.
Proc Natl Acad Sci U S A ; 107(18): 8393-8, 2010 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-20404164

RESUMEN

In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological responses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic neuropeptide Urocortin-3, a specific ligand for the type-2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a neuromodulator linking stress-induced anxiety and energy homeostasis and pave the way toward better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders.


Asunto(s)
Ansiedad/metabolismo , Conducta Animal , Metabolismo Energético , Homeostasis , Estrés Fisiológico , Urocortinas/metabolismo , Animales , Ansiedad/genética , Vectores Genéticos/genética , Lentivirus/genética , Ratones , Ratones Transgénicos , Urocortinas/genética
12.
Proc Natl Acad Sci U S A ; 107(9): 4424-9, 2010 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-20142482

RESUMEN

Administration of synthetic or purified peptides directly into the brain ventricles is a method commonly used by neuroscientists for exploring physiological and behavioral functions of gene products. i.v. administration is controlled by the blood-brain barrier, which limits its effectiveness, and current approaches for acute or chronic intracerebroventricular delivery have significant technical drawbacks resulting from both the chemical properties of the delivered substance and the experimental procedures. Here we describe a genetic approach for the delivery of secreted peptides or proteins into the cerebrospinal fluid (CSF). Using a choroid plexus-specific promoter, we established a lentiviral-based system, which offers inducible and reversible delivery of a gene product into the CSF. The functionality of this system was demonstrated by using the overexpression of the two established neuropeptides, corticotropin-releasing factor and gonadotropin-releasing hormone, modulating anxiety-like behavior and estrus cycle, respectively. We show that this choroid plexus-specific lentiviral-based system is a reliable, effective, and adaptable research tool for intracerebroventricular delivery.


Asunto(s)
Vectores Genéticos , Inyecciones Intraventriculares , Lentivirus/genética , Péptidos/administración & dosificación , Animales , Línea Celular , Humanos , Inmunohistoquímica , Hibridación in Situ , Ratones
13.
Cell ; 122(4): 593-603, 2005 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-16122426

RESUMEN

The "BH3-only" proapoptotic BCL-2 family members are sentinels of intracellular damage. Here, we demonstrated that the BH3-only BID protein partially localizes to the nucleus in healthy cells, is important for apoptosis induced by DNA damage, and is phosphorylated following induction of double-strand breaks in DNA. We also found that BID phosphorylation is mediated by the ATM kinase and occurs in mouse BID on two ATM consensus sites. Interestingly, BID-/- cells failed to accumulate in the S phase of the cell cycle following treatment with the topoisomerase II poison etoposide; reintroducing wild-type BID restored accumulation. In contrast, introducing a nonphosphorylatable BID mutant did not restore accumulation in the S phase and resulted in an increase in cellular sensitivity to etoposide-induced apoptosis. These results implicate BID as an ATM effector and raise the possibility that proapoptotic BID may also play a prosurvival role important for S phase arrest.


Asunto(s)
Apoptosis/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Daño del ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Sitios de Unión/fisiología , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Supervivencia Celular/fisiología , Células Cultivadas , ADN/genética , ADN/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/genética , Etopósido/farmacología , Fibroblastos/metabolismo , Genes cdc/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/fisiología , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Fase S/efectos de los fármacos , Fase S/fisiología , Inhibidores de Topoisomerasa II , Proteínas Supresoras de Tumor/genética
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