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1.
Hum Brain Mapp ; 38(6): 3126-3140, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28321948

RESUMEN

Primary patterns in adult brain connectivity are established during development by coordinated networks of transiently expressed genes; however, neural networks remain malleable throughout life. The present study hypothesizes that structural connectivity from key seed regions may induce effects on their connected targets, which are reflected in gene expression at those targeted regions. To test this hypothesis, analyses were performed on data from two brains from the Allen Human Brain Atlas, for which both gene expression and DW-MRI were available. Structural connectivity was estimated from the DW-MRI data and an approach motivated by network topology, that is, weighted gene coexpression network analysis (WGCNA), was used to cluster genes with similar patterns of expression across the brain. Group exponential lasso models were then used to predict gene cluster expression summaries as a function of seed region structural connectivity patterns. In several gene clusters, brain regions located in the brain stem, diencephalon, and hippocampal formation were identified that have significant predictive power for these expression summaries. These connectivity-associated clusters are enriched in genes associated with synaptic signaling and brain plasticity. Furthermore, using seed region based connectivity provides a novel perspective in understanding relationships between gene expression and connectivity. Hum Brain Mapp 38:3126-3140, 2017. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Encéfalo/metabolismo , Expresión Génica/fisiología , Redes Reguladoras de Genes/fisiología , Vías Nerviosas/metabolismo , Adulto , Encéfalo/citología , Análisis por Conglomerados , Conectoma , Conjuntos de Datos como Asunto , Imagen de Difusión por Resonancia Magnética , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Adulto Joven
2.
J Dev Orig Health Dis ; 14(4): 501-507, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37431265

RESUMEN

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.


Asunto(s)
Resistencia a la Insulina , MicroARNs , Humanos , Masculino , Embarazo , Femenino , Ratas , Animales , Netrina-1/genética , Netrina-1/metabolismo , Células HEK293 , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Insulina/metabolismo , Roedores/genética , Roedores/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Señales (Psicología) , Corteza Prefrontal/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Receptor DCC/metabolismo
3.
Genes (Basel) ; 15(1)2023 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-38254917

RESUMEN

The response of triple-negative breast cancer (TNBC) patients to pre-operative (neoadjuvant chemotherapy) is a critical factor of their outcome. To determine the effects of chemotherapy on the tumor genome and to identify mutations associated with chemoresistance and sensitivity, we performed whole exome sequencing on pre/post-chemotherapy tumors and matched lymphocytes from 26 patients. We observed great inter-tumoral heterogeneity with no gene mutated recurrently in more than four tumors besides TP53. Although the degree of response to chemotherapy in residual tumors was associated with more subclonal changes during chemotherapy, there was minimal evolution between pre/post-tumors. Indeed, gene sets enriched for mutations in pre- and post-chemotherapy tumors were very similar and reflected genes involved in the biological process of neurogenesis. Somatically mutated genes present in chemosensitive tumors included COL1A2, PRMD15, APOBEC3B, PALB2 and histone protein encoding genes, while BRCA1, ATR, ARID1A, XRCC3 and genes encoding for tubulin-associated proteins were present in the chemoresistant tumors. We also found that the mutational spectrum of post-chemotherapy tumors was more reflective of matching metastatic tumor biopsies than pre-chemotherapy samples. These findings support a portrait of modest ongoing genomic instability with respect to single-nucleotide variants induced by or selected for by chemotherapy in TNBCs.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Terapia Neoadyuvante , Mutación , Histonas , Inestabilidad Genómica , Citidina Desaminasa , Antígenos de Histocompatibilidad Menor
4.
Oncogene ; 38(12): 2177-2191, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30459355

RESUMEN

Poly (ADP-ribosylation), known as PARylation, is a post-translational modification catalyzed by poly (ADP-ribose) polymerases (PARP) and primarily removed by the enzyme poly (ADP-ribose) glycohydrolase (PARG). While the aberrant removal of post-translation modifications including phosphorylation and methylation has known tumorigenic effects, deregulation of PARylation has not been widely studied. Increased hydrolysis of PARylation chains facilitates cancer growth through enhancing estrogen receptor (ER)-driven proliferation, but oncogenic transformation has not been linked to increased PARG expression. In this study, we find that elevated PARG levels are associated with a poor prognosis in breast cancers, especially in HER2-positive and triple-negative subtypes. Using both in vitro and in vivo models, we demonstrate that heightened expression of catalytically active PARG facilitates cell transformation and invasion of normal mammary epithelial cells. Catalytically inactive PARG mutants did not recapitulate these phenotypes. Consistent with clinical data showing elevated PARG predicts poor outcomes in HER2+ patients, we observed that PARG acts in synergy with HER2 to promote neoplastic growth of immortalized mammary cells. In contrast, PARG depletion significantly impairs the growth and metastasis of triple-negative breast tumors. Mechanistically, we find that PARG interacts with SMAD2/3 and significantly decreases their PARylation in non-transformed cells, leading to enhanced expression of SMAD target genes. Further linking SMAD-mediated transcription to the oncogenicity of PARG, we show that PARG-mediated anchorage-independent growth and invasion are dependent, at least in part, on SMAD expression. Overall, our study underscores the oncogenic impact of aberrant protein PARylation and highlights the therapeutic potential of PARG inhibition in breast cancer.


Asunto(s)
Carcinogénesis , Glicósido Hidrolasas/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , ADN/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Glicósido Hidrolasas/genética , Humanos , Ratones , Metástasis de la Neoplasia , Fenotipo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Análisis de Supervivencia
5.
PLoS One ; 9(3): e92853, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24658335

RESUMEN

Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn) has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1) as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP) injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.


Asunto(s)
Antineoplásicos/farmacología , Taninos Hidrolizables/farmacología , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/patología , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa de Punto de Control 2/metabolismo , Análisis por Conglomerados , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Taninos Hidrolizables/administración & dosificación , Ratones , Neoplasias de la Mama Triple Negativas/genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Mol Immunol ; 59(1): 46-54, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24486724

RESUMEN

The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap-dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T-B collaborations in the germinal center.


Asunto(s)
Linfocitos B/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Interleucina-4/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Proteínas Adaptadoras Transductoras de Señales , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Técnicas de Cocultivo , Factores Eucarióticos de Iniciación , Citometría de Flujo , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Immunoblotting , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fosfatidilinositol 3-Quinasas/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/inmunología , Fosfoproteínas/metabolismo , Fosforilación/inmunología , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas S6 Ribosómicas 70-kDa/inmunología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Serina-Treonina Quinasas TOR/inmunología , Serina-Treonina Quinasas TOR/metabolismo
7.
Front Pharmacol ; 3: 202, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23293602

RESUMEN

Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.

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