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The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2-acetamido-1,3 benzothiazole-6-carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2-acetamidobenzo[d]thiazole-6-carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position-2 by an acetamido moiety and at position-6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non-aromatic) terminal pharmacophore in the order -C6 H4 -NHSO2 -R or reversely -C6 H4 -SO2 N(H)-R. These analogs were subsequently biologically evaluated as potential BRAFV600E inhibitors and antiproliferative agents in several colorectal cancer and melanoma cell lines. In all assays applied, one analog, namely 2-acetamido-N-[3-(pyridin-2-ylamino)propyl]benzo[d]thiazole-6-carboxamide (22), provided promising results in view of its use in drug development.
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Antineoplásicos , Benzotiazoles , Línea Celular Tumoral , Benzotiazoles/farmacología , Antineoplásicos/farmacología , Proliferación Celular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Cutaneous melanoma (CM) is the most aggressive type of skin cancer, and it is characterised by high mutational load and heterogeneity. In this study, we aimed to analyse the genomic and transcriptomic profile of primary melanomas from forty-six Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from Greek patients. Molecular analysis for both germline and somatic variations was performed in genomic DNA from peripheral blood and melanoma samples, respectively, exploiting whole exome and targeted sequencing, and transcriptomic analysis. Detailed clinicopathological data were also included in our analyses and previously reported associations with specific mutations were recognised. Most analysed samples (43/46) were found to harbour at least one clinically actionable somatic variant. A subset of samples was profiled at the transcriptomic level, and it was shown that specific melanoma phenotypic states could be inferred from bulk RNA isolated from FFPE primary melanoma tissue. Integrative bioinformatics analyses, including variant prioritisation, differential gene expression analysis, and functional and gene set enrichment analysis by group and per sample, were conducted and molecular circuits that are implicated in melanoma cell programmes were highlighted. Integration of mutational and transcriptomic data in CM characterisation could shed light on genes and pathways that support the maintenance of phenotypic states encrypted into heterogeneous primary tumours.
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Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERß1 and ERß2 (isoforms of ERß), the second ER isotype. At present, the impact of ERß isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERß1 or ERß2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERß1 and MCF7-ERß2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT-ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERß1 cells and cancer-promoting effects in MCF7-ERß2 cells. Our data are favorable to ERß1 being a marker of responsiveness and ERß2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Receptor beta de Estrógeno , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Moduladores de los Receptores de Estrógeno/uso terapéutico , Fulvestrant/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Isoformas de Proteínas , Tamoxifeno/uso terapéutico , Tretinoina/uso terapéuticoRESUMEN
The deregulated DNA damage response (DDR) network is associated with the onset and progression of cancer. Herein, we searched for DDR defects in peripheral blood mononuclear cells (PBMCs) from lung cancer patients, and we evaluated factors leading to the augmented formation of DNA damage and/or its delayed/decreased removal. In PBMCs from 20 lung cancer patients at diagnosis and 20 healthy controls (HC), we analyzed oxidative stress and DDR-related parameters, including critical DNA repair mechanisms and apoptosis rates. Cancer patients showed higher levels of endogenous DNA damage than HC (p < 0.001), indicating accumulation of DNA damage in the absence of known exogenous genotoxic insults. Higher levels of oxidative stress and apurinic/apyrimidinic sites were observed in patients rather than HC (all p < 0.001), suggesting that increased endogenous DNA damage may emerge, at least in part, from these intracellular factors. Lower nucleotide excision repair and double-strand break repair capacities were found in patients rather than HC (all p < 0.001), suggesting that the accumulation of DNA damage can also be mediated by defective DNA repair mechanisms. Interestingly, reduced apoptosis rates were obtained in cancer patients compared with HC (p < 0.001). Consequently, the expression of critical DDR-associated genes was found deregulated in cancer patients. Together, oxidative stress and DDR-related aberrations contribute to the accumulation of endogenous DNA damage in PBMCs from lung cancer patients and can potentially be exploited as novel therapeutic targets and non-invasive biomarkers.
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Electronic health record (EHR) systems improve health care services by allowing the combination of health data with clinical decision support features and clinical image analyses. This study presents a modular and distributed platform that is able to integrate and accommodate heterogeneous, multidimensional (omics, histological images and clinical) data for the multi-angled portrayal and management of skin cancer patients. The proposed design offers a layered analytical framework as an expansion of current EHR systems, which can integrate high-volume molecular -omics data, imaging data, as well as relevant clinical observations. We present a case study in the field of dermatology, where we attempt to combine the multilayered information for the early detection and characterization of melanoma. The specific architecture aspires to lower the barrier for the introduction of personalized therapeutic approaches, towards precision medicine. The paper describes the technical issues of implementation, along with an initial evaluation of the system and discussion.
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Sistemas de Apoyo a Decisiones Clínicas , Melanoma , Neoplasias Cutáneas , Sistemas de Computación , Manejo de Datos , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapiaRESUMEN
PLX7904 and PLX8394 are novel BRAFV600E inhibitors-BRAFi that are designed to evade the paradoxical MAPK activation, a trait for the name "paradox breakers"-PB. Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. mtBRAF Colorectal Cancer (CRC) is resistant to the approved BRAF inhibitors, although combinatorial treatment co-targeting BRAF and EGFR/MEK is offering a promising prospect. In an effort to explore the potential of the novel BRAF inhibitors-PB to impede CRC cell proliferation, they were tested on RKO, HT29 and Colo-205 cells, bearing the BRAFV600E mutation. This study shows that the BRAF paradox breakers PLX7904 and PLX8394 cause a more prolonged MAPK pathway inhibition and achieve a stronger blockage of proliferation and reduced viability than PLX4720, the sister compound of Vemurafenib. In some treatment conditions, cells can undergo apoptosis. Genomic analysis on the more resistant RKO cells treated with PLX7904, PLX8394 and PLX4720 showed similar gene expression pattern, but the alterations imposed by the PB were more intense. Bioinformatic analysis resulted in a short list of genes representing potential master regulators of the cellular response to BRAF inhibitors' treatments. From our results, it is clear that the BRAF paradox breakers present a notable differential regulation of major pathways, like MAPK signalling, apoptosis, cell cycle, or developmental signalling pathways. Combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than mono-treatments. Additional pathways could be further exploited in novel efficient combinatorial treatment protocols with BRAFi.
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Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mutación Puntual/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses.
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Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Mucoproteínas/metabolismo , Proteínas Oncogénicas/metabolismo , Multimerización de Proteína , Proteostasis , Animales , Retículo Endoplásmico/genética , Células HEK293 , Humanos , Masculino , Ratones , Mucoproteínas/genética , Proteínas Oncogénicas/genéticaRESUMEN
PURPOSE: Transcriptomic profiling has enabled the neater genomic characterization of several cancers, among them colorectal cancer (CRC), through the derivation of genes with enhanced causal role and informative gene sets. However, the identification of small-sized gene signatures, which can serve as potential biomarkers in CRC, remains challenging, mainly due to the great genetic heterogeneity of the disease. METHODS: We developed and exploited an analytical framework for the integrative analysis of CRC datasets, encompassing transcriptomic data and positron emission tomography (PET) measurements. Profiling data comprised two microarray datasets, pertaining biopsy specimen from 30 untreated patients with primary CRC, coupled by their F-18-Fluorodeoxyglucose (FDG) PET values, using tracer kinetic analysis measurements. The computational framework incorporates algorithms for semantic processing, multivariate analysis, data mining and dimensionality reduction. RESULTS: Transcriptomic and PET data feature sets, were evaluated for their discrimination performance between primary colorectal adenocarcinomas and adjacent normal mucosa. A composite signature was derived, pertaining 12 features: 7 genes and 5 PET variables. This compact signature manifests superior performance in classification accuracy, through the integration of gene expression and PET data. CONCLUSIONS: This work represents an effort for the integrative, multilayered, signature-oriented analysis of CRC, in the context of radio-genomics, inferring a composite signature with promising results for patient stratification.
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Melanoma is a lethal type of skin cancer, unless it is diagnosed early. Formalin-fixed, paraffin-embedded (FFPE) tissue is a valuable source for molecular assays after diagnostic examination, but isolated nucleic acids often suffer from degradation. Here, for the first time, we examine primary melanomas from Greek patients, using whole exome sequencing, so as to derive their mutational profile. Application of a bioinformatic framework revealed a total of 10,030 somatic mutations. Regarding the genes containing putative protein-altering mutations, 73 were common in at least three patients. Sixty-five of these 73 top common genes have been previously identified in melanoma cases. Biological processes related to melanoma were affected by varied genes in each patient, suggesting differences in the components of a pathway possibly contributing to pathogenesis. We performed a multi-level analysis highlighting a short list of candidate genes with a probable causative role in melanoma.
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Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
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Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Endorribonucleasas/metabolismo , Glioblastoma/enzimología , Glioblastoma/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias Encefálicas/genética , Carcinogénesis/genética , Línea Celular Tumoral , Endorribonucleasas/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Humanos , Modelos Biológicos , Mutación/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Microambiente Tumoral/genéticaRESUMEN
Ionizing radiation-induced bystander effects (RIBE) encompass a number of effects with potential for a plethora of damages in adjacent non-irradiated tissue. The cascade of molecular events is initiated in response to the exposure to ionizing radiation (IR), something that may occur during diagnostic or therapeutic medical applications. In order to better investigate these complex response mechanisms, we employed a unified framework integrating statistical microarray analysis, signal normalization, and translational bioinformatics functional analysis techniques. This approach was applied to several microarray datasets from Gene Expression Omnibus (GEO) related to RIBE. The analysis produced lists of differentially expressed genes, contrasting bystander and irradiated samples versus sham-irradiated controls. Furthermore, comparative molecular analysis through BioInfoMiner, which integrates advanced statistical enrichment and prioritization methodologies, revealed discrete biological processes, at the cellular level. For example, the negative regulation of growth, cellular response to Zn2+-Cd2+, and Wnt and NIK/NF-kappaB signaling, thus refining the description of the phenotypic landscape of RIBE. Our results provide a more solid understanding of RIBE cell-specific response patterns, especially in the case of high-LET radiations, like α-particles and carbon-ions.
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Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metilnitrosourea/farmacología , Transducción de Señal/efectos de los fármacos , Células A549 , Alquilantes/farmacología , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Muerte Celular/genética , Línea Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Ontología de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , TemozolomidaRESUMEN
Advanced ovarian cancer (AOC) is one of the leading lethal gynecological cancers in developed countries. Based on the important role of angiogenesis in ovarian cancer oncogenesis and expansion, we hypothesized that the development of an "angiogenic signature" might be helpful in prediction of prognosis and efficacy of anti-angiogenic therapies in this disease. Sixty-nine samples of ascitic fluid- 35 from platinum sensitive and 34 from platinum resistant patients managed with cytoreductive surgery and 1st-line carboplatin-based chemotherapy- were analyzed using the Proteome ProfilerTM Human Angiogenesis Array Kit, screening for the presence of 55 soluble angiogenesis-related factors. A protein profile based on the expression of a subset of 25 factors could accurately separate resistant from sensitive patients with a success rate of approximately 90%. The protein profile corresponding to the "sensitive" subset was associated with significantly longer PFS (8 [95% Confidence Interval {CI}: 8-9] vs. 20 months [95% CI: 15-28]; Hazard ratio {HR}: 8.3, p<0.001) and OS (20.5 months [95% CI: 13.5-30] vs. 74 months [95% CI: 36-not reached]; HR: 5.6 [95% CI: 2.8-11.2]; p<0.001). This prognostic performance was superior to that of stage, histology and residual disease after cytoreductive surgery and the levels of vascular endothelial growth factor (VEGF) in ascites. In conclusion, we developed an "angiogenic signature" for patients with AOC, which can be used, after appropriate validation, as a prognostic marker and a tool for selection for anti-angiogenic therapies.
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Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Ascitis/metabolismo , Líquido Ascítico/metabolismo , Carboplatino/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Pronóstico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF-induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and "mitotic cell cycle/cell division" along with "cholesterol biosynthesis" as the most significantly altered biological processes.
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Inhibidores de la Angiogénesis/síntesis química , Neovascularización Patológica/tratamiento farmacológico , Transcriptoma/efectos de los fármacos , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Diseño de Fármacos , Células Endoteliales/efectos de los fármacos , Humanos , Ratones , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. However, any functional association is missing. Here, we show that reconstitution of KLK5 expression in non-expressing MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo dose-dependently. Reactivation of KLK5 suppressed key EMT genes. Unexpectedly, we identified altered expression of genes encoding enzymes of the mevalonate pathway typical of those observed upon cholesterol starvation. Consistently, we found that SREBF1, the master regulator of the mevalonate pathway was induced. KLK5 re-expression leads to reduced cellular cholesterol and fatty acid synthesis and enhanced uptake of LDL-cholesterol. Suppression of the mevalonate pathway in KLK5 transfectants was further shown by reduced synthesis of isoprenoids. Indeed, we found diminished levels of active RhoA, a signaling oncoprotein that requires prenylation for activation. We propose that reduced RhoA activation plays a dominant role in suppression of malignancy by KLK5, since geranylgeranyl pyrophosphate restored active RhoA in KLK5-reverted cells resulting in increased malignancy. For the first time, we suggest that a protease may suppress breast cancer by modulating the mevalonate pathway.
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Neoplasias de la Mama/prevención & control , Calicreínas/fisiología , Ácido Mevalónico/metabolismo , Transducción de Señal , Animales , Apoptosis , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Ácidos Grasos/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones SCID , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP)-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO) mouse embryonic fibroblast (MEF) cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced) with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart) within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle) indicating their concerted function in mRNA metabolism.
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Proteínas ELAV/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Animales , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas ELAV/metabolismo , Fibroblastos/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Ratones , Proteínas de Unión al ARN/metabolismoRESUMEN
Schizophrenia affecting almost 1% and bipolar disorder affecting almost 3%-5% of the global population constitute two severe mental disorders. The catecholaminergic and the serotonergic pathways have been proved to play an important role in the development of schizophrenia, bipolar disorder, and other related psychiatric disorders. The aim of the study was to perform and interpret the results of a comparative genomic profiling study in schizophrenic patients as well as in healthy controls and in patients with bipolar disorder and try to relate and integrate our results with an aberrant amino acid transport through cell membranes. In particular we have focused on genes and mechanisms involved in amino acid transport through cell membranes from whole genome expression profiling data. We performed bioinformatic analysis on raw data derived from four different published studies. In two studies postmortem samples from prefrontal cortices, derived from patients with bipolar disorder, schizophrenia, and control subjects, have been used. In another study we used samples from postmortem orbitofrontal cortex of bipolar subjects while the final study was performed based on raw data from a gene expression profiling dataset in the postmortem superior temporal cortex of schizophrenics. The data were downloaded from NCBI's GEO datasets.
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Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Trastorno Bipolar/epidemiología , Trastorno Bipolar/metabolismo , Perfilación de la Expresión Génica/métodos , Esquizofrenia/epidemiología , Esquizofrenia/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Aminoácidos/genética , Trastorno Bipolar/genética , Mapeo Cromosómico/métodos , Femenino , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Prevalencia , Proteoma/metabolismo , Esquizofrenia/genéticaRESUMEN
Atherosclerosis is a multifactorial disease involving a lot of genes and proteins recruited throughout its manifestation. The present study aims to exploit bioinformatic tools in order to analyze microarray data of atherosclerotic aortic lesions of ApoE knockout mice, a model widely used in atherosclerosis research. In particular, a dynamic analysis was performed among young and aged animals, resulting in a list of 852 significantly altered genes. Pathway analysis indicated alterations in critical cellular processes related to cell communication and signal transduction, immune response, lipid transport, and metabolism. Cluster analysis partitioned the significantly differentiated genes in three major clusters of similar expression profile. Promoter analysis applied to functional related groups of the same cluster revealed shared putative cis-elements potentially contributing to a common regulatory mechanism. Finally, by reverse engineering the functional relevance of differentially expressed genes with specific cellular pathways, putative genes acting as hubs, were identified, linking functionally disparate cellular processes in the context of traditional molecular description.