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1.
Int J Mol Sci ; 24(3)2023 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-36768150

RESUMEN

Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on a larger scale, are deemed responsible not only for tumor initiation but also for recurrent tumors, often resistant to chemotherapy and radiotherapy. Long noncoding RNAs are RNA molecules longer than 200 nt, lacking the ability to code for proteins, with recognized roles as fine regulators of gene expression. They can exert these functions through a variety of mechanisms, acting at almost all steps of gene expression, from modulation of the epigenetic state of chromatin to modulation of protein stability. In all cases, lncRNAs do not work alone, but they always interact with other RNA molecules, either coding or non-coding, or with protein factors. In this review, we summarize the latest results obtained about the involvement of lncRNAs in the initiating cells of several types of tumors, and highlight the different mechanisms through which they work, while discussing how the modulation of a lncRNA can affect several aspects of tumor onset and progression.


Asunto(s)
ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Recurrencia Local de Neoplasia/genética , Cromatina , Células Madre Neoplásicas/metabolismo , Regulación Neoplásica de la Expresión Génica
2.
RNA Biol ; 18(sup1): 75-87, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34224323

RESUMEN

Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosines to inosines in double-stranded RNAs (RNA editing A-to-I). ADAR1 and ADAR2 were previously reported as HIV-1 proviral factors. The aim of this study was to investigate the composition of the ADAR2 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 10 non-ribosomal ADAR2-interacting factors. A significant fraction of these proteins was previously found associated to the Long INterspersed Element 1 (LINE1 or L1) ribonucleoparticles and to regulate the life cycle of L1 retrotransposons. Considering that we previously demonstrated that ADAR1 is an inhibitor of LINE-1 retrotransposon activity, we investigated whether also ADAR2 played a similar function. To reach this goal, we performed specific cell culture retrotransposition assays in cells overexpressing or ablated for ADAR2. These experiments unveil a novel function of ADAR2 as suppressor of L1 retrotransposition. Furthermore, we showed that ADAR2 binds the basal L1 RNP complex.Overall, these data support the role of ADAR2 as regulator of L1 life cycle.


Asunto(s)
Adenosina Desaminasa/metabolismo , Elementos de Nucleótido Esparcido Largo , Edición de ARN , Proteínas de Unión al ARN/metabolismo , Adenosina Desaminasa/genética , Células HEK293 , Células HeLa , Humanos , Proteínas de Unión al ARN/genética
3.
Int J Mol Sci ; 21(8)2020 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-32316617

RESUMEN

N6-methyladenosine (m6A) is one of the most widespread and abundant internal messenger RNA modifications found in eukaryotes. Emerging evidence suggests that this modification is strongly linked to the activation and inhibition of cancer pathways and is associated with prognostically significant tumour subtypes. The present review describes the dynamic nature of m6A regulator enzymes, as methyltransferases, demethylases and m6A binding proteins, and points out thevalue of the balance among these proteins in regulating gene expression, cell metabolism and cancer development. The main focus of this review is on the roles of m6A modification in glioblastoma, the most aggressive and invariably lethal brain tumour. Although the study of m6A in glioblastoma is a young one, and papers in this field can yield divergent conclusions, the results collected so far clearly demonstrate that modulation of mRNA m6A levels impacts multiple aspects of this tumour, including growth, glioma stem cells self-renewal, and tumorigenesis, suggesting that mRNA m6A modification may serve as a promising target for glioblastoma therapy. We also present recent data about another type of epitranscriptomic modification, the methylation of cytosine at a specific site of 28S rRNA, as it was recently shown to affect the biology of glioma cells, with high potential of clinical implications.


Asunto(s)
Adenosina/análogos & derivados , Neoplasias Encefálicas/genética , Glioblastoma/genética , Adenosina/metabolismo , Citosina/química , Epigénesis Genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación , ARN Ribosómico 28S/genética
4.
Chromosome Res ; 26(1-2): 45-59, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29396793

RESUMEN

Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within double-stranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.


Asunto(s)
Desaminasas APOBEC/metabolismo , Adenosina Desaminasa/metabolismo , Citidina Desaminasa/metabolismo , Elementos de Nucleótido Esparcido Largo , Retroelementos , ADN/metabolismo , Humanos , ARN/metabolismo , ARN Bicatenario/metabolismo
5.
Nucleic Acids Res ; 45(1): 155-168, 2017 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-27658966

RESUMEN

Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosines to inosines in double-stranded RNAs. ADAR1 was demonstrated to be functional on different viruses exerting either antiviral or proviral effects. Concerning HIV-1, several studies showed that ADAR1 favors viral replication. The aim of this study was to investigate the composition of the ADAR1 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 14 non-ribosomal ADAR1-interacting proteins, most of which are novel. A significant fraction of these proteins were previously demonstrated to be associated to the Long INterspersed Element 1 (LINE1 or L1) ribonucleoparticles and to regulate the life cycle of L1 retrotransposons that continuously re-enter host-genome.Hence, we investigated the function of ADAR1 in the regulation of L1 activity.By using different cell-culture based retrotransposition assays in HeLa cells, we demonstrated a novel function of ADAR1 as suppressor of L1 retrotransposition. Apparently, this inhibitory mechanism does not occur through ADAR1 editing activity. Furthermore, we showed that ADAR1 binds the basal L1 RNP complex. Overall, these data support the role of ADAR1 as regulator of L1 life cycle.


Asunto(s)
Adenosina Desaminasa/genética , VIH-1/genética , Elementos de Nucleótido Esparcido Largo , Proteínas de Unión al ARN/genética , Retroelementos , Ribonucleoproteínas/genética , Adenosina Desaminasa/metabolismo , Bioensayo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Células HEK293 , VIH-1/metabolismo , Células HeLa , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Interacciones Huésped-Patógeno , Humanos , Anotación de Secuencia Molecular , Unión Proteica , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteínas/metabolismo , Transducción de Señal
6.
Int J Mol Sci ; 20(10)2019 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-31117166

RESUMEN

Glioblastoma (GBM) is a primary brain tumor whose prognosis is inevitably dismal, leading patients to death in about 15 months from diagnosis. Tumor cells in the mass of the neoplasm are in continuous exchange with cells of the stromal microenvironment, through the production of soluble molecules, among which chemokines play prominent roles. CXCL14 is a chemokine with a pro-tumor role in breast and prostate carcinoma, where it is secreted by cancer associated fibroblasts, and contributes to tumor growth and invasion. We previously observed that CXCL14 expression is higher in GBM tissues than in healthy white matter. Here, we study the effects of exogenously supplemented CXCL14 on key tumorigenic properties of human GBM cell lines. We show that CXCL14 enhances the migration ability and the proliferation of U87MG and LN229 GBM cell lines. None of these effects was affected by the use of AMD3100, an inhibitor of CXCR4 receptor, suggesting that the observed CXCL14 effects are not mediated by this receptor. We also provide evidence that CXCL14 enhances the sphere-forming ability of glioblastoma stem cells, considered the initiating cells, and is responsible for tumor onset, growth and recurrence. In support of our in vitro results, we present data from several GBM expression datasets, demonstrating that CXCL14 expression is inversely correlated with overall survival, that it is enriched at the leading edge of the tumors and in infiltrating tumor areas, and it characterizes mesenchymal and NON G-CIMP tumors, known to have a particularly bad prognosis. Overall, our results point to CXCL14 as a protumorigenic chemokine in GBM.


Asunto(s)
Movimiento Celular , Proliferación Celular , Quimiocinas CXC/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Línea Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/fisiopatología , Humanos , Microambiente Tumoral
7.
EMBO Rep ; 17(12): 1872-1889, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27852622

RESUMEN

MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes myc , Glioblastoma/genética , Células Madre Neoplásicas/fisiología , Fragmentos de Péptidos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/genética , Inhibidores de la Angiogénesis , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Proliferación Celular , Receptores ErbB/genética , Glioblastoma/fisiopatología , Humanos , Proteínas Inhibidoras de la Diferenciación/genética , MicroARNs/genética , Proteínas del Tejido Nervioso/genética , Factor de Transcripción 2 de los Oligodendrocitos , Unión Proteica , Activación Transcripcional , Microambiente Tumoral/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética
8.
Biochim Biophys Acta ; 1849(8): 919-29, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26003733

RESUMEN

BACKGROUND AND AIMS: Epithelial-to-mesenchymal transition (EMT) and the reverse mesenchymal-to-epithelial transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. While a major epigenetic code controlling the coordinated regulation of a whole transcriptional profile is guaranteed by DNA methylation, DNA methyltransferase (DNMT) activities in EMT/MET dynamics are still largely unexplored. Here, we investigated the molecular mechanisms directly linking HNF4α, the master effector of MET, to the regulation of both de novo of DNMT 3A and 3B. METHODS: Correlation among EMT/MET markers, microRNA29 and DNMT3s expression was evaluated by RT-qPCR, Western blotting and immunocytochemical analysis. Functional roles of microRNAs and DNMT3s were tested by anti-miRs, microRNA precursors and chemical inhibitors. ChIP was utilized for investigating HNF4α DNA binding activity. RESULTS: HNF4α silencing was sufficient to induce positive modulation of DNMT3B, in in vitro differentiated hepatocytes as well as in vivo hepatocyte-specific Hnf4α knockout mice, and DNMT3A, in vitro, but not DNMT1. In exploring the molecular mechanisms underlying these observations, evidence have been gathered for (i) the inverse correlation between DNMT3 levels and the expression of their regulators miR-29a and miR-29b and (ii) the role of HNF4α as a direct regulator of miR-29a-b transcription. Notably, during TGFß-induced EMT, DNMT3s' pivotal function has been proved, thus suggesting the need for the repression of these DNMTs in the maintenance of a differentiated phenotype. CONCLUSIONS: HNF4α maintains hepatocyte identity by regulating miR-29a and -29b expression, which in turn control epigenetic modifications by limiting DNMT3A and DNMT3B levels.


Asunto(s)
Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Epigénesis Genética/fisiología , Transición Epitelial-Mesenquimal/genética , Factor Nuclear 4 del Hepatocito/fisiología , Hepatocitos/citología , MicroARNs/fisiología , Animales , Células Cultivadas , Reprogramación Celular/genética , ADN Metiltransferasa 3A , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hepatocitos/metabolismo , Ratones , Ratones Noqueados
9.
Int J Mol Sci ; 17(8)2016 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-27483257

RESUMEN

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells.


Asunto(s)
Diferenciación Celular , Células Madre Pluripotentes Inducidas/patología , MicroARNs/genética , Neuronas Motoras/patología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Animales , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Neuronas Motoras/metabolismo , Embarazo , Reacción en Cadena en Tiempo Real de la Polimerasa
10.
Int J Mol Sci ; 16(8): 18312-27, 2015 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-26258776

RESUMEN

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.


Asunto(s)
MicroARNs/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Células-Madre Neurales/patología , Médula Espinal/patología , Transcriptoma , Animales , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Ratones , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Mutación , Células-Madre Neurales/metabolismo , Médula Espinal/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/genética
11.
RNA Biol ; 11(4): 334-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24717285

RESUMEN

Several cellular microRNAs show substantial changes in expression during HIV-1 infection and their active role in the viral life cycle is progressively emerging. In the present study, we found that HIV-1 infection of Jurkat T cells significantly induces the expression of miR-222. We show that this induction depends on HIV-1 Tat protein, which is able to increase the transcriptional activity of NFkB on miR-222 promoter. Moreover, we demonstrate that miR-222 directly targets CD4, a key receptor for HIV-1, thus reducing its expression. We propose that Tat, by inducing miR-222 expression, complements the CD4 downregulation activity exerted by other viral proteins (i.e., Nef, Vpu, and Env), and we suggest that this represents a novel mechanism through which HIV-1 efficiently represses CD4 expression in infected cells.


Asunto(s)
Antígenos CD4/genética , Regulación de la Expresión Génica , Infecciones por VIH/genética , VIH-1/fisiología , MicroARNs/genética , Subgrupos de Linfocitos T/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Antígenos CD4/metabolismo , Línea Celular , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , FN-kappa B/metabolismo , ARN Mensajero/genética , Subgrupos de Linfocitos T/inmunología
12.
RNA Biol ; 10(6): 935-42, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23696003

RESUMEN

In the last decade, an ever-growing number of connections between microRNAs (miRNAs) and RNA-binding proteins (RBPs) have uncovered a new level of complexity of gene expression regulation in cancer. In this review, we examine several aspects of the functional interactions between miRNAs and RBPs in cancer models. We will provide examples of reciprocal regulation: miRNAs regulating the expression of RBPs, or the converse, where an RNA-binding protein specifically regulates the expression of a specific miRNA, or when an RBP can exert a widespread effect on miRNAs via the modulation of a key protein for miRNA production or function. Moreover, we will focus on the ever-growing number of functional interactions that have been discovered in the last few years: RBPs that were shown to cooperate with microRNAs in the downregulation of shared target mRNAs or, on the contrary, that inhibit microRNA action, thus resulting in a protection of the specific target mRNAs. We surely need to obtain a deeper comprehension of such intricate networks to have a chance of understanding and, thus, fighting cancer.


Asunto(s)
MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regulación hacia Abajo , Factor de Transcripción E2F3/genética , Factor de Transcripción E2F3/metabolismo , Proteínas ELAV/genética , Proteínas ELAV/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos
13.
Mol Oncol ; 17(2): 238-260, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36495079

RESUMEN

Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC-like), and another by proteins upregulated in mesenchymal GSCs (GM-like). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non-protein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Proteómica , Neoplasias Encefálicas/metabolismo , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral
14.
Cancers (Basel) ; 14(9)2022 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-35565433

RESUMEN

The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.

15.
J Gen Virol ; 92(Pt 5): 1228-1232, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21289159

RESUMEN

The adenosine deaminases acting on RNA (ADAR) enzymes catalyse conversion of adenosine to inosine in dsRNA. A positive effect of ADAR1 on human immunodeficiency virus type 1 (HIV-1) replication has recently been reported. Here, we show that another ADAR enzyme, ADAR2, positively affects the replication process of HIV-1. We found that, analogously to ADAR1, ADAR2 enhances the release of progeny virions by an editing-dependent mechanism. However, differently from the ADAR1 enzyme, ADAR2 does not increase the infectious potential of the virus. Importantly, downregulation of ADAR2 in Jurkat cells significantly impairs viral replication. Therefore, ADAR2 shares some but not all proviral functions of ADAR1. These results suggest a novel role of ADAR2 as a viral regulator.


Asunto(s)
Adenosina Desaminasa/metabolismo , VIH-1/patogenicidad , Interacciones Huésped-Patógeno , Provirus/patogenicidad , Replicación Viral , Humanos , Células Jurkat , Proteínas de Unión al ARN
16.
Methods Mol Biol ; 2181: 269-286, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32729086

RESUMEN

The type I interferonopathies comprise a heterogenous group of monogenic diseases associated with a constitutive activation of type I interferon signaling.The elucidation of the genetic causes of this group of diseases revealed an alteration of nucleic acid processing and signaling.ADAR1 is among the genes found mutated in patients with this type of disorders.This enzyme catalyzes the hydrolytic deamination of adenosines in inosines within a double-stranded RNA target (RNA editing of A to I). This RNA modification is widespread in human cells and deregulated in a variety of human diseases, ranging from cancers to neurological abnormalities.In this review, we briefly summarize the knowledge about the RNA editing alterations occurring in patients with mutations in ADAR1 gene and how these alterations might cause the inappropriate IFN activation.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Interferón Tipo I/genética , Edición de ARN/fisiología , Adenosina Desaminasa/genética , Enfermedades de la Aorta/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Hipoplasia del Esmalte Dental/genética , Humanos , Inmunidad Innata/genética , Interferón Tipo I/metabolismo , Metacarpo/anomalías , Enfermedades Musculares/genética , Malformaciones del Sistema Nervioso/genética , Odontodisplasia/genética , Osteoporosis/genética , ARN Bicatenario/genética , Proteínas de Unión al ARN/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Calcificación Vascular/genética
17.
FASEB J ; 23(12): 4276-87, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19713529

RESUMEN

MicroRNAs are a class of sophisticated regulators of gene expression, acting as post-transcriptional inhibitors that recognize their target mRNAs through base pairing with short regions along the 3'UTRs. Several microRNAs are tissue specific, suggesting a specialized role in tissue differentiation or maintenance, and quite a few are critically involved in tumorigenesis. We studied miR-128, a brain-enriched microRNA, in retinoic acid-differentiated neuroblastoma cells, and we found that this microRNA is up-regulated in treated cells, where it down-modulates the expression of two proteins involved in the migratory potential of neural cells: Reelin and DCX. Consistently, miR-128 ectopic overexpression suppressed Reelin and DCX, whereas the LNA antisense-mediated miR-128 knockdown caused the two proteins to increase. Ectopic miR-128 overexpression reduced neuroblastoma cell motility and invasiveness, and impaired cell growth. Finally, the analysis of a small series of primary human neuroblastomas showed an association between high levels of miR-128 expression and favorable features, such as favorable Shimada category or very young age at diagnosis. Thus, we provide evidence for a role for miR-128 in the molecular events modulating neuroblastoma progression and aggressiveness.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Regulación de la Expresión Génica/fisiología , MicroARNs/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuropéptidos/metabolismo , Serina Endopeptidasas/metabolismo , Secuencia de Bases , Moléculas de Adhesión Celular Neuronal/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Proteínas de la Matriz Extracelular/genética , Humanos , MicroARNs/genética , Proteínas Asociadas a Microtúbulos/genética , Datos de Secuencia Molecular , Invasividad Neoplásica , Proteínas del Tejido Nervioso/genética , Neuroblastoma/metabolismo , Neuronas/efectos de los fármacos , Neuronas/fisiología , Neuropéptidos/genética , Proteína Reelina , Serina Endopeptidasas/genética , Tretinoina/farmacología
18.
Mol Cell Neurosci ; 42(4): 341-9, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19698788

RESUMEN

In the adult mammalian brain, multipotential neural stem cells (NSC) persist throughout life in areas where neurogenesis is maintained. A distinctive trait of NSCs growing in vitro as neurospheres (NS), is their ability to self-renew, differentiate and migrate to sites of injury, such as gliomas. We have studied the role of Reelin, an extracellular matrix protein involved in brain development, in NSCs derived from normal newborn mice or from reeler, a natural mutant in which Reelin is not expressed. We show that the absence of Reelin negatively affects proliferation, NS-forming ability, and neuronal differentiation. Reeler NSCs are unable to migrate in chains, a migration mode typical of neural precursors homing to injury sites in adult CNS. All these effects are partially rescued by ectopic Reelin supplementation. Finally, we show that reeler NSCs fail to migrate in vivo towards gliomas. Overall, our results indicate that Reelin affects all major features of postnatal NSCs, and that it is required for the proper homing of NSCs to tumor sites in adult brain.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Serina Endopeptidasas/metabolismo , Células Madre/fisiología , Animales , Encéfalo/citología , Encéfalo/fisiología , Moléculas de Adhesión Celular Neuronal/genética , Células Cultivadas , Proteínas de la Matriz Extracelular/genética , Femenino , Glioma/metabolismo , Glioma/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Proteínas del Tejido Nervioso/genética , Neuronas/citología , Proteína Reelina , Serina Endopeptidasas/genética , Células Madre/citología
20.
Oncotarget ; 9(21): 15512-15525, 2018 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-29643989

RESUMEN

The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2. By employing a factor analysis on a SAGE dataset of 12 glioblastoma samples, we show that H19 expression in glioblastoma tissues correlates with that of several genes involved in glioblastoma growth and progression. H19 knock-down reduces viability, migration and invasiveness of two distinct human glioblastoma cell lines. Most importantly, we provide a mechanistic perspective about the role of H19 in glioblastoma cells, by showing that its expression is inversely linked to that of NKD1, a negative regulator of Wnt pathway, suggesting that H19 might regulate NKD1 transcription via EZH2-induced H3K27 trimethylation of its promoter. Indeed, we showed that H19 binds EZH2 in glioblastoma cells, and that EZH2 binding to NKD1 and other promoters is impaired by H19 silencing. In this work we describe H19 as part of an epigenetic modulation program executed by EZH2, that results in the repression of Nkd1. We believe that our results can provide a new piece to the complex puzzle of H19 function in glioblastoma.

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