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Avitabile C.,University of Naples Federico II | Cimmino A.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Cimmino A.,Instituto Of Ricovero E Cura A Carattere Scientifico Sdn Irccs Sdn | Romanelli A.,University of Naples Federico II
Journal of Medicinal Chemistry | Year: 2014

ncRNAs are emerging as key regulators of physiological and pathological processes and therefore have been identified as pharmacological targets and as markers for some diseases. Oligonucleotide analogues represent so far the most widely employed tool for the modulation of the expression of ncRNAs. In this perspective we briefly describe most of the known classes of ncRNAs and then we discuss the design and the applications of oligonucleotide analogues for their targeting. The effects of modifications of the chemical structure of the oligonucleotides on properties such as the binding affinity toward targets and off targets, and the stability to degradation and their biological effects (when known) are discussed. Examples of molecules currently used in clinical trials are also reported. © 2014 American Chemical Society.


Monfregola J.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Napolitano G.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | D'Urso M.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Lappalainen P.,University of Helsinki | Ursini M.V.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Journal of Biological Chemistry | Year: 2010

The Arp2/3 complex is essential for actin filament nucleation in a variety of cellular processes. The activation of the Arp2/3 complex is mediated by nucleation-promoting factors, such as the Wiskott-Aldrich syndrome family proteins, which share a WCA (WH2 domain, central region, acidic region) catalytic module at the C-terminal region, required for Arp2/3 activation, but diverge at the N-terminal region, required for binding to specific activators. Here, we report the characterization of WASH, a new member of the WAS family that has nucleation-promoting factor activity and recently has been demonstrated to play a role in endosomal sorting. We found that overexpression of the WASH-WCA domain induced disruption of the actin cytoskeleton, whereas overexpression of full-length WASH in mammalian cells did not affect stress fiber organization. Furthermore, our analysis has revealed that nerve growth factor treatment of PC12 cells overexpressing full-length WASH leads to disruption of the actin cytoskeleton. We have also found that WASH interacts through its N-terminal region with BLOS2, a centrosomal protein belonging to the BLOC-1 complex that functions as a scaffolding factor in the biogenesis of lysosome-related organelles. In addition to BLOS2, WASH also interacts with centrosomal γ-tubulin and with pallidin, an additional component of the BLOC-1 complex. Collectively, our data propose thatWASHis a bimodular protein in which the C terminus is involved in Arp2/3-mediated actin nucleation, whereas the N-terminal portion is required for its regulation and localization in the cells. Moreover, our data suggest that WASH is also a component of the BLOC-1 complex that is associated with the centrosomes. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Costa V.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Angelini C.,CNR Institute for applied mathematics Mauro Picone | De Feis I.,CNR Institute for applied mathematics Mauro Picone | Ciccodicola A.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Journal of Biomedicine and Biotechnology | Year: 2010

In recent years, the introduction of massively parallel sequencing platforms for Next Generation Sequencing (NGS) protocols, able to simultaneously sequence hundred thousand DNA fragments, dramatically changed the landscape of the genetics studies. RNA-Seq for transcriptome studies, Chip-Seq for DNA-proteins interaction, CNV-Seq for large genome nucleotide variations are only some of the intriguing new applications supported by these innovative platforms. Among them RNA-Seq is perhaps the most complex NGS application. Expression levels of specific genes, differential splicing, allele-specific expression of transcripts can be accurately determined by RNA-Seq experiments to address many biological-related issues. All these attributes are not readily achievable from previously widespread hybridization-based or tag sequence-based approaches. However, the unprecedented level of sensitivity and the large amount of available data produced by NGS platforms provide clear advantages as well as new challenges and issues. This technology brings the great power to make several new biological observations and discoveries, it also requires a considerable effort in the development of new bioinformatics tools to deal with these massive data files. The paper aims to give a survey of the RNA-Seq methodology, particularly focusing on the challenges that this application presents both from a biological and a bioinformatics point of view. Copyright © 2010 Valerio Costa et al.


Benedetti R.,The Second University of Naples | Conte M.,The Second University of Naples | Altucci L.,The Second University of Naples | Altucci L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Antioxidants and Redox Signaling | Year: 2015

Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Conte M.,The Second University of Naples | Altucci L.,The Second University of Naples | Altucci L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Clinical Cancer Research | Year: 2012

Human cancer is causally linked to genomic and epigenomic deregulations. Epigenetic abnormalities occurring within signaling pathways regulating proliferation, migration, growth, differentiation, transcription, and death signals may be critical in the progression of malignancies. Consequently, identification of epigenetic marks and their bioimplications in tumors represents a crucial step toward defining new therapeutic strategies both in cancer treatment and prevention. Alterations of writers, readers, and erasers in cancer may affect, for example, the methylation and acetylation state of huge areas of chromatin, suggesting that epi-based treatments may require "distinct" therapeutic strategies compared with "canonical" targeted treatments. Whereas anticancer treatments targeting histone deacetylase and DNA methylation have entered the clinic, additional chromatin modification enzymes have not yet been pharmacologically targeted for clinical use in patients. Thus, a greater insight into alterations occurring on chromatin modifiers and their impact in tumorigenesis represents a crucial advancement in exploiting epigenetic targeting in cancer prevention and treatment. Here, the interplay of the best known epi-mutations and how their targeting might be optimized are addressed. ©2012 AACR.


Carafa V.,The Second University of Naples | Nebbioso A.,The Second University of Naples | Altucci L.,The Second University of Naples | Altucci L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Frontiers in Pharmacology | Year: 2012

Sirtuins represent a promising new class of conserved histone deacetylases, originally identified in yeast. The activity of the sirtuin (SirT) family - made up of seven members (SirT1-7) - is NAD+ dependent. Sirtuins target a wide range of cellular proteins in nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SirT1, 2, 3, and 5) or ADP-ribosylation (SirT4 and 6). Sirtuins regulate responses to stress and ensure that damaged DNA is not propagated, thus contrasting the accumulation of mutations. To date, sirtuins have emerged as potential therapeutic targets for treatment of human pathologies such as metabolic, cardiovascular and neurodegenerative diseases, and cancer. SirT1 is the founding member of this class of enzymes and is currently the best known of the group. SirT1 acts in various cellular processes, deacetylating both chromatin and non-histone proteins, and its role in cancer and aging has been extensively studied. SirT1 may play a critical role in tumor initiation and progression as well as drug resistance by blocking senescence and apoptosis, and by promoting cell growth and angiogenesis. Recently, growing interest in sirtuin modulation has led to the discovery and characterization of small molecules able to modify sirtuin activity.The present review highlights SirT mechanism(s) of action and deregulation in cancer, focusing on the therapeutic potential of SirT modulators both in cancer prevention and treatment. © 2012 Carafa, Nebbioso and Altucci.


Dell'Aversana C.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Lepore I.,The Second University of Naples | Altucci L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Altucci L.,The Second University of Naples
Experimental Cell Research | Year: 2012

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two opposing classes of enzymes, which finely regulate the balance of histone acetylation affecting chromatin packaging and gene expression. Imbalanced acetylation has been associated with carcinogenesis and cancer progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. This implies that epigenetic alterations are amenable to pharmacological interventions. Accordingly, some epigenetic-based drugs (epidrugs) have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment. Here, we focus on the biological features of HDAC inhibitors (HDACis), analyzing the mechanism(s) of action and their current use in clinical practice. © 2012 Elsevier Inc.


Bianco C.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Defez R.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Applied and Environmental Microbiology | Year: 2010

Nitrogen (N) and phosphorus (P) are the most limiting factors for plant growth. Some microorganisms improve the uptake and availability of N and P, minimizing chemical fertilizer dependence. It has been published that the RD64 strain, a Sinorhizobium meliloti 1021 strain engineered to overproduce indole-3-acetic acid (IAA), showed improved nitrogen fixation ability compared to the wild-type 1021 strain. Here, we present data showing that RD64 is also highly effective in mobilizing P from insoluble sources, such as phosphate rock (PR). Under P-limiting conditions, the higher level of P-mobilizing activity of RD64 than of the 1021 wild-type strain is connected with the upregulation of genes coding for the high-affinity P transport system, the induction of acid phosphatase activity, and the Increased secretion into the growth medium of malic, succinic, and fumarle acids. Medicago truncatula plants nodulated by RD64 (Mt-RD64), when grown under P-deficient conditions, released larger amounts of another P-solubilizing organic acid, 2-hydroxyglutaric acid, than plants nodulated by the wild-type strain (Mt-1021). It has already been shown that Mt-RD64 plants exhibited higher levels of dry-weight production than Mt-1021 plants. Here, we also report that P-starved Mt-RD64 plants show significant increases in both shoot and root fresh weights when compared to P-starved Mt-1021 plants. We discuss how, in a Rhizobium-legume model system, a balanced interplay of different factors linked to bacterial IAA overproduction rather than IAA production per se stimulates plant growth under stressful environmental conditions and, in particular, under P starvation. Copyright © 2010, American Society for Microbiology, All Rights Reserved.


Nebbioso A.,The Second University of Naples | Carafa V.,The Second University of Naples | Benedetti R.,The Second University of Naples | Altucci L.,The Second University of Naples | Altucci L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Molecular Oncology | Year: 2012

Epigenetic inactivation of pivotal genes involved in correct cell growth is a hallmark of human pathologies, in particular cancer. These epigenetic mechanisms, including crosstalk between DNA methylation, histone modifications and non-coding RNAs, affect gene expression and are associated with disease progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. Re-expression of genes epigenetically inactivated can result in the suppression of disease state or sensitization to specific therapies. Small molecules that reverse epigenetic inactivation, so-called epi-drugs, are now undergoing clinical trials. Accordingly, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment have approved some of these drugs. Here, we focus on the biological features of epigenetic molecules, analyzing the mechanism(s) of action and their current use in clinical practice. © 2012 Federation of European Biochemical Societies.


Manganelli G.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Masullo U.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Passarelli S.,IRCCS | Filosa S.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Cardiovascular and Hematological Disorders - Drug Targets | Year: 2013

We review here some recent data about Glucose-6-phosphate dehydrogenase (G6PD), the housekeeping X-linked gene encoding the first enzyme of the pentose phosphate pathway (PPP), a NADPH-producing dehydrogenase. This enzyme has been popular among clinicians, biochemists, geneticists and molecular biologists because it is the most common form of red blood cell enzymopathy. G6PD deficient erythrocytes do not generate NADPH in any other way than through the PPP and for this reason they are more susceptible than any other cells to oxidative damage. Moreover, this enzyme has also been of crucial importance in many significant discoveries; indeed, G6PD polymorphisms have been instrumental in studying X-inactivation in the human species, as well as in establishing the clonal nature of certain tumors. G6PD deficiency, generally considered as a mild and benign condition, is significantly disadvantageous in certain environmental conditions like in presence of certain drugs. Nevertheless, G6PD deficiency has been positively selected by malaria, and recent knowledge seems to show that it also confers an advantage against the development of cancer, reduces the risk of coronary diseases and has a beneficial effect in terms of longevity. © 2013 Bentham Science Publishers.

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