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Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,CNR Institute of Neurobiology and Molecular Medicine | Sardo F.L.,Dulbecco Telethon Institute | Diamantini A.,Cervello | Orlando V.,Dulbecco Telethon Institute
PLoS Genetics | Year: 2011

Polycomb group (PcG) proteins are part of a conserved cell memory system that conveys epigenetic inheritance of silenced transcriptional states through cell division. Despite the considerable amount of information about PcG mechanisms controlling gene silencing, how PcG proteins maintain repressive chromatin during epigenome duplication is still unclear. Here we identified a specific time window, the early S phase, in which PcG proteins are recruited at BX-C PRE target sites in concomitance with H3K27me3 repressive mark deposition. Notably, these events precede and are uncoupled from PRE replication timing, which occurs in late S phase when most epigenetic signatures are reduced. These findings shed light on one of the key mechanisms for PcG-mediated epigenetic inheritance during S phase, suggesting a conserved model in which the PcG-dependent H3K27me3 mark is inherited by dilution and not by de novo methylation occurring at the time of replication. © 2011 Lanzuolo et al.

Gurtner A.,Regina Elena Cancer Institute | Starace G.,CNR Institute of Neurobiology and Molecular Medicine | Norelli G.,Regina Elena Cancer Institute | Piaggio G.,Regina Elena Cancer Institute | And 2 more authors.
Journal of Biological Chemistry | Year: 2010

Mitogen-activated protein kinase kinase 3 (MAP2K3) is a member of the dual specificity kinase group. Growing evidence links MAP2K3 to invasion and tumor progression. Here, we identify MAP2K3 as a transcriptional target of endogenous gain-of-function p53 mutants R273H, R175H, and R280K. We show thatMAP2K3modulation occurred at the mRNA and protein levels and that endogenous mutant p53 proteins are capable of binding to and activate the MAP2K3 promoter. In addition, we found that the studied p53 mutants regulate MAP2K3 gene expression through the involvement of the transcriptional cofactors NF-Y and NF-κB. Finally, functional studies showed that endogenous MAP2K3 knockdown inhibits proliferation and survival of human tumor cells, whereas the ectopic expression of MAP2K3 can rescue the proliferative defect induced by mutant p53 knockdown. Taken together, our findings define a novel player through which mutant p53 exerts its gain-of-function activity in cancer cells. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Vene R.,Italian National Cancer Institute | Castellani P.,Italian National Cancer Institute | Delfino L.,Italian National Cancer Institute | Lucibello M.,CNR Institute of Neurobiology and Molecular Medicine | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2011

Aims: Cancer chemoresistance is often due to upregulation of antioxidant systems. Therapeutic targeting of these systems is however hampered by their redundancy. Here, we have performed a functional dissection of the antioxidant systems in different melanoma cases aimed at the identification of the most effective redox active drug. Results: We have identified two crucial antioxidant mechanisms: glutathione (GSH), the major intracellular redox buffer, and the cystine/cysteine cycle, which switches the extracellular redox state from an oxidized to a reduced state. The two mechanisms are independent in melanoma cells and may be substitutes for each other, but targeting both of them is lethal. Exposure to the pro-oxidant compound As 2O 3 induces an antioxidant response. However, while in these cells the intracellular redox balance remains almost unaffected, a reduced environment is generated extracellularly. GSH depletion by buthioninesulfoximine (BSO), or cystine/cysteine cycle inhibition by (S)-4-carboxyphenylglycine (sCPG), enhanced the sensitivity to As 2O 3. Remarkably, sCPG also prevented the remodeling of the microenvironment redox state. Innovation: We propose that the definition of the prevalent antioxidant system(s) in tumors is crucial for the design of tailored therapies involving redox-directed drugs in association with pro-oxidant drugs. Conclusion: In melanoma cells, BSO is the best enhancer of As 2O 3 sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As 2O 3 may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended. © 2011 Mary Ann Liebert, Inc.

Chiarella P.,Biomedical University of Rome | Chiarella P.,CNR Institute of Neurobiology and Molecular Medicine | Fazio V.M.,Biomedical University of Rome | Signori E.,Biomedical University of Rome | Signori E.,CNR Institute of Neurobiology and Molecular Medicine
Current Gene Therapy | Year: 2010

Vaccination is historically one of the most important methods for preventing infectious diseases in humans and animals. Due to recent advances in understanding the biology of the immune system, a more rational design of vaccines and vaccination strategies such as those based on gene transfer has been proposed. In particular, naked DNA vaccination is emerging as a promising approach for introducing foreign antigens into the host, inducing protective immunity against infectious diseases and malignant tumours. Plasmid DNA vaccines offer several advantages in comparison to traditional vaccines such as safety, tolerability and feasibility in manufacture. Nevertheless, because of their poor immunogenicity, plasmid DNA vaccines need further implementation. Recent data suggest electroporation as a useful strategy to improve DNA-based vaccination protocols, being able to stimulate both the humoural and cellular immune responses. In preclinical trials, electroporation is successfully used in prime-boost combination protocols and its efficacy and tolerability have been demonstrated in Phase I clinical trials. Since these initial results appear promising, in the next future we will assist further developments of naked DNA vaccination associated to the electroporation technology. This approach not only provides the basis for human studies but also a practical application to veterinary medicine. © 2010 Bentham Science Publishers Ltd.

Sornelli F.,CNR Institute of Neurobiology and Molecular Medicine | Lambiase A.,Biomedical University of Rome | Mantelli F.,Biomedical University of Rome | Aloe L.,CNR Institute of Neurobiology and Molecular Medicine
Molecular Vision | Year: 2010

Purpose: Several growth factors, including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), play an important role in the homeostasis of the ocular surface. The involvement of both these growth factors in the pathophysiology of intraocular tissues has been extensively investigated. Despite the expression of NGF receptors by corneal endothelium, to date the role of NGF on the endothelial cell remains to be determined. Using a clonal cell line of human corneal endothelial cells, the aim of this study was to investigate the expression of the NGF-receptor and the potential partnership of NGF and VEGF in maintaining cell viability in vitro. Methods: A human endothelial cell line (B4G12), was cultured under serum-free conditions as previously described with and without addition of different concentrations of NGF, anti-NGF-antibody (ANA), or VEGF for 4 days and these cells were used for immuno-istochemical, biochemical, and molecular analyses. Results: NGF induces overexpression of NGF-receptors and synthesis and release of VEGF by endothelial cells and these cells are able to produce and secrete NGF. Conclusions: These observations indicate that human corneal endothelial cells are receptive to the action of NGF and that these cells may regulate NGF activity through autocrine/paracrine mechanisms. © 2010 Molecular Vision.

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