Sergio Nasi

Sapienza University of Rome

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Daniela Annibali

KU Leuven

Barbara Illi

National Research Council

Laura Soucek

Institució Catalana de Recerca i Estudis Avançats

Mauro Savino

Institute of Molecular Biology and Pathology

Gérard I. Evan

King's College London

Richard Jucker

University of Zurich

Fiorella Scagnoli

Institute of Molecular Biology and Pathology

Emilia Favuzzi

Harvard University

Lamorna Brown Swigart

University of California, San Francisco

Jonathan R. Whitfield

Vall d'Hebron Institute of Oncology

Cooperative Institutions

Sapienza University of Rome

Istituti di Ricovero e Cura a Carattere Scientifico

National Research Council

Institute of Molecular Biology and Pathology

University of Rome Tor Vergata

National Academies of Sciences, Engineering, and Medicine

Institute of Cell Biology and Neurobiology

Università Cattolica del Sacro Cuore

Istituto Pasteur

Institute of Neurobiology and Molecular Medicine

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The Protein Arginine Methyltransferases 1 and 5 affect Myc properties in glioblastoma stem cells

Scientific Reports (2019)

Annarita Favia Luisa Salvatori Simona Nanni Lisa K. Iwamoto-Stohl Sérgio Valente

Abstract Protein Arginine (R) methylation is the most common post-translational methylation in mammalian cells. Protein Arginine Methyltransferases (PRMT) 1 and 5 dimethylate their substrates on R residues, asymmetrically and symmetrically, respectively. They are ubiquitously expressed and play fundamental roles in tumour malignancies, including glioblastoma multiforme (GBM) which presents largely deregulated Myc activity. Previously, we demonstrated that PRMT5 associates with Myc in GBM cells, modulating, at least in part, its transcriptional properties. Here we show that Myc/PRMT5 protein complex includes PRMT1, in both HEK293T and glioblastoma stem cells (GSCs). We demonstrate that Myc is both asymmetrically and symmetrically dimethylated by PRMT1 and PRMT5, respectively, and that these modifications differentially regulate its stability. Moreover, we show that the ratio between symmetrically and asymmetrically dimethylated Myc changes in GSCs grown in stem versus differentiating conditions. Finally, both PRMT1 and PRMT5 activity modulate Myc binding at its specific target promoters. To our knowledge, this is the first work reporting R asymmetrical and symmetrical dimethylation as novel Myc post-translational modifications, with different functional properties. This opens a completely unexplored field of investigation in Myc biology and suggests symmetrically dimethylated Myc species as novel diagnostic and prognostic markers and druggable therapeutic targets for GBM.

HEK 293 cells

Proto-Oncogene Proteins c-myc

Protein methylation

Temozolomide

10.1038/s41598-019-52291-6

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Citations (36)

A New Module in Neural Differentiation Control: Two MicroRNAs Upregulated by Retinoic Acid, miR-9 and -103, Target the Differentiation Inhibitor ID2

PLoS ONE (2012)

Daniela Annibali Ubaldo Gioia Mauro Savino Pietro Laneve Elisa Caffarelli

The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs) are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells – miR-9 and miR-103 – restrain ID2 expression by directly targeting the coding sequence and 3′ untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

10.1371/journal.pone.0040269

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Citations (69)

Interplay of the E Box, the Cyclic AMP Response Element, and HTF4/HEB in Transcriptional Regulation of the Neurospecific, Neurotrophin-InduciblevgfGene†

Molecular and Cellular Biology (1997)

Giuliana Di Rocco Maria Pennuto Barbara Illi Nadia Canu Gessica Filocamo

vgf is a neurotrophin response-specific, developmentally regulated gene that codes for a neurosecretory polypeptide. Its transcription in neuronal cells is selectively activated by the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin 3, which induce survival and differentiation, and not by epidermal growth factor. We studied a short region of the rat vgf promoter which is essential for its regulated expression. A cyclic AMP response element (CRE) within this region is necessary for NGF induction of vgf transcription. Two sites upstream of CRE, an E box and a CCAAT sequence, bind nuclear protein complexes and are involved in transcriptional control. The E box has a dual role. It acts as an inhibitor in NIH 3T3 fibroblasts, together with a second E box located downstream, and as a stimulator in the NGF-responsive cell line PC12. By expression screening, we have isolated the cDNA for a basic helix-loop-helix transcription factor, a homolog of the HTF4/HEB E protein, that specifically binds the vgf promoter E box. The E protein was present in various cell lines, including PC12 cells, and was a component of a multiprotein nuclear complex that binds the promoter in vitro. The E box and CRE cooperate in binding to this complex, which may be an important determinant for neural cell-specific expression.

CAAT box

Serum Response Element

10.1128/mcb.17.3.1244

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Citations (30)

Isolation and properties of DMSO resistant variant clones of friend leukemia cells

Cell Differentiation (1978)

Sergio Nasi Di Girolamo E. Calef

Glycophorin

Hemin

10.1016/0045-6039(78)90022-2

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Citations (9)

Non coding RNA and brain

BMC Neuroscience (2006)

Carlo Presutti Jessica Rosati Sara Vincenti Sergio Nasi

Abstract Small non coding RNAs are a group of very different RNA molecules, present in virtually all cells, with a wide spectrum of regulatory functions which include RNA modification and regulation of protein synthesis. They have been isolated and characterized in all organisms and tissues, from Archaeobacteria to mammals. In mammalian brain there are a number of these small molecules, which are involved in neuronal differentiation as well as, possibly, in learning and memory. In this manuscript, we analyze the present knowledge about the function of the most important groups of small non-coding RNA present in brain: small nucleolar RNAs, small cytoplasmic RNAs, and microRNAs. The last ones, in particular, appear to be critical for dictating neuronal cell identity during development and to play an important role in neurite growth, synaptic development and neuronal plasticity.

Small nucleolar RNA

Neurite

10.1186/1471-2202-7-s1-s5

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Citations (60)

Isolation of suppressor sensitive mutants in the Ai gene of phage λ

MGG Molecular & General Genetics (1976)

Gianni Cesareni Sergio Nasi

Isolation

Phagemid

10.1007/bf00332889

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Citations (1)

Cancer: We Should Not Forget The Past

Journal of Cancer (2014)

Anna Di Lonardo Sergio Nasi Simonetta Pulciani

Cancer has been in existence longer than human beings, and man has been facing the illness ever since he made his appearance on Earth. Amazingly, the first human cancer gene was cloned only thirty years ago. This, and other extraordinary scientific goals achieved by molecular cancer research in the last 30 years, seems to suggest that definitive answers and solutions to this severe disease have been finally found. This was not the case, as cancer still remains to be defeated. To do so, cancer must be first understood. This review highlights how cancer onset and progression has been tackled from ancient times to present day. Old theories and achievements have provided the pillars of cancer understanding, in laying the basis of 'modern era' cancer research, are discussed. The review highlights the discovery of oncogenes and suppressor tumor genes, underlining the crucial role of these achievements in cancer diagnosis and therapies. Finally, an overview of how the modern technologies have given impetuous to expedite these goals is also considered.

Human disease

10.7150/jca.10336

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Citations (55)

The effect of Ha-ras oncogene expression on EBV immortalized B lymphocytes

Cell Biology International Reports (1990)

Richard Jucker Maria Isabella Sirinian Alessandra Marchetti G DIROCCO Sergio Nasi

Expression (computer science)

10.1016/0309-1651(90)90461-7

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MiR-21 is an Ngf-Modulated MicroRNA That Supports Ngf Signaling and Regulates Neuronal Degeneration in PC12 Cells

NeuroMolecular Medicine (2014)

Enrica Montalban Nicola Mattugini Roberta Ciarapica Claudia Provenzano Mauro Savino

The neurotrophins Ngf, Bdnf, NT-3, NT4–5 have key roles in development, survival, and plasticity of neuronal cells. Their action involves broad gene expression changes at the level of transcription and translation. MicroRNAs (miRs)—small RNA molecules that control gene expression post-transcriptionally—are increasingly implicated in regulating development and plasticity of neural cells. Using PC12 cells as a model system, we show that Ngf modulates changes in expression of a variety of microRNAs, including miRs known to be modulated by neurotrophins—such as the miR-212/132 cluster—and several others, such as miR-21, miR-29c, miR-30c, miR-93, miR-103, miR-207, miR-691, and miR-709. Pathway analysis indicates that Ngf-modulated miRs may regulate many protein components of signaling pathways involved in neuronal development and disease. In particular, we show that miR-21 enhances neurotrophin signaling and controls neuronal differentiation induced by Ngf. Notably, in a situation mimicking neurodegeneration—differentiated neurons deprived of Ngf—this microRNA is able to preserve the neurite network and to support viability of the neurons. These findings uncover a broad role of microRNAs in regulating neurotrophin signaling and suggest that aberrant expression of one or more Ngf-modulated miRs may be involved in neurodegenerative diseases.

Neurite

10.1007/s12017-014-8292-z

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Citations (52)

Hidden receptors for nerve growth factor in PC12 cells

European Journal of Biochemistry (1983)

Antonino Cattaneo Silvia Biocca Sergio Nasi Pietro Calissano

The binding of nerve growth factor (NGF) to its receptors in PC12 cells was studied in two experimental conditions: (a) cell fixation with paraformaldehyde followed by permeabilization of the plasma membrane with methanol and (b) metabolic poisoning of living cells with sodium azide. Paraformaldehyde fixation of PC12 cells causes a 60–70% reduction of NGF binding capacity; the original binding capacity is restored following permeabilization with methanol. A kinetic analysis of NGF binding under these conditions reveals a single homogeneous population of receptors at variance with experiments performed in living cells where two kinetically distinct types of NGF receptors were demonstrated [Landreth, G. E. and Shooter, E. M. (1980) Proc. Natl Acad. Sci. USA, 77, 4751–4755; Schechter, A. L. and Bothwell, M. A. (1981) Cell, 24, 867–874]. Our results suggest that a proportion of the NGF receptors in PC12 cells is hidden, i.e. not available for binding to the ligand, and in a dynamic equilibrium with exposed receptors. The existence of hidden receptors is confirmed by treatment of PC12 cells with sodium azide, which causes a 50% reduction in NGF binding capacity and protection from trypsin digestion of the remaining pool of hidden receptors. The latter become exposed at the cell surface following removal of sodium azide. Our data provide an interpretation for the as yet unsatisfactorily explained data on NGF receptors.

Paraformaldehyde

Sodium azide

10.1111/j.1432-1033.1983.tb07650.x

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Citations (20)