Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia

Rome, Italy

Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia

Rome, Italy

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Saccone V.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Consalvi S.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Giordani L.,Sanford Burnham Institute for Medical Research | Mozzetta C.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | And 23 more authors.
Genes and Development | Year: 2014

Fibro-adipogenic progenitors (FAPs) are important components of the skeletal muscle regenerative environment. Whether FAPs support muscle regeneration or promote fibro-adipogenic degeneration is emerging as a key determinant in the pathogenesis of muscular diseases, including Duchenne muscular dystrophy (DMD). However, the molecular mechanism that controls FAP lineage commitment and activity is currently unknown. We show here that an HDAC-myomiR-BAF60 variant network regulates the fate of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray, genome-wide chromatin remodeling by nuclease accessibility (NA) combined with next-generation sequencing (NA-seq), small RNA sequencing (RNA-seq), and microRNA (miR) high-throughput screening (HTS) against SWI/SNF BAF60 variants revealed that HDAC inhibitors (HDACis) derepress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease. Specifically, HDAC inhibition induces two core components of the myogenic transcriptional machinery, MYOD and BAF60C, and up-regulates the myogenic miRs (myomiRs) (miR-1.2, miR-133, and miR-206), which target the alternative BAF60 variants BAF60A and BAF60B, ultimately directing promyogenic differentiation while suppressing the fibro-adipogenic phenotype. In contrast, FAPs from late stage dystrophic muscles are resistant to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the promyogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bipotency by epigenetic intervention with HDACis provides a molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. © 2014 Saccone et al.

Cervelli M.,Third University of Rome | Bellavia G.,Third University of Rome | D'Amelio M.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Cavallucci V.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | And 9 more authors.
PLoS ONE | Year: 2013

Spermine oxidase is a FAD-containing enzyme involved in polyamines catabolism, selectively oxidizing spermine to produce H2O2, spermidine, and 3-aminopropanal. Spermine oxidase is highly expressed in the mouse brain and plays a key role in regulating the levels of spermine, which is involved in protein synthesis, cell division and cell growth. Spermine is normally released by neurons at synaptic sites where it exerts a neuromodulatory function, by specifically interacting with different types of ion channels, and with ionotropic glutamate receptors. In order to get an insight into the neurobiological roles of spermine oxidase and spermine, we have deregulated spermine oxidase gene expression producing and characterizing the transgenic mouse model JoSMOrec, conditionally overexpressing the enzyme in the neocortex. We have investigated the effects of spermine oxidase overexpression in the mouse neocortex by transcript accumulation, immunohistochemical analysis, enzymatic assays and polyamine content in young and aged animals. Transgenic JoSMOrec mice showed in the neocortex a higher H2O2 production in respect to Wild-Type controls, indicating an increase of oxidative stress due to SMO overexpression. Moreover, the response of transgenic mice to excitotoxic brain injury, induced by kainic acid injection, was evaluated by analysing the behavioural phenotype, the immunodistribution of neural cell populations, and the ultrastructural features of neocortical neurons. Spermine oxidase overexpression and the consequently altered polyamine levels in the neocortex affects the cytoarchitecture in the adult and aging brain, as well as after neurotoxic insult. It resulted that the transgenic JoSMOrec mouse line is more sensitive to KA than Wild-Type mice, indicating an important role of spermine oxidase during excitotoxicity. These results provide novel evidences of the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. © 2013 Cervelli et al.

Carbone F.,CNR Institute Experimental Endocrinology and Oncology Gaetano Salvatore | Carbone F.,University of Salerno | De Rosa V.,CNR Institute Experimental Endocrinology and Oncology Gaetano Salvatore | De Rosa V.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | And 9 more authors.
Nature Medicine | Year: 2014

Human CD4 + CD25 high CD127 - FoxP3 + regulatory T (T reg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral T reg cells has been previously reported in autoimmune disorders. T reg cells represent the most actively replicating compartment within the CD4 + cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of T reg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27 kip1) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of T reg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in T reg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of T reg cells in autoimmune disease.

Furlan A.,Institut Universitaire de France | Stagni V.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Stagni V.,University of Rome Tor Vergata | Hussain A.,Institut Universitaire de France | And 9 more authors.
Cell Death and Differentiation | Year: 2011

The simplicity of BCR-ABL oncogene addiction characterizing leukemia contrasts with the complexity of solid tumors where multiple core pathways, including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser 392 and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature. © 2011 Macmillan Publishers Limited All rights reserved.

Calabresi P.,University of Perugia | Calabresi P.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Castrioto A.,University of Perugia | Castrioto A.,Joseph Fourier University | And 2 more authors.
The Lancet Neurology | Year: 2013

Parkinson's disease is a common progressive neurodegenerative disease, of which the main neuropathological hallmark is dopaminergic neuronal loss. Increased attention has been directed towards non-motor symptoms in Parkinson's disease, such as cognitive impairment and behavioural disorders. Clinical and experimental findings support the view that the hippocampus, a temporal lobe structure involved in physiological learning and memory, is also implicated in the cognitive dysfunction seen in some patients with Parkinson's disease. Moreover, emerging data suggest interactions between the dopaminergic systems and the hippocampus in synaptic plasticity, adaptive memory, and motivated behaviour. This structure is also implicated in the pathophysiology of other non-motor symptoms, such as impulse control disorders, anosmia, and fatigue. Evidence from clinical observations and experimental studies suggest a complex hippocampal cross-talk among the dopaminergic and other transmitter systems. Furthermore, neurotrophic factors might interact with the hippocampal dopaminergic system having possible implications on the non-motor symptoms seen in patients with Parkinson's disease. © 2013 Elsevier Ltd.

Tierney M.T.,Sanford Burnham Institute for Medical Research | Aydogdu T.,Sanford Burnham Institute for Medical Research | Aydogdu T.,Thermo Fisher Scientific | Sala D.,Sanford Burnham Institute for Medical Research | And 7 more authors.
Nature Medicine | Year: 2014

The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases. © 2014 Nature America, Inc. All rights reserved.

PubMed | University of Rome Tor Vergata, Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia and Regina Elena Cancer Institute
Type: | Journal: Nature communications | Year: 2015

ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATMs tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

Cai W.,Sanford Burnham Institute for Medical Research | Albini S.,Sanford Burnham Institute for Medical Research | Wei K.,Sanford Burnham Institute for Medical Research | Willems E.,Sanford Burnham Institute for Medical Research | And 11 more authors.
Genes and Development | Year: 2013

A critical but molecularly uncharacterized step in heart formation and regeneration is the process that commits progenitor cells to differentiate into cardiomyocytes. Here, we show that the endoderm-derived dual Nodal/bone morphogenetic protein (BMP) antagonist Cerberus-1 (Cer1) in embryonic stem cell cultures orchestrates two signaling pathways that direct the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent (KDR/Flk1+) progenitors, activating lineage-specific transcription. Transient inhibition of Nodal by Cer1 induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into SWI/SNF. Blocking Nodal and BMP also induces lineage-specific transcription factors Gata4 and Tbx5, which interact with Baf60c. siRNA to Cer1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented the developmental opening of chromatin surrounding the Nkx2.5 early cardiac enhancer and cardiomyocyte differentiation. Overexpression of Baf60c fully rescued these deficits, positioning Baf60c and SWI/ SNF function downstream from Cer1. Thus, antagonism of Nodal and BMP coordinates induction of the myogenic Baf60c variant and interacting transcription factors to program the developmental opening of cardiomyocytespecific loci in chromatin. This is the first demonstration that cues from the progenitor cell environment direct the subunit variant composition of SWI/SNF to remodel the transcriptional landscape for lineage-specific differentiation. © 2013 Cai et al.

Stagni V.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Stagni V.,University of Rome Tor Vergata | Mingardi M.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | Santini S.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia | And 4 more authors.
Carcinogenesis | Year: 2010

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a potent tool to trigger apoptosis in cancer therapy. However, since ~60% of tumour cell lines and most primary cancers are resistant to TRAIL-induced apoptosis, several combined therapy approaches aimed to sensitize cells to TRAIL have been developed. One of the major targets of these approaches are cFLIP proteins as they interfere with the initiation of apoptosis induction by TRAIL, are over-expressed in many cancers and their down-regulation enhances TRAIL sensitivity. Although, DNA-damaging agents such as 5-fluorouracil (5-FU), etoposide and adriamycin have been successfully employed due to their ability to trigger cFLIP L and cFLIP s down-regulation the molecular mechanisms underneath their action have been only partially elucidated. We have recently identified ataxia telangiectasia mutated (ATM) as a modulator of cFLIP L and cFLIP S protein levels in the DNA damage response. Here, we provide genetic evidence that ATM kinase activity is required to trigger 5-FUand neocarzinostatin-dependent cFLIP L and cFLIP S downregulation, which in turn sensitize hepatocellular carcinoma (HCC) cell lines to TRAIL. ATM activity triggers cFLIP proteins down-regulation in HCC cells independently on p53 and enhances cFLIP L ubiquitination in response to DNA damage. Therefore, we propose that ATM kinase mediates the interplay between DNA damage and death receptor signalling and suggest that expression of catalytically competent ATM in tumour cells may play a key role for successful combinatorial use of TRAIL receptor agonists and DNA-damaging drugs in cancer therapy. © The Author 2010. Published by Oxford University Press. All rights reserved.

PubMed | University of Rome Tor Vergata and Instituto Of Ricovero E Cura A Carattere Scientifico Irccs Fondazione Santa Lucia
Type: Journal Article | Journal: Molecular & cellular oncology | Year: 2016

ATM kinase is a gatekeeper of genome stability. However, its role in several other signaling pathways suggests that it might not always act as a tumor suppressor. Here, we discuss recent data that unveil a function of ATM as a tumor promoter in HER2-positive breast cancer.

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