Gerry Melino

University of Rome Tor Vergata, Roma, Latium, Italy

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Publications (451)2828.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: p53 family members, p63 and p73, play a role in controlling early stage of myogenic differentiation. We demonstrated that TAp63gamma, unlike the other p53 family members, is markedly up-regulated during myogenic differentiation in murine C2C7 cell line. We also found that myotubes formation was inhibited upon TAp63gamma knock-down, as also indicated by atrophyic myotubes and reduction of myoblasts fusion index. Analysis of TAp63gamma-dependend transcripts identified several target genes involved in skeletal muscle contractility energy metabolism, myogenesis and skeletal muscle autocrine signaling. These results indicate that TAp63gamma is a late marker of myogenic differentiation and, by controlling different sub-sets of target genes, it possibly contributes to muscle growth, remodeling, functional differentiation and tissue homeostasis.
    Cell cycle (Georgetown, Tex.) 03/2015; 14(6):894-901. DOI:10.4161/15384101.2014.988021 · 5.24 Impact Factor
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    ABSTRACT: Recently, AMP-activated protein kinase (AMPK) has emerged as a key regulator of energy balance at cellular and whole-body levels. Due to the involvement in multiple signaling pathways, AMPK efficiently controls ATP-consuming/ATP-generating processes to maintain energy homeostasis under stress conditions. Loss of the kinase activity or attenuation of its expression leads to a variety of metabolic disorders and increases cancer risk. In this review, we discuss recent findings on the structure of AMPK, its activation mechanisms, as well as the consequences of its targets in regulation of metabolism. Particular attention is given to low-molecular-weight compounds that activate or inhibit AMPK; the perspective of therapeutic use of such modulators in treatment of several common diseases is discussed.
    Biochemistry (Moscow) 02/2015; 80(2):127-144. DOI:10.1134/S0006297915020017 · 1.35 Impact Factor
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    ABSTRACT: Atherosclerosis is a chronic inflammatory disease characterized by the infiltration of pro-inflammatory macrophages into a lipid-laden plaque. ITCH is an E3 ubiquitin ligase that has been shown to polarize macrophages to an anti-inflammatory phenotype. We therefore investigated the effect of ITCH deficiency on the development of atherosclerosis. ApoE-/-ITCH-/- mice fed a western diet for 12 weeks showed increased circulating M2 macrophages together with a reduction in plaque formation. Bone marrow transplantation recreated the haemopoietic phenotype of increased circulating M2 macrophages but failed to affect plaque development. Intriguingly, the loss of ITCH lead to a reduction in circulating cholesterol levels through interference with nuclear SREBP2 clearance. This resulted in increased LDL reuptake through upregulation of LDL receptor expression. Furthermore, ApoE-/-ITCH-/- mice exhibit reduced hepatic steatosis, increased mitochondrial oxidative capacity and an increased reliance on fatty acids as energy source. We found that ITCH ubiquitinates SIRT6, leading to its breakdown, and thus promoting hepatic lipid infiltration through reduced fatty acid oxidation. The E3 Ubiquitin Ligase ITCH modulates lipid metabolism impacting on atherosclerosis progression independently from effects on myeloid cells polarization through control of SIRT6 and SREBP2 ubiquitination. Thus, modulation of ITCH may provide a target for the treatment of hypercholesterolemia and hyperlipidemia.
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    ABSTRACT: Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascu- larization. Mechanistically, TAp73 interacts with the regulatory sub- unit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen- independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.
    Proceedings of the National Academy of Sciences 12/2014; DOI:10.1073/pnas.1410609111 · 9.81 Impact Factor
  • European journal of dermatology: EJD 12/2014; DOI:10.1684/ejd.2014.2446 · 1.95 Impact Factor
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    ABSTRACT: Serine and glycine are amino acids that provide the essential precursors for the synthesis of proteins, nucleic acids and lipids. Employing 3 subsequent enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine phosphatase (PSPH), phosphoserine aminotransferase 1 (PSAT1), 3-phosphoglycerate from glycolysis can be converted in serine, which in turn can by converted in glycine by serine methyl transferase (SHMT). Besides proving precursors for macromolecules, serine/glycine biosynthesis is also required for the maintenance of cellular redox state. Therefore, this metabolic pathway has a pivotal role in proliferating cells, including cancer cells. In the last few years an emerging literature provides genetic and functional evidences that hyperactivation of serine/glycine biosynthetic pathway drives tumorigenesis. Here, we extend these observations performing a bioinformatics analysis using public cancer datasets. Our analysis highlighted the relevance of PHGDH and SHMT2 expression as prognostic factor for breast cancer, revealing a substantial ability of these enzymes to predict patient survival outcome. However analyzing patient datasets of lung cancer our analysis reveled that some other enzymes of the pathways, rather than PHGDH, might be associated to prognosis. Although these observations require further investigations they might suggest a selective requirement of some enzymes in specific cancer types, recommending more cautions in the development of novel translational opportunities and biomarker identification of human cancers.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (ΔNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S-adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S)pPtransPPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.
    Cell cycle (Georgetown, Tex.) 11/2014; 13(20):3207-3217. DOI:10.4161/15384101.2014.951285 · 5.01 Impact Factor
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    ABSTRACT: TAp73, a member of the p53 family, has been traditionally considered a tumor suppressor gene, but a recent report has claimed that it can promote cellular proliferation. This assumption is based on biochemical evidence of activation of anabolic metabolism, with enhanced pentose phosphate shunt (PPP) and nucleotide biosynthesis. Here, while we confirm that TAp73 expression enhances anabolism, we also substantiate its role in inhibiting proliferation and promoting cell death. Hence, we would like to propose an alternative interpretation of the accumulating data linking p73 to cellular metabolism: we suggest that TAp73 promotes anabolism to counteract cellular senescence rather than to support proliferation.
    Aging 11/2014; 6(11):921-30. · 4.89 Impact Factor
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    ABSTRACT: Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as /`accidental cell death/' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. /`Regulated cell death/' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects i
    Cell death and differentiation 09/2014; DOI:10.1038/cdd.2014.137 · 8.24 Impact Factor
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    ABSTRACT: The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.
    Oncotarget 09/2014; 5(18). · 6.63 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are a class of small noncoding RNAs that suppress the expression of protein-coding genes by repressing protein translation. Although the roles that miRs and the miR processing machinery have in regulating epithelial stem cell biology are not fully understood, their fundamental contributions to these processes have been demonstrated over the last few years. The p53-family member p63 is an essential transcription factor for epidermal morphogenesis and homeostasis. p63 functions as a determinant for keratinocyte cell fate and helps to regulate the balance between stemness, differentiation and senescence. An important factor that regulates p63 function is the reciprocal interaction between p63 and miRs. Some miRs control p63 expression, and p63 regulates the miR expression profile in the epidermis. p63 controls miR expression at different levels. It directly regulates the transcription of several miRs and indirectly regulates their processing by regulating the expression of the miR processing components Dicer and DGCR8. In this review, we will discuss the recent findings on the miR-p63 interaction in epidermal biology, particularly focusing on the ΔNp63-dependent regulation of DGCR8 recently described in the ΔNp63(-/-) mouse. We provide a unified view of the current knowledge and discuss the apparent discrepancies and perspective therapeutic opportunities.Cell Death and Differentiation advance online publication, 29 August 2014; doi:10.1038/cdd.2014.113.
    Cell Death and Differentiation 08/2014; DOI:10.1038/cdd.2014.113 · 8.39 Impact Factor
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    ABSTRACT: During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.Cell Death and Differentiation advance online publication, 15 August 2014; doi:10.1038/cdd.2014.108.
    Cell Death and Differentiation 08/2014; DOI:10.1038/cdd.2014.108 · 8.39 Impact Factor
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    ABSTRACT: TAp63α is a member of the p53 family, which plays a central role in epithelial cancers. Recently, a role has emerged for p53 family members in cancer metabolic modulation. In order to assess whether TAp63α plays a role in cancer metabolism, we exploited p53-null osteosarcoma Tet-On Saos-2 cells, in which the expression of TAp63α was dependent on doxycycline supplementation to the medium. Metabolomics labeling experiments were performed by incubating the cells in 13C-glucose or 13C15Nglutamine- labeled culture media, as to monitor metabolic fluxes upon induced expression of TAp63α. Induced expression of TAp63α resulted in cell cycle arrest at the G1 phase. From a metabolic standpoint, expression of Tap63α promoted glycolysis and the pentose phosphate pathway, which was uncoupled from nucleotide biosynthesis, albeit prevented oxidative stress in the form of oxidized glutathione. Double 13C-glucose and 13C15N-glutamine metabolic labeling confirmed that induced expression of TAp63α corresponded to a decreased flux of pyruvate to the Krebs cycle and decreased utilization of glutamine for catabolic purposes in the TCA cycle. Results were not conclusive in relation to anabolic utilization of labeled glutamine, since it is unclear to what extent the observed minor TAp63α-dependent increases of glutamine-derived labeling in palmitate could be tied to increased rates of reductive carboxylation and de novo synthesis of fatty acids. Finally, bioinformatics elaborations highlighted a link between patient survival rates and the co-expression of p63 and rate limiting enzymes of the pentose phosphate pathway, G6PD and PGD.
    Oncotarget 07/2014; 5(17). · 6.63 Impact Factor
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    ABSTRACT: In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63 and TP73, respectively). The usage of two alternative promoters produces protein variants either with (TA isoforms) or without (ΔN isoforms) the N-terminal transactivation domain. In general, the TA proteins exert TP53-like tumor suppressive activities through their ability to activate a common set of target genes. The ΔN proteins can act as dominant negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic specific biological activities due to the presence of alternative transactivation domains, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those, which are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks amongst the TP53 family members, their modulators as well as the transcriptional targets. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2014; 35(6). DOI:10.1002/humu.22523 · 5.05 Impact Factor
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    ABSTRACT: nhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto- ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine – a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologues of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologues, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologues might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications.
    Cell Death & Disease 05/2014; 5(e1203). DOI:10.1038/cddis.2014.113 · 5.18 Impact Factor
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    ABSTRACT: The skin protects humans from the surrounding environment. Tissues undergo continuous renewal throughout an individual's lifetime; however, there is a decline in the regenerative potential of tissue with age. The accumulation of senescent cells over time probably reduces tissue regenerative capacity and contributes to the physiological ageing of the tissue itself. The mechanisms that govern ageing remain unclear and are under intense investigation, and insight could be gained by studying the mechanisms involved in cellular senescence. In vitro, keratinocytes and dermal fibroblasts undergo senescence in response to multiple cellular stresses, including the overproduction of reactive oxygen species and the shortening of telomeres, or simply by reaching the end of their replicative potential (i.e., reaching replicative senescence). Recent findings demonstrate that microRNAs play key roles in regulating the balance between a cell's proliferative capacity and replicative senescence. Here, we will focus on the molecular mechanisms regulated by senescence-associated microRNAs and their validated targets in both keratinocytes and dermal fibroblasts.
    Ageing research reviews 04/2014; DOI:10.1016/j.arr.2014.04.003 · 7.63 Impact Factor
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    I Amelio, G Melino
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    ABSTRACT: A prokaryotic immune component may potentially open a new era of gene silencing.
    Cell death and differentiation 04/2014; DOI:10.1038/cdd.2014.39 · 8.24 Impact Factor
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Publication Stats

19k Citations
2,828.65 Total Impact Points

Institutions

  • 1988–2015
    • University of Rome Tor Vergata
      • • Dipartimento di Medicina dei Sistemi
      • • Dipartimento di Biologia
      Roma, Latium, Italy
  • 2003–2014
    • University of Leicester
      • Medical Research Council Toxicology Unit
      Leiscester, England, United Kingdom
    • Imperial College London
      Londinium, England, United Kingdom
  • 2013
    • Cineca
      Casalecchio di Reno, Emilia-Romagna, Italy
    • University Health Network
      • Campbell Family Institute for Breast Cancer Research
      Toronto, Ontario, Canada
    • Saint-Petersburg State Institute of Technology
      Sankt-Peterburg, St.-Petersburg, Russia
  • 2006–2013
    • Istituto Dermopatico dell'Immacolata
      Roma, Latium, Italy
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
    • Vlaams Instituut voor Biotechnologie
      • Inflammation Research Center (IRC)
      Gand, Flemish, Belgium
  • 2011
    • European Brain Research Institute
      Roma, Latium, Italy
  • 2004–2011
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1997–2010
    • The American University of Rome
      Roma, Latium, Italy
  • 2009
    • Foundation Santa Lucia
      Roma, Latium, Italy
    • Hungarian Academy of Sciences
      Budapeŝto, Budapest, Hungary
  • 2008
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2007
    • Harvard Medical School
      • Department of Cell Biology
      Boston, MA, United States
  • 2002
    • Ospedale Pediatrico Bambino Gesù
      Roma, Latium, Italy
  • 1997–2002
    • Newcastle University
      • Northern Institute for Cancer Research
      Newcastle upon Tyne, ENG, United Kingdom
  • 2001
    • Sungkyunkwan University
      • Department of Dermatology
      Sŏul, Seoul, South Korea
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 1998–2001
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1999
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases
      베서스다, Maryland, United States
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany
  • 1996–1997
    • Università degli Studi dell'Aquila
      • Department of Biology
      Aquila, Abruzzo, Italy
  • 1994–1995
    • Mediterranean University of Reggio Calabria
      Reggio di Calabria, Calabria, Italy
  • 1993
    • Universidade Federal do Ceará
      • Departamento de Fisiologia e Farmacologia
      Fortaleza, Estado do Ceara, Brazil