Gerry Melino

Medical Research Council (UK), Londinium, England, United Kingdom

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Publications (479)3085.15 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: ZNF281 is a zinc-finger factor involved in the control of cellular stemness and epithelial-mesenchymal transition (EMT). Here, we report that ZNF281 expression increased after genotoxic stress caused by DNA-damaging drugs. Comet assays demonstrated that DNA repair was delayed in cells silenced for the expression of ZNF281 and treated with etoposide. Furthermore, the expression of 10 DNA damage response genes was downregulated in cells treated with etoposide and silenced for ZNF281. In line with this finding, XRCC2 and XRCC4, two genes that take part in homologous recombination and non-homologous end joining, respectively, were transcriptionally activated by ZNF281 through a DNA-binding-dependent mechanism, as demonstrated by luciferase assays and Chromatin crosslinking ImmunoPrecipitation experiments. c-Myc, which also binds to the promoters of XRCC2 and XRCC4, was unable to promote their transcription or to modify ZNF281 activity. Of interest, bioinformatic analysis of 1971 breast cancer patients disclosed a significant correlation between the expression of ZNF281 and that of XRCC2. In summary, our data highlight, for the first time, the involvement of ZNF281 in the cellular response to genotoxic stress through the control exercised on the expression of genes that act in different repair mechanisms.Oncogene advance online publication, 24 August 2015; doi:10.1038/onc.2015.320.
    Oncogene 08/2015; DOI:10.1038/onc.2015.320 · 8.56 Impact Factor
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    ABSTRACT: The p53-family member, p73, plays a key role in the development of the central nervous system (CNS), in senescence, and in tumor formation. The role of p73 in neuronal differentiation is complex and involves several downstream pathways. Indeed, in the last few years, we have learnt that TAp73 directly or indirectly regulates several genes involved in neural biology. In particular, TAp73 is involved in the maintenance of neural stem/progenitor cell self-renewal and differentiation throughout the regulation of SOX-2, Hey-2, TRIM32 and Notch. In addition, TAp73 is also implicated in the regulation of the differentiation and function of postmitotic neurons by regulating the expression of p75NTR and GLS2 (glutamine metabolism). Further still, the regulation of miR-34a by TAp73 indicates that microRNAs can also participate in this multifunctional role of p73 in adult brain physiology. However, contradictory results still exist in the relationship between p73 and brain disorders, and this remains an important area for further investigation.
    Molecular Neurobiology 08/2015; DOI:10.1007/s12035-015-9381-1 · 5.29 Impact Factor
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    ABSTRACT: In stratified epithelial and glandular tissues, homeostasis relies on the self-renewing capacity of stem cells, which are within the basal layer. The p53 family member p63 is an indispensable transcription factor for epithelial morphogenesis and stemness. A splice variant of the transcription factor p63 that lacks an amino-terminal domain, ΔNp63, is selectively found in the basal compartments of several ectoderm-derived tissues such as stratified and glandular epithelia, in which it is required for the replenishment of stem cells. Thus far, the transcriptional programs downstream of p63 in stemness regulation remain incompletely defined. Unveiling the molecular basis of stem cell self-renewal may be relevant in understanding how this process may contribute to cancer development. In this review, we specifically highlight experimental investigations, which suggest that p63 is a marker of normal epithelial stem cells and describe p63 transcriptional targets that may be involved in stemness regulation. Finally, we discuss relevant findings implicating p63 in epithelial cancer stem cell biology. Copyright © 2015, American Association for the Advancement of Science.
    Science Signaling 07/2015; 8(387):re9. DOI:10.1126/scisignal.aaa1033 · 7.65 Impact Factor
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    ABSTRACT: In many cases, individuality in metabolism of a drug is a reliable predictor of the drug efficacy/safety. Modern high-throughput metabolomics is an ideal instrument to track drug metabolism in an individual after treatment. Productivity and low cost of the metabolomics is sufficient to analyse a large cohort of patients to explore individual variations in drug metabolism and to discover drug metabolic biomarkers indicative of drug efficacy/safety. The only potential disadvantage of metabolomics becoming a routine clinical procedure is a need to treat the patient once before making a prognosis. However, in many clinical applications this would not be a limitation. Here, we explore current opportunities and challenges for translating high-throughput metabolomics into the platform for personalized medicine. Copyright © 2015. Published by Elsevier Ltd.
    Drug discovery today 07/2015; DOI:10.1016/j.drudis.2015.07.011 · 5.96 Impact Factor
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    ABSTRACT: Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer.
    Oncotarget 07/2015; 6(19):16926-38. · 6.63 Impact Factor
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    ABSTRACT: A series of isatin Schiff base derivatives were identified during in silico screening of the small molecule library for novel activators of p53. The compounds selected based on molecular docking results were further validated by a high-content screening assay using U2OS human osteosarcoma cells with an integrated EGFP-expressing p53-dependent reporter. The hit compounds activated and stabilized p53, as shown by Western blotting, at higher rates than the well-known positive control Nutlin-3. Thus, the p53-activating compounds identified by this approach represent useful molecular probes for various cancer studies. KEYWORDS: in silico, isatin Mannich and Schiff bases, p53 activators, in vivo assay, protein−protein interactions, MDM2
    ACS Medicinal Chemistry Letters 07/2015; 6(8). DOI:10.1021/acsmedchemlett.5b00011 · 3.07 Impact Factor
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    ABSTRACT: Metastasis is a multistep cell-biological process, which is orchestrated by many factors, including metastasis activators and suppressors. Metastasis Suppressor 1 (MTSS1) was originally identified as a metastasis suppressor protein whose expression is lost in metastatic bladder and prostate carcinomas. However, recent findings indicate that MTSS1 acts as oncogene and pro-migratory factor in melanoma tumors. Here, we identify and characterized a molecular mechanism controlling MTSS1 expression, which impinges on a pro-tumorigenic role of MTSS1 in breast tumors. We found that in normal and in cancer cell lines ΔNp63 is able to drive the expression of MTSS1 by binding to a p63-binding responsive element localized in the MTSS1 locus. We reported that ΔNp63 is able to drive the migration of breast tumor cells by inducing the expression of MTSS1. Notably, in three human breast tumors data sets the MTSS1/p63 co-expression is a negative prognostic factor on patient survival, suggesting that the MTSS1/p63 axis might be functionally important to regulate breast tumor progression.Oncogene advance online publication, 29 June 2015; doi:10.1038/onc.2015.230.
    Oncogene 06/2015; DOI:10.1038/onc.2015.230 · 8.56 Impact Factor
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    ABSTRACT: During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the ΔNp63α isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of ΔNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by ΔNp63α. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that ΔNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The ΔNp63-CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.222.
    Oncogene 06/2015; DOI:10.1038/onc.2015.222 · 8.56 Impact Factor
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    Ivano Amelio · Gerry Melino
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    ABSTRACT: HIFs have long been associated with resistance to therapy, metastasis, and poor survival rates in cancer patients. In parallel, although the tumor-suppressor p53 acts as the first barrier against tumor transformation, its inactivation also appears to be crucial for enabling cancer progression at advanced stages. p53 has been proposed to antagonize HIF, and emerging evidence suggests that the p53 siblings p63 and p73 also participate in this interplay. Crosstalk between HIFs and the p53 family acts as a determinant of cancer progression through regulating angiogenesis, the tumor microenvironment, dormancy, metastasis, and recurrence. We discuss the possible mechanisms underlying this regulation and the controversies in this field in an attempt to provide a unified view of current knowledge. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Biochemical Sciences 05/2015; 40(8). DOI:10.1016/j.tibs.2015.04.007 · 13.52 Impact Factor
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    ABSTRACT: TAp73 is a tumour suppressor transcriptional factor, belonging to p53 family. Alteration of TAp73 in tumours might lead to reduced DNA damage response, cell cycle arrest and apoptosis. Carcinogen-induced TAp73−/− tumours display also increased angiogenesis, associated to hyperactivition of hypoxia inducible factor signaling. Here, we show that TAp73 suppresses BNIP3 expression, directly binding its gene promoter. BNIP3 is a hypoxia responsive protein, involved in a variety of cellular processes, such as autophagy, mitophagy, apoptosis and necrotic-like cell death. Therefore, through different cellular process altered expression of BNIP3 may differently contribute to cancer development and progression. We found a significant upregulation of BNIP3 in human lung cancer datasets, and we identified a direct association between BNIP3 expression and survival rate of lung cancer patients. Our data therefore provide a novel transcriptional target of TAp73, associated to its antagonistic role on HIF signaling in cancer, which might play a role in tumour suppression.
    Cell cycle (Georgetown, Tex.) 05/2015; DOI:10.1080/15384101.2015.1044178 · 5.01 Impact Factor
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    ABSTRACT: Targeting the ubiquitin-proteasome system (UPS) and ubiquitin-like signalling systems (UBL) has been considered a promising therapeutic strategy to treat cancer, neurodegenerative and immunological disorders. There have been multiple efforts recently to identify novel compounds that efficiently modulate the activities of different disease-specific components of the UPS-UBL. However, it is evident that polypharmacology (the ability to affect multiple independent protein targets) is a basic property of small molecules and even highly potent molecules would have a number of "off target" effects. Here we have explored publicly available high-throughput screening data covering a wide spectrum of currently accepted drug targets in order to understand polypharmacology of small molecules targeting different components of the UPS-UBL. We have demonstrated that molecules targeting a given UPS-UBL protein also have high odds to target a given off target spectrum. Moreover, the off target spectrum differs significantly between different components of UPS-UBL. This information can be utilized further in drug discovery efforts, to improve drug efficiency and to reduce the risk of potential side effects of the prospective drugs designed to target specific UPS-UBL components
    Oncotarget 04/2015; 6(12). · 6.63 Impact Factor
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    ABSTRACT: Platelets play an important role in cardiovascular thrombosis as well as in many other pathological conditions such as inflammation, atherosclerosis and cancer. While multi-target strategies to treat complex diseases are gaining considerable attention, current development of antiplatelet therapies is mostly oriented towards several single targets, arising from our present understanding of the regulation of platelet activation. Limited efforts to develop multi-target agents or multidrug therapies are mostly due to a lack of a systematic basis to define target combinations with synergistic effects. Here we discuss the perspective to use high content phenotypic screening of in vitro models as a potential source for inference of synergetic multi-target strategies to control platelet activation.
    Mini Reviews in Medicinal Chemistry 04/2015; 15(8):622-9. DOI:10.2174/1389557515666150219124018 · 3.19 Impact Factor
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    ABSTRACT: Epidermolytic ichthyosis (BCIE, OMIM 113800), is an autosomal dominant disorder of the skin caused by mutations in keratin genes KRT1 and KRT10. We present two sporadic patients showing a mild diffuse ichthyosis with palmoplantar keratoderma. Interestingly, one of them shows a significant hyperkeratosis of palms and soles similar to those present in the Meleda disease (OMIM 248300). In this paper we would clarify the genetic difference between the two patients, giving rise to the different phenotype. Clinical evaluation, followed by histological and molecular analysis has been established for these patients. We demonstrated the presence of a genetic cutaneous mosaicism. Both patients carry the KRT1 pI479T substitution, but in the palmoplantar areas of one of them, only the mutated allele is expressed (hemizygous). This leads to highlight a new type of cutaneous mosaic, the palmoplantar mosaicism. © 2015 European Academy of Dermatology and Venereology.
    Journal of the European Academy of Dermatology and Venereology 04/2015; DOI:10.1111/jdv.13153 · 3.11 Impact Factor
  • S Cefalù · A M Lena · B Vojtesek · A Musarò · A Rossi · G Melino · E Candi
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    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 · 5.01 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.
    Scientific Reports 03/2015; 5:9023. DOI:10.1038/srep09023 · 5.58 Impact Factor
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    ABSTRACT: The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.
    Proceedings of the National Academy of Sciences 03/2015; 112(11). DOI:10.1073/pnas.1500762112 · 9.81 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: 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; 5(22). · 6.63 Impact Factor

Publication Stats

21k Citations
3,085.15 Total Impact Points

Institutions

  • 2004–2015
    • Medical Research Council (UK)
      • Medical Research Council Toxicology Unit
      Londinium, England, United Kingdom
  • 1988–2015
    • University of Rome Tor Vergata
      • • Dipartimento di Medicina dei Sistemi
      • • Dipartimento di Scinze e Tecnologie Chimiche
      • • Dipartimento di Biologia
      Roma, Latium, Italy
  • 2013–2014
    • Saint-Petersburg State Institute of Technology
      Sankt-Peterburg, St.-Petersburg, Russia
  • 2006–2013
    • Istituto Dermopatico dell'Immacolata
      Roma, Latium, Italy
  • 2003–2013
    • University of Leicester
      • • Medical Research Council Toxicology Unit
      • • Department of Biochemistry
      Leiscester, England, United Kingdom
    • Imperial College London
      Londinium, England, United Kingdom
  • 2012
    • Vlaams Instituut voor Biotechnologie
      • Inflammation Research Center (IRC)
      Gand, Flemish, Belgium
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 1997–2012
    • The American University of Rome
      Roma, Latium, Italy
  • 2011
    • European Brain Research Institute
      Roma, Latium, Italy
  • 2009–2011
    • Foundation Santa Lucia
      Roma, Latium, Italy
    • Hungarian Academy of Sciences
      Budapeŝto, Budapest, Hungary
  • 2007
    • Harvard Medical School
      • Department of Cell Biology
      Boston, MA, United States
  • 2002–2003
    • Newcastle University
      • Northern Institute for Cancer Research
      Newcastle upon Tyne, ENG, United Kingdom
  • 2001
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 1999
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany
  • 1998
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1995–1997
    • Università degli Studi dell'Aquila
      • Department of Biology
      Aquila, Abruzzo, Italy
  • 1996
    • University of Milan
      Milano, Lombardy, Italy
  • 1993
    • Universidade Federal do Ceará
      • Departamento de Fisiologia e Farmacologia
      Fortaleza, Estado do Ceara, Brazil