on Biochimica et biophysica acta. Gene regulatory mechanisms
by Federico A, Sepe R, Cozzolino F, Piccolo C, Iannone C, Iacobucci I, Pucci P, Monti M, Fusco A
The Chromobox protein homolog 7 (CBX7) belongs to the Polycomb Group (PcG) family, and, as part of the Polycomb repressive complex (PRC1), contributes to maintain transcriptional gene repression. Loss of CBX7 expression has been reported in several human malignant neoplasias, where it often correlates with an advanced cancer state and poor survival, proposing CBX7 as a candidate tumor-suppressor gene in cancer progression. Indeed, CBX7 is able to positively or negatively regulate the expression of genes involved in cell proliferation and cancer progression, such as E-cadherin, cyclin E, osteopontin, EGR1. To understand the molecular mechanisms that underlie the involvement of CBX7 in cancer progression, we designed a functional proteomic experiment based on CHIP-MS to identify novel CBX7 protein partners. Among the identified CBX7-interacting proteins we focused our attention on the Protein Arginine Methyltransferase 1 (PRMT1) whose critical role in epithelial-mesenchymal transition (EMT), cancer cell migration and invasion has been already reported. We confirmed the interaction between CBX7 and PRMT1 and demonstrated that this interaction is crucial for PRMT1 enzymatic activity both in vitro and in vivo and for the regulation of E-cadherin expression, an important hallmark of EMT. These results suggest a general mechanism by which CBX7 interacting with histone modification enzymes like HDAC2 and PRMT1 enhances E-cadherin expression. Therefore, disruption of this equilibrium may induce impairment of E-cadherin expression and increased cell migration eventually leading to EMT and, then, cancer progression.
on International journal of molecular sciences
by Florio D, Malfitano AM, Di Somma S, Mügge C, Weigand W, Ferraro G, Iacobucci I, Monti M, Morelli G, Merlino A, Marasco D
Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.
on Biochimica et biophysica acta. General subjects
by Venuto S, Castellana S, Monti M, Appolloni I, Fusilli C, Fusco C, Pucci P, Malatesta P, Mazza T, Merla G, Micale L
We recently reported TRIM8, encoding an E3 ubiquitin ligase, as a gene aberrantly expressed in glioblastoma whose expression suppresses cell growth and induces a significant reduction of clonogenic potential in glioblastoma cell lines.
on International journal of molecular sciences
by Monti M, De Rosa V, Iommelli F, Carriero MV, Terlizzi C, Camerlingo R, Belli S, Fonti R, Di Minno G, Del Vecchio S
Neutrophil extracellular traps (NETs), in addition to their function as a host defense mechanism, play a relevant role in thrombus formation and metastatic dissemination of cancer cells. Here we screened different cancer cell lines endogenously expressing a variety of integrins for their ability to bind to NETs. To this end, we used NETs isolated from neutrophil-like cells as a substrate for adhesion assays of HT1080, U-87 MG, H1975, DU 145, PC-3 and A-431 cells. Levels of α5, αIIb, αv, β1, β3 and β5 chains were determined by western blot analysis in all cell lines and levels of whole integrins on the plasma membrane were assessed by fluorescence-activated cell sorting (FACS) analysis. We found that high levels of α5β1, αvβ3 and αvβ5 enhance cell adhesion to NETs, whereas low expression of α5β1 prevents cell attachment to NETs. Excess of cyclic RGD peptide inhibited cell adhesion to NETs by competing with fibronectin within NETs. The maximal reduction of such adhesion was similar to that obtained by DNase 1 treatment causing DNA degradation. Our findings indicate that NETs from neutrophil-like cells may be used as a substrate for large screening of the adhesion properties of cancer cells expressing a variety of RGD-binding integrins.
on Biology of the cell
by Armentano MF, Caterino M, Miglionico R, Ostuni A, Pace MC, Cozzolino F, Monti M, Milella L, Carmosino M, Pucci P, Bisaccia F
Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is upregulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signaling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown.
on Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
by Del Giudice R, Pesce A, Cozzolino F, Monti M, Relini A, Piccoli R, Arciello A, Monti DM
Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis.
on Clinical cancer research : an official journal of the American Association for Cancer Research
by Iommelli F, De Rosa V, Terlizzi C, Monti M, Panico M, Fonti R, Del Vecchio S
Our aim was to test whether imaging with F-fluorothymidine (F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.
on Free radical biology & medicine
by Butturini E, Cozzolino F, Boriero D, Carcereri de Prati A, Monti M, Rossin M, Canetti D, Cellini B, Pucci P, Mariotto S
STAT1 and STAT3 are two transcription factors involved in a lot of cellular functions such as immune response, proliferation, apoptosis, and cell survival. A number of literature evidences described a yin-yang relationship between activation of STAT1 and STAT3 in neurodegenerative disorders where STAT1 exerts a pro-apoptotic effect whereas STAT3 shows neuroprotective properties through the inhibition of apoptosis. Although the role of oxidative-stress in the pathogenesis of neurodegeneration is clearly described, its influence in the regulation of these pathways is poorly understood. Herein, we demonstrate that HO rapidly induces phosphorylation of STAT1 whereas it is not able to influence phosphorylation of STAT3 in mouse microglia BV2 cells. The analysis of the molecular mechanism of STATs signaling reveals that HO induces S-glutathionylation of both STAT1 and STAT3. The same post-translational event exerts an opposing role in the regulation of STAT1 and STAT3 signaling. These data not only confirm redox sensibility of STAT3 signaling but also reveal for the first time that STAT1 is susceptible to redox regulation. A deep study of the molecular mechanism of STAT1 redox regulation, identifies Cys324 and Cys492 as the main targets of S-glutathionylation and confirms that S-glutathionylation does not impair JAK2 mediated STAT1 tyrosine phosphorylation. These results demonstrate that both phosphorylation and glutathionylation contribute to activation of STAT1 during oxidative stress and underline that the same post-translation event exerts an opposing role in the regulation of STAT1 and STAT3 signaling in microglia cells.
on PloS one
by Kondili LA, Gaeta GB, Brunetto MR, Di Leo A, Iannone A, Santantonio TA, Giammario A, Raimondo G, Filomia R, Coppola C, Amoruso DC, Blanc P, Del Pin B, Chemello L, Cavalletto L, Morisco F, Donnarumma L, Rumi MG, Gasbarrini A, Siciliano M, Massari M, Corsini R, Coco B, Madonia S, Cannizzaro M, Zignego AL, Monti M, Russo FP, Zanetto A, Persico M, Masarone M, Villa E, Bernabucci V, Taliani G, Biliotti E, Chessa L, Pasetto MC, Andreone P, Margotti M, Brancaccio G, Ieluzzi D, Borgia G, Zappulo E, Calvaruso V, Petta S, Falzano L, Quaranta MG, Weimer LE, Rosato S, Vella S, Giannini EG
Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure.
on Bioscience reports
by Bilancio A, Rinaldi B, Oliviero MA, Donniacuo M, Monti MG, Boscaino A, Marino I, Friedman L, Rossi F, Vanhaesebroeck B, Migliaccio A
Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δ(D910A/D910A) PI3K mice). Wild-type (WT) and p110δ(D910A/D910A) mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury.