title: DRAGO (KIAA0247), a new DNA damage-responsive, p53-inducible gene that cooperates with p53 as oncosuppressor. [Corrected].
abstract: BACKGROUND
  p53 influences genomic stability, apoptosis, autophagy, response to stress, and DNA damage. New p53-target genes could elucidate mechanisms through which p53 controls cell integrity and response to damage.
  
  
  METHODS
  DRAGO (drug-activated gene overexpressed, KIAA0247) was characterized by bioinformatics methods as well as by real-time polymerase chain reaction, chromatin immunoprecipitation and luciferase assays, time-lapse microscopy, and cell viability assays. Transgenic mice (94 p53(-/-) and 107 p53(+/-) mice on a C57BL/6J background) were used to assess DRAGO activity in vivo. Survival analyses were performed using Kaplan-Meier curves and the Mantel-Haenszel test. All statistical tests were two-sided.
  
  
  RESULTS
  We identified DRAGO as a new p53-responsive gene induced upon treatment with DNA-damaging agents. DRAGO is highly conserved, and its ectopic overexpression resulted in growth suppression and cell death. DRAGO(-/-) mice are viable without macroscopic alterations. However, in p53(-/-) or p53(+/-) mice, the deletion of both DRAGO alleles statistically significantly accelerated tumor development and shortened lifespan compared with p53(-/-) or p53(+/-) mice bearing wild-type DRAGO alleles (p53(-/-), DRAGO(-/-) mice: hazard ratio [HR] = 3.25, 95% confidence interval [CI] = 1.7 to 6.1, P < .001; p53(+/-), DRAGO(-/-) mice: HR = 2.35, 95% CI = 1.3 to 4.0, P < .001; both groups compared with DRAGO(+/+) counterparts). DRAGO mRNA levels were statistically significantly reduced in advanced-stage, compared with early-stage, ovarian tumors, but no mutations were found in several human tumors. We show that DRAGO expression is regulated both at transcriptional-through p53 (and p73) and methylation-dependent control-and post-transcriptional levels by miRNAs.
  
  
  CONCLUSIONS
  DRAGO represents a new p53-dependent gene highly regulated in human cells and whose expression cooperates with p53 in tumor suppressor functions.
authors.affiliation: Affiliations of authors: Laboratory of Molecular Pharmacology (FP, PR, SZ, FM, MBo, AM, SM, MBr), and Laboratory of Methodology for Biomedical Research (VT), Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Università degli Studi di Milano, Milan, Italy (VC, ES); Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy (VC, ES); Present address: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD (FP).
authors.forename: Federica
authors.initials: F
authors.lastname: Polato
authors.forename: Paolo
authors.initials: P
authors.lastname: Rusconi
authors.forename: Stefano
authors.initials: S
authors.lastname: Zangrossi
authors.forename: Federica
authors.initials: F
authors.lastname: Morelli
authors.forename: Mattia
authors.initials: M
authors.lastname: Boeri
authors.forename: Alberto
authors.initials: A
authors.lastname: Musi
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Valter
authors.initials: V
authors.lastname: Torri
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008853:Microscopy / Q000379:methods; D009154:Mutation; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; D035683:MicroRNAs; C551654:SUSD6 protein, human; D003165:Complement System Proteins