2. Academic Validation
  3. DRAGO (KIAA0247), a new DNA damage-responsive, p53-inducible gene that cooperates with p53 as oncosuppressor. [Corrected]

DRAGO (KIAA0247), a new DNA damage-responsive, p53-inducible gene that cooperates with p53 as oncosuppressor. [Corrected]

  • J Natl Cancer Inst. 2014 Apr;106(4):dju053. doi: 10.1093/jnci/dju053.
Federica Polato 1,  Paolo Rusconi,  Stefano Zangrossi,  Federica Morelli,  Mattia Boeri,  Alberto Musi,  Sergio Marchini,  Vittoria Castiglioni,  Eugenio Scanziani,  Valter Torri,  Massimo Broggini
Affiliations

Affiliation

  • 1 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).
PMID: 24652652 DOI: 10.1093/jnci/dju053
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.

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