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 +/-, DRAGO-/- mice: HR = 2.35, 95% CI = 1.3 to 4.0, P +/+ 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.
ASJC Scopus subject areas
- Cancer Research