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10.1093/jnci/dju053

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suck abstract from ncbi


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pmid24652652      J+Natl+Cancer+Inst 2014 ; 106 (4): ä
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  • DRAGO (KIAA0247), a New DNA Damage?Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosupprossor #MMPMID24652652
  • Polato F; Rusconi P; Zangrossi S; Morelli F; Boeri M; Musi A; Marchini S; Castiglioni V; Scanziani E; Torri V; Broggini M
  • J Natl Cancer Inst 2014[Apr]; 106 (4): ä PMID24652652show ga
  • 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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