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Published on: June 9, 2017
DRAGO (KIAA0247), a new DNA damage-responsive, p53-inducible gene that cooperates with p53 as oncosuppressor.
Federica Polato1, Paolo Rusconi, Stefano Zangrossi
1Affiliations 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).
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.
Insights
DRAGO is a new gene regulated by p53 that suppresses tumor growth. Its absence accelerates tumor development and shortens lifespan in mice, highlighting its role in tumor suppression.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The p53 protein is crucial for maintaining genomic stability and regulating cellular responses to stress and DNA damage.
- Identifying novel p53-target genes is essential for understanding how p53 controls cell integrity and repair mechanisms.
Purpose of the Study:
- To identify and characterize novel p53-responsive genes.
- To investigate the role of the identified gene, DRAGO, in tumor suppression and its interaction with p53.
Main Methods:
- Bioinformatics analysis, real-time PCR, chromatin immunoprecipitation, and luciferase assays were used to characterize DRAGO.
- Transgenic mouse models (p53(-/-) and p53(+/-)) were employed to assess DRAGO's in vivo function and impact on tumor development and lifespan.
- Survival analyses utilized Kaplan-Meier curves and the Mantel-Haenszel test.
Main Results:
- DRAGO was identified as a novel p53-responsive gene induced by DNA-damaging agents, conserved across species.
- Overexpression of DRAGO led to growth suppression and cell death.
- Deletion of DRAGO significantly accelerated tumor development and reduced lifespan in p53-deficient mice, indicating a tumor-suppressive role.
- DRAGO mRNA levels were decreased in advanced ovarian tumors, but mutations were not found in human samples.
Conclusions:
- DRAGO functions as a p53-dependent tumor suppressor gene.
- DRAGO's expression is tightly regulated at multiple levels (transcriptional, post-transcriptional, and epigenetic) in human cells.
- DRAGO cooperates with p53 to exert its tumor suppressor functions, offering potential therapeutic insights.
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