Tumor-suppressing gene restrains mobile elements that can lead to genomic instability
DALLAS – Jan. 22, 2016 – The most commonly mutated gene in cancer, p53, works to prevent tumor formation by keeping mobile elements in check that otherwise lead to genomic instability, UT Southwestern Medical Center researchers have found.
The p53 gene long has been known to suppress tumor formation, but the mechanisms behind this function – and why disabling the gene allows tumors to form – were not fully understood.
Findings from the study, published recently in Genes & Development, answer some of these questions and could one day lead to new ways of diagnosing and treating cancer, said the study's senior author, Dr. John Abrams, Professor of Cell Biology at UT Southwestern.
The investigators found that normal p53 gene action restrains transposons, mobile genetic elements called retroelements that can make copies of themselves and move to different positions on chromosomes. But, they discovered, when p53 is disabled by mutation, dramatic eruptions of these mobile elements occur. The study revealed that in mice with cancer and in human samples of two types of cancer (Wilms' tumors and colon tumors) disabled for p53, transposons became very active.
In a healthy state, certain mechanisms work to keep these retroelements quiet and inactive, explained Dr. Abrams. One of those mechanisms is p53 action. Conversely, when p53 is mutated, retroelements can erupt.
"If you take the gene away, transposons can wreak havoc throughout the genome by causing it to become highly dysregulated, which can lead to disease," Dr. Abrams said. "Our findings help explain why cancer genomes are so much more fluid and destabilized than normal genomes. They also provide a novel framework for understanding how normal cells become tumors."
Although much more research is needed, Dr. Abrams said, the potential clinical implications of the team's findings are significant.
"Understanding how p53 prevents tumors raises the prospect of therapeutic interventions to correct cases in which p53 is disabled," Dr. Abrams said. "If retroelements are at the heart of certain p53-driven cancers, finding ways to suppress them could potentially allow us to prevent those cancers or intervene to keep them from progressing."
This understanding also could lead to advances in diagnosing some cancers through biomarkers related to p53 and transposon activity.
"One possibility is that perhaps blood or urine tests could detect dysregulated retroelements that could be indicative of certain types of cancer," Dr. Abrams said.
Other UT Southwestern researchers involved in this study were Dr. Annika Wylie, former graduate student; Paula Kurtz, graduate student; Dr. Amanda Jones and Dr. Alejandro D'Brot, postdoctoral researchers in Cell Biology; Dr. Kenneth Chen, Assistant Instructor in Pediatrics; Dr. Sarah Comerford, Assistant Professor of Molecular Genetics and in the Green Center for Systems Biology; Dr. Robert Hammer, Professor of Biochemistry and in the Green Center for Systems Biology; Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; and Dr. James Amatruda, Associate Professor of Pediatrics, Internal Medicine, and Molecular Biology.
Dr. Hammer holds the Graydon Heartsill Professorship in Medical Science; Dr. Rakheja holds the John Lawrence and Patsy Louise Goforth Distinguished Professorship in Pathology; and Dr. Amatruda holds the Nearburg Family Professorship in Pediatric Oncology, and is a Horchow Family Scholar in Pediatrics.
Also contributing were researchers from Stanford University Medical Center and the University of Michigan Medical School.
The study was supported by the National Cancer Institute, National Institutes of Health, Welch Foundation, Ellison Medical Foundation, Children's Medical Center Foundation, Society for Pediatric Pathology, Cancer Prevention and Research Institute of Texas, and the Damon Runyon Cancer Research Foundation.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has included six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 92,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.