Schematic of transposable elements from bacteria: Areas on the end of the gene can change places
Schematic of transposable elements from bacteria: Areas on the end of the gene can change places

Research into the molecular mechanisms that lead to genomic instability within various organisms has led scientists to take a hard look at the tumor suppressor protein p53. As one of the most commonly mutated cancer genes, p53 works to prevent tumor formation by keeping mobile elements in check that would seek to degrade genomic fidelity.

Researchers at the University of Texas Southwestern Medical Center now believe they have found the mechanisms behind p53 tumor suppression and why disabling the gene allows tumors to form. The scientists are hopeful that these results will one day lead to ways of diagnosing and treating cancer.

The findings from this study were published recently in Genes and Development through an article entitled “p53 genes function to restrain mobile elements.”

The investigators found that normal p53 gene action restrains mobile genetic elements, called retrotransposons, that can make copies of themselves and move to different positions on chromosomes. However, the researchers discovered that when p53 is disabled by mutation, dramatic eruptions of these mobile elements occur. Furthermore, the results revealed that, both in mice with cancer and human samples from two different types of cancer (Wilms' tumors and colon tumors) disabled for p53, transposons within these cells became extremely active.

“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,” explained senior study author John Abrams, Ph.D., professor of cell biology at UT Southwestern. “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.”

Dr. Abrams went on to remark that although much more research is needed, 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 added. “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.”

The UT Southwestern team is hopeful that this understanding could also 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 stated.

The researchers were excited by their findings and are beginning to take an even larger, more comprehensive view of p53 to place the gene/s role into an evolutionary context of human development and disease pathogenesis.

“Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons,” the authors concluded. “Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.”

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