| Description |
The tumor suppressor gene TP53 plays a key role in the maintenance of genomic stability of cells. Following cellular insult, the p53 protein engages several mechanisms to allow the cell to repair the damage or to signal the cell for death, protecting the organism on a cellular level from mutation accumulation and tumor formation. When one or more alleles of TP53 is mutated, the function of the p53 protein is altered or eliminated, contributing to the formation of tumors in affected individuals. Germline mutations in TP53 is linked to individuals with Li-Fraumeni Syndrome (LFS). LFS individuals have a greater than 90% lifetime risk of developing cancer and frequently suffer from multiple primary tumors. By comparison, healthy individuals without germline mutations in TP53 experience approximately a 50% lifetime risk of cancer. Interestingly, large animals (like elephants) display a low lifetime risk of developing cancer. Analysis of the P53 gene in elephants found an expected complement of two full-length, ancestral copies (EP53anc) and nineteen additional truncated copies lacking introns (EP53retro1-19). The use of EP53 in the treatment of human cancer could decrease the dosage of chemotherapy required, potentially decreasing the side-effects of treatment, which would particularly benefit LFS individuals who have increased susceptibility to tumor formation following chemotherapy. Fibroblasts from LFS patients show variable functional deficiencies in p53-mediated repair mechanisms measured by cell viability, DNA double-strand break repair, iv cellular senescence, and cell cycle arrest, depending on the TP53 mutation present, when compared to healthy control fibroblasts. EP53 coding vectors were inserted into fibroblasts with germline mutations p.His193Pro (LFS 50458), p.Thr18Hisfs*26 (LFS 52513), and p.P128fs (LFS 47115).Following EP53 protein expression, DNA damage was induced and cellular function was measured. Following expression of EP53 proteins, LFS fibroblasts experienced increased apoptosis, increased cellular senescence, increased cell cycle arrest, and an increased rate of double-strand DNA damage repair. These results suggest that deficient p53-mediated cellular functions can be restored using EP53 proteins, supporting further investigation of using EP53 in the potential treatment of cancer in LFS patients, or even possible cancer prevention in the distant future. |
