Unveiling the Developmental and Tumor Suppressive Roles of the p53 variant, p53psi

Through alternative splicing, the TP53 gene can generate multiple protein isoforms with distinct biochemical properties. Among the thirteen splicing isoforms described to date, the p53psi isoform has been identified as a variant that is shorter than full-length p53 as it lacks nuclear localization, oligomerization and part of the DNA binding domains due to the use of an alternative 3' splice site in intron 6. Several TP53-truncating mutations, including those producing p53psi, have been detected in a significant proportion of human tumors. However, the mechanistic roles of these truncated p53 proteins remain poorly understood. Here, we describe the generation and analysis of a genetically engineered mouse model that expresses the p53psi protein in place of the full-length p53 protein. In the C57/BL6J genetic background, mice heterozygous for the targeted p53psi allele (p53KI/+) appear phenotypically normal, survive to adulthood, and reproduce. However, heterozygote mating fails to yield viable p53psi homozygote knock-in (p53KI/KI) pups, indicating that forced p53psi expression disrupts embryogenesis. Timed mating studies revealed that homozygous p53psi expression is embryonically lethal at day E16.5. Embryos at E14.5-16.5 were pale, reduced in size, and exhibited exencephaly, a defect typically associated with a failure in neural tube closure. Mouse embryonic fibroblasts (MEFs) derived from p53psi embryos and transformed with the E1A and H-RasV12 oncogenes formed tumors with a decreased growth rate compared to their p53null counterparts, suggesting that p53psi retains at least some tumor-suppressive functions. Our mechanistic studies suggest that p53psi modulates tumorigenesis by triggering senescence. These findings provide new insights into the role of the p53psi variant, paving the way for a better interpretation of TP53 mutational patterns in human cancers.