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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE324142 | GEO | 2026/03/09

REPOSITORIES: GEO