| Title: |
Unveiling the developmental and tumor-suppressive roles of the p53 variant p53psi |
| Authors: |
Gorrini, C.; Jafari, S.; Duncan, G.; Snow, B.; Hendrikse, L.; McLoughlin, L.; Haight, J.; Wakeham, A.; Tobin, C.; Elia, A.; Ramachandran, P.; Law, R.; Gang, B.; Lu, T.-L.; Morgado-Palacin, I.; You-Ten, A.; Berger, T.; Sordella, R.; Mak, T.W. |
| Publisher Information: |
National Academy of Sciences |
| Publication Year: |
2026 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
Through alternative splicing, the TP53 gene can generate multiple protein isoforms with distinct biochemical properties. The p53psi isoform has been identified as a shorter variant 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 matings fail to yield viable p53psi homozygote knock-in (p53KI/KI) pups, indicating that forced p53psi expression disrupts embryogenesis. Timed matings revealed that homozygous p53psi expression is embryonically lethal on day E16.5. E14.5-16.5 embryos were pale, reduced in size, and exhibited exencephaly, a defect typically associated with neural tube closure failure. 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 insights into the role of the p53psi variant, paving the way for a better interpretation of TP53 mutational patterns in human cancers. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
0027-8424 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/239523/1/gorrini-et-al-2026-unveiling-the-developmental-and-tumor-suppressive-roles-of-the-p53-variant-p53psi%20%281%29.pdf; Gorrini, C. orcid.org/0000-0002-5239-6671 , Jafari, S., Duncan, G. et al. (16 more authors) (2026) Unveiling the developmental and tumor-suppressive roles of the p53 variant p53psi. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 123 (13). e2427242123. ISSN: 0027-8424 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/239523/ |
| Rights: |
cc_by_nc_nd_4 |
| Accession Number: |
edsbas.35AA24CB |
| Database: |
BASE |