Dominant effects of Δ40p53 on p53 function and melanoma cell fate

The p53 gene encodes 12 distinct isoforms some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of p53 mutations is relatively low compared to other cancers suggesting that these isoforms may play a larger role in regulating p53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first forty N-terminal amino acids of the full-length protein including the transactivation and Mdm2 binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear hetero-tetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain (PIDD) and cyclin dependent kinase inhibitor, p21. Δ40p53 altered promoter occupancy of these downstream p53 target genes in such a way that shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.