Functional characterisation of the Δ133p53 isoform and its mouse mimic Δ122p53

Abstract

p53 is a critical tumour suppressor. Recently several p53 isoforms have been discovered whose functions remain unclear. Evidence suggests that the Δ133p53 isoform may act as an antagonist to full length p53 (FLp53) and inhibit apoptosis, senescence, and promote tumourigenesis. This thesis investigated the functions of the Δ133p53 isoform, and a mouse mimic of Δ133p53, Δ122p53. To elucidate the functions of Δ122p53 and Δ133p53 a panel of cell lines expressing either Δ133p53 or Δ122p53 was generated either in the presence or absence of endogenous FLp53. The results reported here suggest that Δ122p53/Δ133p53 can enhance proliferation, as well as increase cellular migration and invasion. However, FLp53 appears to override Δ122p53/Δ133p53-mediated proliferation and migration. Δ122p53/Δ133p53 may function by interacting with the p53 family members (p53, p63, p73), as immunoprecipitation experiments show Δ133p53 can bind to p63 and p73 and inhibit p63 in colony formation assays. Transcriptional analysis showed that Δ122p53/Δ133p53 inhibit p53 transactivation of p21 and Mdm2. The results also reveal that Δ122p53/Δ133p53 stabilise FLp53, suggesting that Δ122p53/Δ133p53 may have properties in addition to its antagonism of FLp53. Together, the results demonstrate that Δ122p53 is overall a good mimic of Δ133p53 and expand the role of Δ133p53 in tumour progression.