Abstract

Abstract: Before p53 became famous as a tumour suppressor it was regarded as an oncogene. However, by the 1990s when it was clearly established that p53 is a tumour suppressor, much of the early work was dismissed as being due to mutant p53. However, not all the data can be dismissed so easily. Furthermore, with the discovery of p53 isoforms that appear to have transforming ability, the question of p53’s contribution to cancer has again arisen. We created a transgenic mouse model of the D133p53 isoform (designated D122p53 in mice). These mice are tumour prone, but unlike other p53 mutant mice, D122p53 mice show widespread inflammation and elevated levels of pro-inflammatory serum cytokines, notably IL-6 1. IL-6 was shown to be important by crossing ∆122p53 mice with IL-6 deficient mice. Loss of IL-6 reduced tumour incidence, metastasis and the levels of cytokines in the JAK -STAT3 pathway and that blocking this pathway prevented cell migration and invasion 2. The studies on these mice led us to explore a role for D133p53 isoform in human cancers. We show that prostate cancers with substantially elevated levels of D133TP53 mRNA grow faster, have a high immune cell content and are more aggressive. We find a similar pattern in a subset of glioblastomas 3. Moreover, elevated isoform expression was found to only occur in tumours with a wild type p53 gene. These studies provide strong evidence that D133p53 isoform can function as an oncogene, suggesting that wild type p53 can contribute to oncogenesis.

References: 1. Slatter, T.J., Hung, N.A., Campbell, H.C., et al. (2011). Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform. Blood 117, 5166-5177 2. Campbell, H.G., Fleming, N., Roth, I. et. al. (2018). D133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK -STAT and RhoA-ROCK signalling. Nature Comm. DOI : 10.1038/s41467-017-02408-0 3. Kazantseva, M., Eiholzer, R., Mehta, S. et al (2018). Elevation of the TP53 isoform D133T P53b in glioblastomas: an alternative to mutant p53 in promoting tumour development. J Path. (in press).