133p53 isoforms cause inflammation and cancer: a novel mechanism for wild type p53 to promote cancer development

We developed a transgenic mouse model of human 133p53 isoform 1, which showed that the isoform can function as an oncogene, but also promotes inflammation by activation of the prototypical NFkB pathway 2,3. These observations led us to explore a role for the 133p53 isoform in cancers and autoimmune conditions. We show that prostate cancers with substantially elevated levels of 133TP53 mRNA are more aggressive and have a high immune cell content. We find a similar pattern in a subset of glioblastomas 4. Of interest, we also find elevated levels 133p53 by IHC in hyperproliferative synovium from Rheumatoid Arthritis patients. These data provide strong evidence that a key role of the 133p53 isoform is in immune signalling which, if left unchecked, can promote malignancy.
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., Slatter, T.L., Jeffs, et al. (2012). Does the Δ133p53 isoform trigger inflammation and autoimmunity? Cell Cycle 11, 446-450
3. Campbell, H.G., Fleming, N., Roth, I. et. al. (2018). 133p53 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 |
4. Kazantseva, M., Eiholzer, R., Mehta, S. et al (2018). Elevation of the TP53 isoform D133TP53b in glioblastomas: an alternative to mutant p53 in promting tumour development. J Pathol. 2018 Jun 10. doi: 10.1002/path.5111.