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SUMMARY:D133p53 isoform\, inflammation and cancer progression - Professor 
 Antony Braithwaite\, Unviersity of Otago\, New Zealand
DTSTART:20180912T113000Z
DTEND:20180912T123000Z
UID:TALK110047@talks.cam.ac.uk
CONTACT:Adelaide Schiemer
DESCRIPTION:Abstract: Before p53 became famous as a tumour suppressor it w
 as regarded as an oncogene. However\, by the 1990s when it was clearly est
 ablished that p53 is a tumour suppressor\, much of the early work was dism
 issed as being due to mutant p53. However\, not all the data can be dismis
 sed so easily. Furthermore\, with the discovery of p53 isoforms that appea
 r to have transforming ability\, the question of p53’s contribution to c
 ancer has again arisen. We created a transgenic mouse model of the D133p53
  isoform (designated D122p53 in mice). These mice are tumour prone\, but u
 nlike other p53 mutant mice\, D122p53 mice show widespread inflammation an
 d 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 deficien
 t mice. Loss of IL-6 reduced tumour incidence\, metastasis and the levels 
 of cytokines in the JAK -STAT3 pathway and that blocking this pathway prev
 ented cell migration and invasion 2. The studies on these mice led us to e
 xplore 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 expre
 ssion 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 on
 cogene\, suggesting that wild type p53 can contribute to oncogenesis.\n\nR
 eferences: 1. Slatter\, T.J.\, Hung\, N.A.\, Campbell\, H.C.\, et al. (201
 1). Hyperproliferation\, cancer\, and inflammation in mice expressing a Δ
 133p53-like isoform. Blood 117\, 5166-5177 2. Campbell\, H.G.\, Fleming\, 
 N.\, Roth\, I. et. al. (2018). D133p53 isoform promotes tumour invasion an
 d metastasis via interleukin-6 activation of JAK -STAT and RhoA-ROCK signa
 lling. Nature Comm. DOI : 10.1038/s41467-017-02408-0 3. Kazantseva\, M.\, 
 Eiholzer\, R.\, Mehta\, S. et al (2018). Elevation of the TP53 isoform D13
 3T P53b in glioblastomas: an alternative to mutant p53 in promoting tumour
  development. J Path. (in press).
LOCATION:CRUK CI Lecture Theatre
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