Suppressing tumour development - the coordinated response of p53 target genes
p53 activates many genes and pathways, thus understanding which are the most important for its tumour suppression function has been a challenge. Our data support the notion that multiple p53-regulated processes must fail for tumours to develop, with coordination of DNA damage repair bring highly critical, earning its title as the ‘guardian of the genome’.
Dr Margs Brennan
Postdoctoral Fellow, Jacobsen Group
Karolinska Institutet
The transcription factor p53, often referred to as ‘the guardian of the genome’, is widely known for its role as an important tumour suppressor and is critical in the response of malignant cells against diverse anti-cancer agents, particularly those that cause DNA damage. Activation of p53 leads to the expression of many diverse target genes, however, the roles of many of these target genes remain poorly understood.
Using focussed in vivo shRNA screens in mice we identified the RNA-splicing regulator Zmat3 as a critical p53 target gene for tumour suppression. The loss of Zmat3 combined with the absence of pro-apoptotic Puma and the CDK inhibitor p21, but not loss of Zmat3 alone, can cause leukaemia.
We generated Puma-/-p21-/-Zmat3-/- deficient mice and found they spontaneously developed diverse tumours at a much higher frequency in the first year of life compared to controlmice. This indicates that in addition to Zmat3 loss, several additional p53-regulated processes must also be disabled simultaneously for tumours to develop.
Thus, our findings further cement the importance of the coordinated action of multiple p53 activated cellular responses for tumour suppression. This may have implications for developing novel strategies for treating cancer as simultaneous activation of several of these responses might be needed for effective therapy.
Dr Margs Brennan completed her Bachelor's degree in Biochemistry and Molecular Biology at the University of Melbourne in 2013, followed by an Honours year at WEHI where she investigated the post-translational regulation of the pro-survival apoptotic regulator A1/BFL-1 in the Herold Lab. In 2015 Margs was awarded a Leukaemia Foundation Award to undertake her PhD studies at WEHI under the supervision of Marco Herold, Andreas Strasser and Gemma Kelly, where she developed a novel humanised MCL-1 mouse model for accurate testing of MCL-1 inhibitors in pre-clinical models of disease.
In 2019 she received a Cancer Council Victoria Postdoctoral Fellowship to continue her research on discovering novel treatments for leukaemia, working in many collaborations in the Parkville precinct, before moving in 2021 to Sten Eirik Jacobsen’s Lab at the Karolinska Institutet in Stockholm, funded by the Swedish Cancer Society. Here her research interests are focused on the mechanisms that regulates blood cell development and how these processes are subverted in leukaemic stem cells. Furthermore, she is interested in using novel immunotherapeutic strategies to target leukaemic stem cells to provide new treatment options for leukaemia patients.