Elucidating p53’s physiological and tumourigenic roles

The key role of p53 as a tumour suppressor is widely acknowledged and based on many observations that p53 suppresses oncogene-mediated transformation of rodent fibroblasts and is the most frequently mutated gene in human cancers. However, the p53 family of transcription factors is evolutionarily very ancient and already found in primordial metazoans where it acts as a pivotal coordinator of reparative responses to cellular stress, cell and DNA damage (“the Guardian of the Genome”). The best guess is that the tumour suppressor functions of p53, principally induction of cell death and senescence, are later additions that serve to rein in rogue somatic cells. The extent to which the immediate stress response and tumour suppression functions of p53 augment or antagonise each other is hotly debated, not the least because of occasional studies that indicate a paradoxical positive selective retention of p53 in some early stage cancers, suggesting that p53 function is indeed in some way beneficial for nascent tumours. Such inherent antagonistically pleiotropic properties make classical genetic analysis of p53 function complicated – as does the confounding presence in the mammalian genome of at least two additional paralogues of p53, p63 and p73 whose functions partially overlap. Therefore, to address the potentially distinct functions of p53 in development, maintenance and repair of normal adult tissues and in tumour suppression, I have built a unique, temporally switchable mouse model in which p53 function may be reversibly toggled between wild type and null states at will in vivo. I show that acute systemic repression of p53 in adult mice elicits no overt symptoms or somatic pathologies. However, spontaneous tumours emerged in the same cellular compartments and with a similar latency to those observed in germline p53-null mice. Detailed analyses of tissues and tumours have yet to be conducted. Temporal dissection of p53’s functions at different stages of chemically-induced skin cancer revealed a window during the initiation stage where p53 retention promoted early carcinogenesis (skin papillomas) while loss of p53 promoted the development of later squamous carcinomas. The ability to rapidly and reversibly switch p53 functional status and to identify windows of p53 pro-tumourigenic and tumour suppressive function will provide new insights into the diverse and perhaps antagonistic roles of p53 in development, tissue homeostasis, cancer and ageing.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Lam, Chun Ming

Advisors dc:contributor.advisor

• Evan, Gerard
• Littlewood, Trevor

• cancer
• mouse model
• switchable genetics
• p53
• tumourigenesis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/2e6bde7c-78b6-49a9-ab79-75eda236dffd/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0003-0412-1216
0000-0003-3475-1462

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/307925