The role of p53/p73 family members in the cytotoxic response

Toxic insult arising from environmental, occupational or therapeutic exposure, is a primary cause of disease and the treatment of these disorders has significant medical, social and economic implications for the UK population. The p53 family of proteins (p53, p63 and p73) is considered as a master regulator in vertebrates, and pathways that it controls range from developmental and homeostatic functions to the remarkable role in cancer. In particular, a predominant aspect of p53 family function in tumourigenesis is the ability to control the cellular stress response. This represents a pivotal aspect in the response to toxic insult.

The overall aim of the Laboratory is to understand the fundamental mechanisms of cellular and tissue response to injury caused by drugs, chemicals and endogenous molecules, e.g. free radicals. Therefore, using both genetically modified mouse model and high throughput analysis, we aim to investigate:

1) How environmental exposure drives tumour progression;
2) How these transcription factors regulate the response to toxic insult;

Moreover, we are dedicated to the development of chemicals compounds that can regulate expression and function of the p53 family members. This could have potential therapeutic applications.

Environmental, occupational or therapeutic exposure to toxic insults account for a substantial proportion of cancer development both in the UK and worldwide. The p53 family (p53, p63 and p73) are transcription factors, which play a key role in several biological processes by regulating cell survival, proliferation, metabolism and stemness. In particular, a key aspect of p53 family function is the ability to control the cellular stress response, which represents a pivotal axis in the response to toxic insult.

By using a multiple scientific approaches ranging from systems biology (proteomic and genomic screenings) to the generation and characterization of genetically modified mouse models, we aim to investigate the role of the p53 family in the cellular stress response in order to understand the molecular basis underling the mechanisms for tumour transformation and progression.

The focus of this programme is on the contribution of p53 family to adaption to micro-environmental stress, investigating the role of p53 family members and isoforms to hypoxia stress and protein synthesis and to genotoxic stress response, investigating new p53 family effectors of DNA damage response machinery. Specifically we will investigate:

1) The molecular basis for cell adaptation to hypoxia: p53 family and HIF interplay
2) p53 family contribution to protein synthesis control in cell adaptation to stress
3) Novel effectors of p73 and p63 in the DNA damage response